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Pesticide-Induced Diseases: Endocrine Disruption
Common household products–detergents, disinfectants, plastics, and pesticides–contain chemical ingredients that enter the body, disrupt hormones and cause adverse developmental, disease, and reproductive problems. Known as endocrine disruptors, these chemicals, which interact with the endocrine system, wreak havoc in humans and wildlife. The endocrine system consists of a set of glands (thyroid, gonads, adrenal and pituitary) and the hormones they produce (thyroxine, estrogen, testosterone and adrenaline), which help guide the development, growth, reproduction, and behavior of animals, including humans. Hormones are signaling molecules, which travel through the bloodstream and elicit responses in other parts of the body.
Download Beyond Pesticides' Endocrine Disruption brochure (bi-fold), or read Beyond Pesticides article, "Pesticides That Disrupt Endocrine System Still Unregulated by EPA."
Endocrine disruptors function by: (i) Mimicking the action of a naturally-produced hormone, such as estrogen or testosterone, thereby setting off similar chemical reactions in the body; (ii) Blocking hormone receptors in cells, thereby preventing the action of normal hormones; or (iii) Affecting the synthesis, transport, metabolism and excretion of hormones, thus altering the concentrations of natural hormones. Endocrine disruptors have been linked to attention deficit hyperactivity disorder (ADHD), Parkinson’s and Alzheimer’s diseases, metabolic disorders diabetes, cardiovascular disease, obesity, early puberty, infertility and other reproductive disorders, childhood and adult cancers, and other metabolic disorders.
More than 50 pesticide active ingredients have been identified as endocrine disruptors by the European Union and endocrine disruptor expert Theo Colborn, PhD. Endocrine disruption is the mechanism for several health effect endpoints. See the related sections (Cancer, Developmental and Learning Disorders, Parkinson’s disease, Reproductive Health) for more information.
Endocrine Disruption • Metabolic Disorders • Thyroid Function
Endocrine Disruption
- Glyphosate formulations cause mortality and diverse sublethal defects during embryonic development of the amphibian Xenopus laevis
The human impact on environmental landscapes, such as land use, climate change or pollution, is threatening global biodiversity and ecosystems maintenance. Pesticides like the herbicide glyphosate have garnered considerable attention due to their well-documented harmful effects on non-target species. During application, the active ingredient glyphosate is utilized in various formulations, each containing different additive adjuvants. However, the possible effects of these formulations on amphibians - the group with the highest decline rates among vertebrates - remain largely unknown.
Therefore, the present study investigated the effects of four glyphosate formulations (Glyphosat TF, Durano TF, Helosate 450 TF, Kyleo) on the embryonic development of the model organism Xenopus laevis (South African clawed frog). Embryos at the 2-cell stage were exposed to various concentrations of glyphosate formulations (glyphosate: 0.01–100 mg/L), and mortality as well as sublethal effects on different organs and tissues were analyzed. The results indicated that the formulations had different effects, particularly on the mortality of Xenopus laevis embryos. At sublethal concentrations, the formulations altered the embryos' external appearance, leading to malformations such as reduced eye and head size. In addition, exposure to formulations impaired heart morphology and function, and the expression of heart-specific genes was altered at a molecular level.
Our results confirmed that glyphosate formulations had a stronger effect on Xenopus laevis embryogenesis than pure glyphosate. Therefore, it is crucial to evaluate the active ingredient and the co-formulations independently, as well as the combined, commercially available products, during pesticide risk assessments and renewal procedures of agrochemicals. The severe global decline of amphibians, partly due to herbicide use, highlights the need for strict and efficient monitoring of environmental pesticide loads and application areas.
[Flach, H. et al. (2024) Glyphosate formulations cause mortality and diverse sublethal defects during embryonic development of the amphibian Xenopus laevis, Chemosphere. Available at: https://www.sciencedirect.com/science/article/pii/S0045653524025244.] - Glyphosate presence in human sperm: First report and positive correlation with oxidative stress in an infertile French population
Environmental exposure to endocrine disruptors, such as pesticides, could contribute to a decline of human fertility. Glyphosate (GLY) is the main component of Glyphosate Based Herbicides (GBHs), which are the most commonly herbicides used in the world. Various animal model studies demonstrated its reprotoxicity. In Europe, GLY authorization in agriculture has been extended until 2034. Meanwhile the toxicity of GLY in humans is still in debate. The aims of our study were firstly to analyse the concentration of GLY and its main metabolite, amino-methyl-phosphonic acid (AMPA) by LC/MS-MS in the seminal and blood plasma in an infertile French men population (n=128). We secondly determined Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) using commercial colorimetric kits and some oxidative stress biomarkers including malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) by ELISA assays. We next analysed potential correlations between GLY and oxidative stress biomarkers concentration and sperm parameters (sperm concentration, progressive speed, anormal forms). Here, we detected for the first time GLY in the human seminal plasma in significant proportions and we showed that its concentration was four times higher than those observed in blood plasma. At the opposite, AMPA was undetectable. We also observed a strong positive correlation between plasma blood GLY concentrations and plasma seminal GLY and 8-OHdG concentrations, the latter reflecting DNA impact. In addition, TOS, Oxidative Stress Index (OSI) (TOS/TAS), MDA blood and seminal plasma concentrations were significantly higher in men with glyphosate in blood and seminal plasma, respectively. Taken together, our results suggest a negative impact of GLY on the human reproductive health and possibly on his progeny. A precaution principle should be applied at the time of the actual discussion of GLY and GBHs formulants uses in Europe by the authorities.
[Vasseur, C. et al. (2024) Glyphosate presence in human sperm: First report and positive correlation with oxidative stress in an infertile French population, Ecotoxicology and Environmental Safety. Available at: https://www.sciencedirect.com/science/article/pii/S014765132400486X. ] - Health Effects of Fossil Fuel–Derived Endocrine Disruptors
Key Points Health Effects of Fossil Fuel–Derived Endocrine Disruptors- Pollution is the leading cause of premature death globally.
- Fossil fuels contribute to chemical pollution through production of petrochemicals, many of which interfere with hormonal function (endocrine-disrupting chemicals [EDCs]). Examples include perfluoroalkyl and polyfluoroalkyl substances in food packaging and fabrics and phthalates in plastics and consumer products.
- Petrochemical production is increasing, and people are exposed through contaminated air, water, food, and manufactured products (e.g., plastics, pesticides, building materials, and cosmetics).
- EDCs can increase several health risks, including cancer, neurodevelopmental harm, and infertility.
- Risks are higher with exposures during fetal and child development and with exposure to multiple EDCs and occur at low exposure levels. Exposures are higher in communities of color and lowincome communities and contribute to health inequities.
- Clinicians can provide advice to patients toward reducing some exposures, but policy change is needed to establish legal requirements for comprehensive safety testing and to reduce health threats from petrochemicals. Clinicians are important advocates for these changes.
[Woodruff, T.J. (2024) ‘Health effects of fossil fuel–derived endocrine disruptors’, New England Journal of Medicine, 390(10), pp. 922–933. doi:10.1056/nejmra2300476. ] - Impact of Endocrine Disrupting Pesticide Use on Obesity: A Systematic Review
Background/Objectives: Endocrine disruptors are substances capable of altering the functions of the endocrine system. There is evidence that some pesticides can be endocrine disruptors and, among some of their effects, we find alterations in pubertal development and in the function of the thyroid gland, which could be related to a greater tendency of obesity. The aim was to evaluate the evidence from clinical and preclinical studies on the association between pesticides used in agriculture and found in plant-based foods with overweight/obesity. Methods: This is a systematic review of articles on the impact of the use of endocrine disrupting pesticides on obesity, conducted according to the PRISMA-2020 guidelines. Results: There was evidence that some pesticides, such as chlorpyrifos, pyrethroids, and neonicotinoids, may promote obesity and other anthropometric changes by altering lipid and glucose metabolism, modifying genes, or altering hormone levels such as leptin. Other studies suggest that perinatal exposure to chlorpyrifos or pesticides such as vinclozolin may alter lipid metabolism and promote weight gain in adulthood, whereas other pesticides such as boscalib, captan, thiacloprid, and ziram were not associated with changes in weight. Exposure to pesticides such as vinclozolin may be associated with a higher prevalence of overweight/obesity in later generations. Conclusions: The few studies that do not show these associations have methodological limitations in data collection with confounding variables. Further studies are needed to provide more and higher quality evidence to determine the true effect of these substances on obesity.
[Pérez-Bermejo, M. et al. (2024) Impact of Endocrine Disrupting Pesticide Use on Obesity: A Systematic Review, Biomedicines. Available at: https://www.mdpi.com/2227-9059/12/12/2677.] - New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project
In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.
[Tal, T. et al. (2024) New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project, Frontiers in Toxicology. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1359507/full. ] - Per-polyfluoroalkyl substances (PFAS) as thyroid disruptors: is there evidence for multi-transgenerational effects?
Introduction
The environmental spread of pollutants has led to a persistent exposure of living beings to multiple chemicals, by now become ubiquitous in the surrounding environment. Environmental exposure to these substances has been reported to cause multi- and/or transgenerational health effects. Per- and Polyfluorinated Substances (PFAS) raise great concern, given their known effects both as endocrine disruptors and potential carcinogens. The multi/trans-generational effects of different endocrine disruptors have been investigated by several studies, and harmful effects observed also for PFAS.Areas covered
This review examines the current data on the multi-trans-generational effects of PFAS, with a focus on their impact on the thyroid axis. The aim is to determine if there is evidence of potential multi-trans-generational effects of PFAS on the thyroid and/or if more research is needed.Expert opinion
PFAS exposure impacts thyroid homeostasis and can cross the placental barrier. In addition PFAS have shown multi-transgenerational effects in laboratory experiences and animal models, but thyroid disruptive effects of PFAS were also investigated only in a small number of these studies. Efforts are needed to study the adverse effects of PFAS, as not all PFAS are regulated and removal strategies are still being developed.
[Coperchini, F. et al. (2024) Per-polyfluoroalkyl substances (PFAS) as thyroid disruptors: is there evidence for multi-transgenerational effects?, Expert Review of Endocrinology & Metabolism. Available at: https://www.tandfonline.com/doi/full/10.1080/17446651.2024.2351885. ] - Pesticides: An alarming detriment to health and the environment
Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.
[Kaur R;Choudhary D;Bali S;Bandral SS;Singh V;Ahmad MA;Rani N;Singh TG;Chandrasekaran B; Pesticides: An alarming detrimental to health and environment, The Science of the total environment. Available at: https://www.pubmed.ncbi.nlm.nih.gov/38232846/ ] - Pre-Conception And First Trimester Exposure To Pesticides And Associations With Stillbirth
Associations of pesticide exposures during pre-conception with stillbirth have not been well explored. We linked Arizona pesticide use records with birth certificates from 2006-2020 and estimated associations of living within 500meters of any pyrethroid, organophosphate (OP), or carbamate pesticide applications during a 90 day pre-conception window or the first trimester, with stillbirth. We considered a binary measure of exposure (any exposure), as well as log-pounds and log-acres applied within 500m, in a negative control exposure framework with log-binomial regression. We included 1,237,750 births, 2,290 stillbirths, and 27 pesticides.During pre-conception, any exposure to pesticides were associated with stillbirth, including cyfluthrin (RR=1.97, 95% CI 1.17,3.32), zeta-cypermethrin (RR=1.81, 95%CI 1.20, 2.74), organophosphates as a class (RR=1.60, 95%CI 1.16, 2.19), malathion (RR=2.02, 95%CI 1.26, 3.24), carbaryl (RR=6.39, 95%CI 2.07, 19.74), and propamocarb hydrochloride (RR=7.72, 95%CI 1.10, 54.20) . During the first trimester, fenpropathrin (RR=4.36, 95%CI 1.09, 17.50), permethrin (RR=1.57, 95%CI 1.02, 2.42), organophosphates as a class (RR=1.50, 95%CI 1.11, 2.01), acephate (RR=2.31, 95%CI 1.22, 4.40), and formetanate hydrochloride (RR=7.22, 95%CI 1.03, 50.58) were associated with stillbirth. Interpretations were consistent when using continuous measures of pounds or acres of exposure. Pesticide exposures during pre-conception and first trimester may be associated with stillbirth.
[Furlong, M. et al. (2024) Pre-conception and first trimester exposure to pesticides and associations with stillbirth, American Journal of Epidemiology. Available at: https://academic.oup.com/aje/advance-article-abstract/doi/10.1093/aje/kwae198/7714541.] - Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function
Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds that interfere with the endocrine system, inducing harmful effects on organisms depending on the dose and period of exposure. Numerous studies have identified concerning amounts of EDCs in environmental and human samples. The thyroid gland is essential for thyroid hormone production and controls several body functions. Several EDCs have been classified as thyroid disruptors, impairing thyroid hormone production, synthesis, metabolism, transport, and/or actions. Notably, thyroid disorders are the second most prevalent endocrine disease worldwide, with incidence increasing significantly in recent years. Some studies have correlated this rise in thyroid dysfunctions and cancers with increased exposure to EDCs. Although many EDCs are linked to thyroid dysfunction, this review focuses on the deleterious effects of plasticizers, organochlorine pesticides, and per- and poly-fluoroalkyl substances on thyroid function. These contaminants are commonly found in food, water, and everyday products. Although the impact of human exposure to these EDCs is controversial, numerous epidemiological, in vivo, and in vitro studies have indicated their harmful effects on thyroid function. Given the critical role of thyroid function and hormone production in growth, metabolism, and development, this review summarizes the consequences of exposure to thyroid disruptors for human health.
[Rodrigues, V.G. et al. (2024) Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function, Endocrines. Available at: https://www.mdpi.com/2673-396X/5/3/32.] - Developmental Exposure to DDT Disrupts Transcriptional Regulation of Postnatal Growth and Cell Renewal of Adrenal Medulla
Dichlorodiphenyltrichloroethane (DDT) is the most widespread persistent pollutant with endocrine-disrupting properties. DDT has been shown to disrupt secretory and morphogenetic processes in the adrenal cortex. The present investigation aimed to evaluate transcriptional regulation of postnatal growth of the adrenal medulla and formation of the pools necessary for self-renewal of medullary cells in rats that developed under low-dose exposure to DDT. The study was performed using male Wistar rats exposed to low doses of o,p'-DDT during prenatal and postnatal development. Light microscopy and histomorphometry revealed diminished medulla growth in the DDT-exposed rats. Evaluation of Ki-67 expression in chromaffin cells found later activation of proliferation indicative of retarded growth of the adrenal medulla. All DDT-exposed rats exhibited a gradual decrease in tyrosine hydroxylase production by adrenal chromaffin cells. Immunohistochemical evaluation of nuclear β-catenin, transcription factor Oct4, and ligand of sonic hedgehog revealed increased expression of all factors after termination of growth in the control rats. The DDT-exposed rats demonstrated diminished increases in Oct4 and sonic hedgehog expression and lower levels of canonical Wnt signaling activation. Thus, developmental exposure to the endocrine disruptor o,p'-DDT alters the transcriptional regulation of morphogenetic processes in the adrenal medulla and evokes a slowdown in its growth and in the formation of a reserve pool of cells capable of dedifferentiation and proliferation that maintain cellular homeostasis in adult adrenals.
[Yaglova, N.V., Nazimova, S.V., Obernikhin, S.S., Tsomartova, D.A., Yaglov, V.V., Timokhina, E.P., Tsomartova, E.S., Chereshneva, E.V., Ivanova, M.Y. and Lomanovskaya, T.A., 2023. International Journal of Molecular Sciences, 24(3), p.2774.] - Endocrine Disruptor Chemicals and Children’s Health
We are all exposed to endocrine-disrupting chemicals (EDCs) starting from embryonic life. The fetus and child set up crucial developmental processes allowing adaptation to the environment throughout life: they are extremely sensitive to very low doses of hormones and EDCs because they are developing organisms. Considering the developmental origin of well-being and diseases, every adult organism expresses consequences of the environment in which it developed. The molecular mechanisms through which the main EDCs manifest their effects and their potential association with endocrine disorders, such as diabetes, obesity, thyroid disease and alteration of adrenal hormones, will be reviewed here. Despite 40 years having passed since the first study on EDCs, little is yet known about them; therefore, our purpose is to take stock of the situation to establish a starting point for further studies. Since there is plenty of evidence showing that exposure to EDCs may adversely impact the health of adults and children through altered endocrine function—suggesting their link to endocrinopathies—it is essential in this context to bear in mind what is already known about endocrine disruptors and to deepen our knowledge to establish rules of conduct aimed at limiting exposure to EDCs’ negative effects. Considering that during the COVID-19 pandemic an increase in endocrine disruptor effects has been reported, it will also be useful to address this new phenomenon for better understanding its basis and limiting its consequences.
[Di Pietro, G., Forcucci, F. and Chiarelli, F. (2023) Endocrine Disruptor Chemicals and Children’s Health, International Journal of Molecular Science. Available at: https://www.mdpi.com/1422-0067/24/3/2671. ] - Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship
Environmental endocrine-disrupting chemicals (EDCs) are a mixture of chemical compounds capable to interfere with endocrine axis at different levels and to which population is daily exposed. This paper aims to review the relationship between EDCs and breast, prostate, testicle, ovary, and thyroid cancer, discussing carcinogenic activity of known EDCs, while evaluating the impact on public health. A literature review regarding EDCs and cancer was carried out with particular interest on meta-analysis and human studies. The definition of EDCs has been changed through years, and currently there are no common criteria to test new chemicals to clarify their possible carcinogenic activity. Moreover, it is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at different ages, even if preclinical and clinical evidence suggest that developing fetus and neonates are most vulnerable to endocrine disruption. EDCs represent a major environmental and health issue that has a role in cancer development. There are currently some EDCs that can be considered as carcinogenic, like dioxin and cadmium for breast and thyroid cancer; arsenic, asbestos, and dioxin for prostate cancer; and organochlorines/organohalogens for testicular cancer. New evidence supports the role of other EDCs as possible carcinogenic and pregnant women should avoid risk area and exposure. The relationship between EDCs and cancer supports the need for effective prevention policies increasing public awareness.
[Modica, R., Benevento, E. and Colao, A., 2023. Journal of Endocrinological Investigation, 46(4), pp.667-677.] - Endocrine-Disrupting Chemicals and Persistent Organic Pollutants in Infant Formulas and Baby Food: Legislation and Risk Assessments
Human milk is the healthiest option for newborns, although, under specific circumstances, infant formula is a precious alternative for feeding the baby. Except for the nutritional content, infant formulas and baby food must be pollutant-free. Thus, their composition is controlled by continuous monitoring and regulated by establishing upper limits and guideline values for safe exposure. Legislation differs worldwide, although there are standard policies and strategies for protecting vulnerable infants. This work presents current regulations and directives for restricting endocrine-disrupting chemicals and persistent organic pollutants in infant formulas. Risk assessment studies, which are limited, are necessary to depict exposure variations and assess the health risks for infants from dietary exposure to pollutants.
[Hatzidaki, E., Pagkalou, M., Katsikantami, I., Vakonaki, E., Kavvalakis, M., Tsatsakis, A.M. and Tzatzarakis, M.N., 2023. Foods, 12(8), p.1697.] - Exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil
Background: Pyrethroids are commonly used insecticides in Brazil. Gestational and early childhood exposure to pyrethroids has been linked to adverse health effects, including neurodevelopmental delays, behavioral issues, and endocrine disruption. This study evaluated the exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil.
Methods: Creatinine-adjusted levels of the pyrethroid metabolites 3-phenoxy benzoic acid (3-PBA) and 4-fluoro-3-phenoxybenzyl acid (4-FPBA) were measured in the urine of 142 pregnant women and their children at birth and in the first, third, and 6th months of life.
Results: The geometric mean (GM) and 95% confidence interval (95% CI) of 3-PBA and 4-FPBA urinary concentrations in pregnant women were 0.50 (0.37–0.67) and 0.37 (0.05–2.90) ng/mg, detected in 47.2 and 10.6%, respectively. Urinary concentrations of 3-PBA in the children were 0.18 (0.15–0.23) ng/mg at birth, 0.36 (0.08–1.56) ng/mg at 1-month-old, 0.68 (0.36–1.27) ng/mg at 3-month-old, and 1.36 (0.77–2.42) ng/mg at 6-month-old, and the detection rates were respectively 10.8, 9.4, 20.9, and 20.7%.
Discussion: This study is one of the few that has evaluated the urinary concentrations of pyrethroids in newborns and children in their 1st year of life. The results of this study show that children's exposure to pyrethroids significantly increases after birth.
[Martins, A.F. et al. (2023) ‘Exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil’, Frontiers in Public Health, 11. doi:10.3389/fpubh.2023.1274724. ] - Hormone receptor activities of complex mixtures of known and suspect chemicals in personal silicone wristband samplers worn in office buildings
Humans are exposed to increasingly complex mixtures of hormone-disrupting chemicals from a variety of sources, yet, traditional research methods only evaluate a small number of chemicals at a time. We aimed to advance novel methods to investigate exposures to complex chemical mixtures. Silicone wristbands were worn by 243 office workers in the USA, UK, China, and India during four work shifts. We analyzed extracts of the wristbands for: 1) 99 known (targeted) chemicals; 2) 1000+ unknown chemical features, tentatively identified through suspect screening; and 3) total hormonal activities towards estrogen (ER), androgen (AR), and thyroid hormone (TR) receptors in human cell assays. We evaluated associations of chemicals with hormonal activities using Bayesian kernel machine regression models, separately for targeted versus suspect chemicals (with detection ≥50%). Every wristband exhibited hormonal activity towards at least one receptor: 99% antagonized TR, 96% antagonized AR, and 58% agonized ER. Compared to men, women were exposed to mixtures that were more estrogenic (180% higher, adjusted for country, age, and skin oil abundance in wristband), anti-androgenic (110% higher), and complex (median 836 detected chemical features versus 780). Adjusted models showed strong associations of jointly increasing chemical concentrations with higher hormonal activities. Several targeted and suspect chemicals were important co-drivers of overall mixture effects, including chemicals used as plasticizers, fragrance, sunscreen, pesticides, and from other or unknown sources. This study highlights the role of personal care products and building microenvironments in hormone-disrupting exposures, and the substantial contribution of chemicals not often identifiable or well-understood to those exposures.
[Young, A. et al. (2023) Hormone receptor activities of complex mixtures of known and suspect chemicals in personal silicone wristband samplers worn in office buildings, Chemosphere. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0045653522041984?via%3Dihub. ] - Impact of Chronic Multi-Generational Exposure to an Environmentally Relevant Atrazine Concentration on Testicular Development and Function in Mice
A common herbicide, atrazine, is associated with poor health. Atrazine acts as an endocrine disruptor at supra-environmental levels. Little research, however, has been conducted regarding chronic exposure to environmental atrazine concentrations across generations. This study utilized comprehensive endpoint measures to investigate the effects of chronic exposure to a conservative atrazine concentration (0.02 ng/mL), measured in Australian waterways, on male mice fertility across two generations. Mice were exposed through the maternal line, from the pre-conception period and through the F1 and F2 generations until three or six months of age. Atrazine did not impact sperm function, testicular morphology nor germ cell parameters but did alter the expression of steroidogenic genes in the F1, down-regulating the expression of Cyp17a1 (Cytochrome P450 family 17, subfamily A member 1; p = 0.0008) and Ddx4 (DEAD-box helicase 4; p = 0.007), and up-regulating the expression of Star (Steroidogenic acute regulatory protein; p = 0.017). In the F2, atrazine induced up-regulation in the expression of Star (p = 0.016). The current study demonstrates that chronic exposure to an environmentally relevant atrazine concentration perturbs testicular steroid-associated gene expression that varies across generations. Future studies through the paternal and combined parental lineages should be undertaken to further elucidate the multigenerational effects of atrazine on male fertility.
[Kolaitis, N.D., Finger, B.J., Merriner, D.J., Nguyen, J., Houston, B.J., O’Bryan, M.K., Stringer, J.M., Zerafa, N., Nguyen, N., Hutt, K.J. and Tarulli, G.A., 2023. Cells, 12(4), p.648.] - Sex-specific effects of acute chlordane exposure in the context of steatotic liver disease, energy metabolism, and endocrine disruption.
Chlordane is an organochlorine pesticide (OCP) that is environmentally persistent. Although exposures to OCPs including chlordane have been associated with elevated liver enzymes, current knowledge on OCPs’ contribution to toxicant-associated steatotic liver disease (TASLD) and underlying sex-specific metabolic/endocrine disruption are still widely limited. Therefore, the objective of this study was to investigate the sex-dependent effects of chlordane in the context of TASLD. Age-matched male and female C57BL/6 mice were exposed to chlordane (20 mg/kg, one-time oral gavage) for two weeks. Female mice generally exhibited lower bodyfat content but more steatosis and hepatic lipid levels, consistent with increased hepatic mRNA levels of genes involved in lipid synthesis and uptake. Surprisingly, chlordane-exposed females demonstrated lower hepatic cholesterol levels. With regards to metabolic disruption, chlordane exposure decreased expression of genes involved in glycogen and glucose metabolism (Pklr, Gck), while chlordane-exposed females also exhibited decreased gene expression of HNF4A, an important regulator of liver identity and function. In terms of endocrine endpoints, chlordane augmented plasma testosterone levels in males. Furthermore, chlordane activated hepatic xenobiotic receptors, including the constitutive androstane receptor, in a sex-dependent manner. Overall, chlordane exposure led to altered hepatic energy metabolism, and potential chlordane-sex interactions regulated metabolic/endocrine disruption and receptor activation outcomes.
[Luo, J., Watson, W.H., Gripshover, T.C., Qaissi, Z. and Wahlang, B., 2023. Food and Chemical Toxicology, 180, p.114024.] - The Global Plastics Treaty: An Endocrinologist's Assessment
Abstract
Plastics are everywhere. They are in many goods that we use every day. However, they are also a source of pollution. In 2022, at the resumed fifth session of the United Nations Environment Assembly, a historic resolution was adopted with the aim of convening an Intergovernmental Negotiating Committee to develop an international legally binding instrument on plastic pollution, including in the marine environment, with the intention to focus on the entire life cycle of plastics. Plastics, in essence, are composed of chemicals. According to a recent report from the secretariat of the Basel, Rotterdam, and Stockholm conventions, around 13 000 chemicals are associated with plastics and plastic pollution. Many of these chemicals are endocrine-disrupting chemicals and, according to reports by members of the Endocrine Society and others, exposure to some of these chemicals causes enormous costs due to the development of preventable diseases. The global plastics treaty brings the opportunity for harmonized, international regulation of chemicals with endocrine disrupting properties present in plastic products.
[Fernandez, M.O. and Trasande, L. (2023) ‘The global plastics treaty: An Endocrinologist’s assessment’, Journal of the Endocrine Society, 8(1). doi:10.1210/jendso/bvad141. ] - Widespread use of toxic agrochemicals and pesticides for agricultural products storage in Africa and developing countries: Possible panacea for ecotoxicology and health implications
Chemicals used for storage majorly possess insecticidal activities - deterring destructive insect pests and microorganisms from stored agricultural produce. Despite the controversy about their safety, local farmers and agro-wholesalers still predominantly use these chemicals in developing countries, especially Africa, to ensure an all-year supply of agriproducts. These chemicals could have short- or long-term effects. Despite the state-of-the-art knowledge, factors such as poor education and awareness, limited agricultural subventions, quests for cheap chemicals, over-dosage, and many more are the possible reasons for these toxic chemicals' setback and persistent use in developing countries. This paper provides an up-to-date review of the environmental and ecological effects, as well as the health impacts arising from the indiscriminate use of toxic chemicals in agriproducts. Existing data link pesticides to endocrine disruption, genetic mutations, neurological dysfunction, and other metabolic disorders, apart from the myriad of acute effects. Finally, this study recommended several naturally sourced preservatives as viable alternatives to chemical counterparts and emphasized the invaluable role of education and awareness programs in mitigating the use in developing nations for a sustainable society.
[Anaduaka, E.G., Uchendu, N.O., Asomadu, R.O., Ezugwu, A.L., Okeke, E.S. and Ezeorba, T.P.C., 2023. Heliyon.] - Associations between persistent organic pollutants and endometriosis: A multiblock approach integrating metabolic and cytokine profiling
Humans are exposed daily to complex mixtures of chemical pollutants through their environment and diet, some of which have the potential to disrupt the bodies’ natural endocrine functions and contribute to reproductive diseases like endometriosis. Increasing epidemiological and experimental evidence supports the association between endometriosis and certain persistent organic pollutants (POPs) like dioxins; however, little is known about the underlying linking mechanisms. The main objective of this study is to proof the methodological applicability and discovery potential of integrating ultra-trace mass spectrometry (MS) profiling of POP biomarkers and endogenous biomarker profiling (MS metabolomics and cytokines) in a case-control study for the etiological research of endometriosis. The approach is applied in a pilot clinical-based study conducted in France where women with and without surgically confirmed endometriosis were recruited. Serum samples were analysed with high-resolution MS for about 30 polychlorinated biphenyls (PCBs), organochlorinated pesticides and perfluoroalkyl substances (PFAS). About 600 serum metabolites and lipids were identified with targeted metabolomics using tandem MS with the Biocrates MxP® Quant 500 Kit. A panel of 4 pro-inflammatory cytokines were analysed using ELISA-based 4-PLEX analyser. Statistical analysis included a battery of variable selection approaches, multivariate logistic regression for single-chemical associations, Bayesian kernel machine regressions (BKMR) to identify mixture effects of POPs and a multiblock approach to identify shared biomarker signatures among high risk clusters. The results showed the positive associations between some POPs and endometriosis risk, including the pesticide trans-nonachlor Odds Ratio (95% Confidence Interval) 3.38 (2.06–5.98), p < 0.0001 and PCB 114 OR (95% CI) 1.83 (1.17–2.93), p = 0.009. The BKMR approach showed a tendency of a positive cumulative effect of the mixture, however trans-nonachlor exhibited significant associations within the mixture and interacted with other PCBs, strengthening the effects at highest concentrations. Finally, the multiblock analysis, relating the various blocks of data, revealed a latent cluster of women with higher risk of endometrioma presenting higher concentrations of trans-nonachlor, PCB 114 and dioxin-like toxic equivalents from PCBs, together with an increased inflammatory profile (i.e. elevated interleukin-8 and monocyte chemoattractant protein-1). It was also highlighted a specific metabolic pattern characterized by dysregulation of bile acid homeostasis and lipase activity. Further research will be required with larger sample size to confirm these findings and gain insight on the underlying mechanisms between POPs and endometriosis.
[Matta, K., Lefebvre, T., Vigneau, E., Cariou, V., Marchand, P., Guitton, Y., Royer, A.L., Ploteau, S., Le Bizec, B., Antignac, J.P. and Cano-Sancho, G. Environment International, 158, p.106926.] - Endocrine-disrupting chemicals: implications for human health
Abstract
Since reports published in 2015 and 2016 identified 15 probable exposure–outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure–outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure–outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs.
[Trasande, L. et al. (2022) ‘Endocrine disrupting chemicals: New knowledge of health effects and policy implications’, Endocrine Abstracts, 8(8), pp. 703–718. doi:10.1530/endoabs.86.ce1.1. ] - Failure to Launch: The Endocrine Disruptor Screening Program at the U.S. Environmental Protection Agency
It has been 25 years since the U.S. Congress passed the Food Quality Protection Act of 1996, an amendment to the Food Drug and Cosmetic Act, which mandated that the US Environmental Protection Agency (EPA) test all pesticide chemicals used in food for endocrine disruption. Soon after the law passed, EPA established the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide recommendations to the agency on how its Endocrine Disruptor Screening Program (EDSP) should work. Among them, the committee recommended that EDSP screening should 1) evaluate both human and ecological effects; 2) test for disruption of the estrogen, androgen, and thyroid systems; 3) evaluate pesticide and non-pesticide chemicals; and 4) implement a tiered approach. EPA adopted the recommendations and the EDSP was created in 1998. To date, the EPA has yet to fully implement the law; in other words, it has failed to test all pesticide chemicals for endocrine disruption. Of the small number that have been tested, not a single pesticide chemical has been determined to be an endocrine disruptor, and no regulatory actions have been taken. Here, we review the missed opportunities EPA had to make the EDSP a functional and effective program aimed at protecting human health and the environment. Two reports by the EPA’s Office of Inspector General from 2011 to 2021 provide the framework for our discussion.
[Maffini, M.V. and Vandenberg, L.N. (2022) Failure to Launch: The Endocrine Disruptor Screening Program at the U.S. Environmental Protection Agency, Frontiers in Toxicology. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2022.908439/full. ] - Pesticides as endocrine disruptors: programming for obesity and diabetes
Exposure to pesticides has been associated with obesity and diabetes in humans and experimental models mainly due to endocrine disruptor effects. First contact with environmental pesticides occurs during critical phases of life, such as gestation and lactation, which can lead to damage in central and peripheral tissues and subsequently programming disorders early and later in life. We reviewed epidemiological and experimental studies that associated pesticide exposure during gestation and lactation with programming obesity and diabetes in progeny. Maternal exposure to organochlorine, organophosphate and neonicotinoids, which represent important pesticide groups, is related to reproductive and behavioral dysfunctions in offspring; however, few studies have focused on glucose metabolism and obesity as outcomes. We provide an update regarding the use and metabolic impact of early pesticide exposure. Considering their bioaccumulation in soil, water, and food and through the food chain, pesticides should be considered a great risk factor for several diseases. Thus, it is urgent to reformulate regulatory actions to reduce the impact of pesticides on the health of future generations.
[Miranda, R.A., Silva, B.S., de Moura, E.G. and Lisboa, P.C., 2022. Endocrine, pp.1-11.] - PFAS Molecules: A Major Concern for the Human Health and the Environment
Per- and polyfluoroalkyl substances (PFAS) are a group of over 4700 heterogeneous compounds with amphipathic properties and exceptional stability to chemical and thermal degradation. The unique properties of PFAS compounds has been exploited for almost 60 years and has largely contributed to their wide applicability over a vast range of industrial, professional and non-professional uses. However, increasing evidence indicate that these compounds represent also a serious concern for both wildlife and human health as a result of their ubiquitous distribution, their extreme persistence and their bioaccumulative potential. In light of the adverse effects that have been already documented in biota and human populations or that might occur in absence of prompt interventions, the competent authorities in matter of health and environment protection, the industries as well as scientists are cooperating to identify the most appropriate regulatory measures, substitution plans and remediation technologies to mitigate PFAS impacts. In this review, starting from PFAS chemistry, uses and environmental fate, we summarize the current knowledge on PFAS occurrence in different environmental media and their effects on living organisms, with a particular emphasis on humans. Also, we describe present and provisional legislative measures in the European Union framework strategy to regulate PFAS manufacture, import and use as well as some of the most promising treatment technologies designed to remediate PFAS contamination in different environmental compartments.
[Panieri, E. et al. (2022) Pfas molecules: A major concern for the human health and the environment, Toxics. Available at: https://www.mdpi.com/2305-6304/10/2/44. ] - Temporal decline of sperm concentration: role of endocrine disruptors
Abstract
Introduction
Male infertility is a widespread disease with an etiology that is not always clear. A number of studies have reported a decrease in sperm production in the last forty years. Although the reasons are still undefined, the change in environmental conditions and the higher exposure to endocrine-disrupting chemicals (EDCs), namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyl-dichloroethylene, pesticides, and herbicides, organophosphates, and heavy metals, starting from prenatal life may represent a possible factor justifying the temporal decline in sperm count.
Aim
The aim of this study is to provide a comprehensive description of the effects of the exposure to EDCs on testicular development, spermatogenesis, the prevalence of malformations of the male genital tract (cryptorchidism, testicular dysgenesis, and hypospadias), testicular tumor, and the mechanisms of testicular EDC-mediated damage.
Narrative review
Animal studies confirm the deleterious impact of EDCs on the male reproductive apparatus. EDCs can compromise male fertility by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering the epigenetic mechanisms. In humans, exposure to EDCs has been associated with poor semen quality, increased sperm DNA fragmentation, increased gonadotropin levels, a slightly increased risk of structural abnormalities of the genital apparatus, such as cryptorchidism and hypospadias, and development of testicular tumor. Finally, maternal exposure to EDCs seems to predispose to the risk of developing testicular tumors.
Conclusion
EDCs negatively impact the testicular function, as suggested by evidence in both experimental animals and humans. A prenatal and postnatal increase to EDC exposure compared to the past may likely represent one of the factors leading to the temporal decline in sperm counts.
[Cannarella, R. et al. (2022) ‘Temporal decline of sperm concentration: Role of endocrine disruptors’, Endocrine, 79(1), pp. 1–16. doi:10.1007/s12020-022-03136-2. ] - The chemical landscape of tropical mammals in the Anthropocene
Sixty years ago, Rachel Carson published her book Silent Spring, which focused the world's attention on the dangers of pesticides. Since that time human impacts on the environment have accelerated and this has included reshaping the chemical landscape. Here we evaluate the severity of exposure of tropical terrestrial mammals to pesticides, pharmaceuticals, plastics, particulate matter associated with forest fires, and nanoparticles. We consider how these environmental contaminants interact with one another, with the endocrine and microbiome systems of mammals, and with other environmental changes to produce a larger negative impact than might initially be expected. Using this background and building on past conservation success, such as mending the ozone layer and decreasing acid rain, we tackle the difficult issue of how to construct meaningful policies and conservation plans that include a consideration of the chemical landscape. We document that policy solutions to improving the chemical landscape are already known and the path of how to construct a healthier planet is discernible.
[Chapman, C.A., Steiniche, T., Benavidez, K.M., Sarkar, D., Amato, K., Serio-Silva, J.C., Venier, M. and Wasserman, M.D., Biological Conservation, 269, p.109522.] - A cross-species comparative approach to assessing multi- and transgenerational effects of endocrine disrupting chemicals
A wide range of chemicals have been identified as endocrine disrupting chemicals (EDCs) in vertebrate species. Most studies of EDCs have focused on exposure of both male and female adults to these chemicals; however, there is clear evidence that EDCs have dramatic effects when mature or developing gametes are exposed, and consequently are associated with in multigenerational and transgenerational effects. Several publications have reviewed such actions of EDCs in subgroups of species, e.g., fish or rodents. In this review, we take a holistic approach synthesizing knowledge of the effects of EDCs across vertebrate species, including fish, anurans, birds, and mammals, and discuss the potential mechanism(s) mediating such multi- and transgenerational effects. We also propose a series of recommendations aimed at moving the field forward in a structured and coherent manner.
[Robaire, B. et al. (2021) A cross-species comparative approach to assessing multi- and transgenerational effects of endocrine disrupting chemicals, Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S001393512101358X. ] - Effects of the endocrine disruptor vinclozolin in male reproduction: a systematic review and meta-analysis
Endocrine disrupting chemicals (EDCs) have become an issue of scientific and public discussion. Vinclozolin (VNZ) is a fungicide that competitively antagonizes the binding of natural androgens to their receptor, disturbing the function of tissues that are sensitive to these hormones, as is the case of the male reproductive organs. A systematic review with meta-analyses of rodent studies was conducted to answer the following question: does exposure to VNZ affect sperm parameters and testicular/epididymal weight? The methodology was prespecified according to the Cochrane Handbook for Systematic Reviews and PRISMA recommendations. Sixteen articles met the inclusion criteria, comprising a total of 1189 animals. The risk of publication bias was assessed using the Trim and Fill adjustment, funnel plot and Egger's regression test. Heterogeneity and inconsistency across the findings were tested using the Q-statistic and I2 of Higgins, respectively. Sensitivity was also analysed. Statistical analysis was performed on Comprehensive Meta-Analysis software (Version 2.0), using random models and weighted mean differences along with a 95% confidence interval. Sperm motility, counts, daily sperm production (DSP, evidence of publication bias) and epididymis weight were decreased in VNZ-treated animals. Exposure length and dose, as well as the time point of exposure, influenced the obtained results. Despite the moderate/high heterogeneity observed, the sensitivity analysis overall demonstrated the robustness of the findings. The quality scores of the included studies were superior to 4 in a total of 9, then classified as good. The obtained data corroborate the capability of VNZ exposure to disrupt spermatogenic output and compromise male fertility.
[Feijó, M., Martins, R.V., Socorro, S., Pereira, L. and Correia, S., 2021. Biology of Reproduction.] - Endocrine disrupting chemicals and breast cancer: a systematic review of epidemiological studies
Abstract
Background: Endocrine-disrupting compounds (EDCs) are ubiquitous substances that are found in our everyday lives, including pesticides, plasticizers, pharmaceutical agents, personal care products, and also in food products and food packaging. Increasing epidemiological evidence suggest that EDCs may affect the development or progression of breast cancer and consequently lead to lifelong harmful health consequences, especially when exposure occurs during early life in humans. Yet so far no appraisal of the available evidence has been conducted on this topic.
Objective: To systematically review all the available epidemiological studies about the association of the levels of environmental exposures of EDCs with breast cancer risk.
Methods: The search was performed in accordance with the PRISMA guidelines. We retrieved articles from PubMed (MEDLINE) until 10 March 2021. The key words used in this research were: "Endocrine disruptor(s)" OR "Endocrine disrupting chemical(s)" OR any of the EDCs mentioned below AND "Breast cancer" to locate all relevant articles published. We included only cohort studies and case-control studies. All relevant articles were accessed in full text and were evaluated and summarized in tables.
Results: We identified 131 studies that met the search criteria and were included in this systematic review. EDCs reviewed herein included pesticides (e.g. p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), atrazine, 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD or dioxin)), synthetic chemicals (e.g. bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), parabens, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), contraceptive pills), phytoestrogens (e.g. genistein, resveratrol), and certain mycotoxins (e.g. zearalenone). Most studies assessed environmental EDCs exposure via biomarker measurements.
Conclusion: We identified certain EDC exposures could potentially elevate the risk of breast cancer. As majority of EDCs are highly persistent in the environment and bio-accumulative, it is essential to assess the long-term impacts of EDC exposures, especially multi-generational and transgenerational. Also, since food is often a major route of exposure to EDCs, well-designed exposure assessments of potential EDCs in food and food packing are necessary and their potential link to breast cancer development need to be carefully evaluated for subsequent EDC policy making and regulations.
Keywords: Breast cancer; dietary; endocrine-disrupting chemicals; environmental; epidemiological studies; systematic review.
[Wan, M.L., Co, V.A. and El-Nezami, H. (2021) ‘Endocrine disrupting chemicals and breast cancer: A systematic review of Epidemiological Studies’, Critical Reviews in Food Science and Nutrition, 62(24), pp. 6549–6576. doi:10.1080/10408398.2021.1903382. ] - Endocrine disruptors also function as nervous disruptors and can be renamed endocrine and nervous disruptors (ENDs)
Endocrine disruption (ED) and endocrine disruptors (EDs) emerged as scientific concepts in 1995, after numerous chemical pollutants were found to be responsible for reproductive dysfunction. The World Health Organization established in the United Nations Environment Programme a list of materials, plasticizers, pesticides, and various pollutants synthesized from petrochemistry that impact not only reproduction, but also hormonal functions, directly or indirectly. Cells communicate via either chemical or electrical signals transmitted within the endocrine or nervous systems. To investigate whether hormone disruptors may also interfere directly or indirectly with the development or functioning of the nervous system through either a neuroendocrine or a more general mechanism, we examined the scientific literature to ascertain the effects of EDs on the nervous system, specifically in the categories of neurotoxicity, cognition, and behaviour. To date, we demonstrated that all of the 177 EDs identified internationally by WHO are known to have an impact on the nervous system. Furthermore, the precise mechanisms underlying this neurodisruption have also been established. It was previously believed that EDs primarily function via the thyroid. However, this study presents substantial evidence that approximately 80 % of EDs operate via other mechanisms. It thus outlines a novel concept: EDs are also neurodisruptors (NDs) and can be collectively termed endocrine and nervous disruptors (ENDs). Most of ENDs are derived from petroleum residues, and their various mechanisms of action are similar to those of “spam” in electronic communications technologies. Therefore, ENDs can be considered as an instance of spam in a biological context.
[Seralini, G.E. and Jungers, G. Toxicology Reports, 8, pp.1538-1557.] - Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis
There are increased concerns about the thyroidal effects of many anthropogenic substances in the environment. These substances include agricultural pesticides and industrial and pharmaceutical chemicals among others. Their potential thyroidal effects are of serious health and ecological concerns, as thyroid hormones mediate numerous physiological processes, including growth regulation, general metabolism and metamorphosis in metamorphic animals. This study assessed thyroidal activities of Arsenal formulation (Imazapyr) at environmentally relevant concentrations of 0.5, 2.0 and 3.5 mg/L following a Xenopus metamorphosis assay (XEMA). The result shows that the Arsenal formulation significantly delayed the tadpole development, reduced the hind-limb length (HLL) and increased the whole-body mass (WBM) at a concentration of 3.5 mg/L relative to the control exposure. In histopathology, the formulation increased the epithelium height, at all exposure concentrations, but reduced the colloidal area at 0.5 and 2 mg/L, respectively, and the gland area at 2 mg/L relative to the control. Consequently, the Arsenal formulation is thyroid-active at environmentally relevant concentrations and poses a threat to both human and wildlife, especially metamorphic organisms. With this exposure impact, more studies are imperative to further characterise other endocrine-disrupting potential of this formulation.
[Babalola, O.O. and van Wyk, J.H. (2021) Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis, Environmental Science and Pollution Research. Available at: https://link.springer.com/article/10.1007/s11356-021-14227-4. ] - Genetic Polymorphisms of Pesticide-Metabolizing Enzymes and Transporters in Agricultural Workers and Thyroid Hormone Levels
Chronic exposure to pesticides has been associated with thyroid dysfunction owing to their endocrine disruption ability. Genetic variations in genes encoding phase I and II enzymes and phase III transporters are partly responsible for individual responses to chemical pesticides. This study investigated the association between variations in genes involved in pesticide metabolism and altered thyroid hormone concentrations. The study assessed thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in organic agriculture workers (n = 216) and workers who used chemical pesticides (n = 229). A questionnaire was used to collect sociodemographic, pesticide exposure, and health status data. Blood samples were analyzed for TSH, FT3, and FT4. Genomic DNA was extracted and genotyped using the TaqMan real-time PCR genotyping assay and restriction fragment length polymorphism method for 15 metabolically related genes. Results: Significant differences in the TSH (1.58 vs 1.12 µIU/mL) and FT3 (0.34 vs 0.31 ng/dL) concentrations between the chemical and organic worker groups were observed. The frequencies of all single nucleotide polymorphisms were in Hardy–Weinberg equilibrium and were mostly consistent with Asian populations. The findings showed the association between SNPs of enzymes and transporters and TSH, FT3, and FT4. The odd ratio and adjusted odd ratio (with sex, age, smoking status, alcohol consumption and exposure parameters) for subclinical thyroid disease by the variant alleles CYP1A1 rs1048943, CYP2B6 rs2279343, CYP2C19 rs4244285, NAT2 rs1799931, and PON1 rs662 in the chemical workers compared with the organic workers were found (P values < 0.05). This is the first study to assess gene–environment interactions in Thai agricultural workers by investigating disruptions of the hypothalamic–pituitary–thyroid axis. The investigated SNP profiles revealed several gene–thyroid hormone associations in which even low levels of pesticide exposure could disturb thyroid homeostasis. These findings provide a foundation for planning future studies investigating associations between complex diseases and occupational pesticide exposure
[Sirivarasai, J., Chanprasertyothin, S., Kongtip, P. and Woskie, S. Risk Management and Healthcare Policy, 14, p.3435.] - Inhalation of particulate and emissions from 3 dimensional (3D) printers: Effects on the olfactory bulb (OB) and hypothalamic-pituitary-endocrine axes
Abstract
There is increasing concern regarding the potential health effects associated with exposure to plastic nanoparticles and the chemicals released when plastic is heated or dissolved in water. Although exposure to plastic particles and their composite chemicals can be generated by a number of different processes, 3D printers used in manufacturing, schools and homes, are sources of fumes and particulate that humans are exposed to. This study examined whether inhalation of particulate and fumes generated during 3D printing with polycarbonate (PC) affects the OB and neuroendocrine system, and if there is a dose-response relationship between exposure levels and measures of cell function.
Methods
Male rats (n= 6/group, 200 – 250 g at arrival) were exposed to filtered air, or black PC particulate and fumes generated by 3 desktop 3D-printers (exposure was 4 h/day). The 4h average particulate concentration delivered to the animals breathing space was 500 µg/m3. Animals were exposed 4 days/week until the specified number of days of exposure (1, 4, 8, 15 or 30) had been reached. The morning after the last exposure, animals were euthanized, blood was collected and circulating hormone levels were measured in serum samples using ELISAs. The OB and brain were also collected, frozen, sectioned and stored at -80°C until processed for immunohistochemistry.
Results
In the OB, exposure to 3D-emissions resulted in reductions in tyrosine hydroxylase (TH; rate limiting enzyme in dopamine synthesis) and glial derived neurotrophic factor immunolabeling. There were also reductions in myelin basic protein and cAMP nucleotide phosphatase staining, suggesting that there was myelin damage and dysfunction in the OB. In the hypothalamus, the major effects of exposure to 3D-emissions were reductions in immunostaining for TH and glial fibrillary acidic protein, a marker of astrocyte activation. Changes in immunostaining in the OB suggest there is cellular dysfunction and potentially an alteration in the transmission of olfactory information to the brain. Changes in activity and morphology of astrocytes in the hypothalamus have been shown to affect the release of hormones, including those regulating reproductive and metabolic processes; In the current study, exposure to 3D-emissions also resulted in changes in circulating concentrations of follicle stimulating hormone, and thyroid stimulating hormone.
Conclusions
Inhalation of PC particulate and/or fumes may act through olfactory pathways and affect neuroendocrine function. Although is not clear if these changes are the result of particulate matter interfering with various cellular and physiological processes, or due to endocrine disrupting bisphenols that are present in polycarbonate plastics, the results of this study are consistent with other experiments showing that exposure to PC particulate and the composite chemicals interfere with neuroendocrine processes that regulate reproduction and metabolism.
[Krajnak, K. et al. (2021) ‘Inhalation of particulate and emissions from 3 dimensional (3D) printers: Effects on the olfactory bulb (OB) and hypothalamic‐pituitary‐endocrine axes’, The FASEB Journal, 35(S1). doi:10.1096/fasebj.2021.35.s1.00277. ] - Plasticenta: First evidence of microplastics in human placenta
Microplastics are particles smaller than five millimeters deriving from the degradation of plastic objects present in the environment. Microplastics can move from the environment to living organisms, including mammals. In this study, six human placentas, collected from consenting women with physiological pregnancies, were analyzed by Raman Microspectroscopy to evaluate the presence of microplastics. In total, 12 microplastic fragments (ranging from 5 to 10 μm in size), with spheric or irregular shape were found in 4 placentas (5 in the fetal side, 4 in the maternal side and 3 in the chorioamniotic membranes); all microplastics particles were characterized in terms of morphology and chemical composition. All of them were pigmented; three were identified as stained polypropylene a thermoplastic polymer, while for the other nine it was possible to identify only the pigments, which were all used for man-made coatings, paints, adhesives, plasters, finger paints, polymers and cosmetics and personal care products.
[Ragusa, A. (2021) Plasticenta: First evidence of microplastics in human placenta, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412020322297. ] - Agrochemicals disrupt multiple endocrine axes in amphibians
Concern over global amphibian declines and possible links to agrochemical use has led to research on the endocrine disrupting actions of agrochemicals, such as fertilizers, fungicides, insecticides, acaricides, herbicides, metals, and mixtures. Amphibians, like other species, have to partition resources for body maintenance, growth, and reproduction. Recent studies suggest that metabolic impairments induced by endocrine disrupting chemicals, and more particularly agrichemicals, may disrupt physiological constraints associated with these limited resources and could cause deleterious effects on growth and reproduction. Metabolic disruption has hardly been considered for amphibian species following agrichemical exposure. As for metamorphosis, the key thyroid hormone-dependent developmental phase for amphibians, it can either be advanced or delayed by agrichemicals with consequences for juvenile and adult health and survival. While numerous agrichemicals affect anuran sexual development, including sex reversal and intersex in several species, little is known about the mechanisms involved in dysregulation of the sex differentiation processes. Adult anurans display stereotypical male mating calls and female phonotaxis responses leading to successful amplexus and spawning. These are hormone-dependent behaviours at the foundation of reproductive success. Therefore, male vocalizations are highly ecologically-relevant and may be a non-invasive low-cost method for the assessment of endocrine disruption at the population level. While it is clear that agrochemicals disrupt multiple endocrine systems in frogs, very little has been uncovered regarding the molecular and cellular mechanisms at the basis of these actions. This is surprising, given the importance of the frog models to our deep understanding of developmental biology and thyroid hormone action to understand human health. Several agrochemicals were found to have multiple endocrine effects at once (e.g., targeting both the thyroid and gonadal axes); therefore, the assessment of agrochemicals that alter cross-talk between hormonal systems must be further addressed. Given the diversity of life-history traits in Anura, Caudata, and the Gymnophiona, it is essential that studies on endocrine disruption expand to include the lesser known taxa. Research under ecologically-relevant conditions will also be paramount. Closer collaboration between molecular and cellular endocrinologists and ecotoxicologists and ecologists is thus recommended.
[Trudeau, V. et al. (2020) Agrochemicals disrupt multiple endocrine axes in amphibians, Molecular and Cellular Endocrinology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0303720720301611. ] - Assessment of genetic effects and pesticide exposure of farmers in NW Greece
The present study aims at evaluating potential genotoxic and cytotoxic effects caused by the occupational exposure of farmers to pesticide mixtures in the Aitoloakarnania Prefecture (Greece). The aforementioned assessment was conducted through in vivo Cytokinesis Block Micronucleus assay (CBMN assay) in peripheral blood lymphocytes, in relation to chemical analysis of pesticide residues in blood samples. The exposure of the farmers' population studied to different combinations of pesticides induced significant differences in the frequencies of micronuclei (MN) compared to those of the control group. Furthermore, our results indicated a possible clastogenic and aneugenic effect of pesticides on the genetic material of the farmers exposed. Five pesticides (trifluralin, chlorpyriphos methyl, metolachlor, fenthion and dimethoate) and three metabolites (fenthion sulfone, fenthion sulfoxide and 4,4′ DDE) were detected in the 62.5% of blood samples, with mean concentrations ranging from 0.4 ng/ml to 48 ng/ml. Since the farmers studied probably exhibit detectable levels of systematic exposure to the pesticides applied, continuous educational programs focused on the rational and safe use of pesticides, together with implementation of risk communication strategies among farmers are highly recommended.
[Moshou, H., Karakitsou, A., Yfanti, F., Hela, D., Vlastos, D., Paschalidou, A.K., Kassomenos, P. and Petrou, I., 2020. Environmental Research, p.109558.] - Association of urinary metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides with endometriosis
Endometriosis is a hormone-responsive gynecologic disease, signifying its connotations across a woman’s life span. Previous studies suggested that endocrine disrupting chemicals were risk factors for endometriosis. Nevertheless, little is known on exposure to organophosphate, pyrethroid and phenoxy acid pesticides on endometriosis diagnosis. In this study, we determined the concentrations of 11 pesticides, metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides, in urine collected from 619 reproductive-age women in Utah and California, using liquid chromatography-tandem mass spectrometry. The association of urinary concentrations of pesticides with an increase in the odds of endometriosis diagnosis was examined in 594 women who underwent laparoscopy/laparotomy (operative cohort: n = 471) or pelvic magnetic resonance imaging (population cohort: n = 123), during 2007–2009. 2-Isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPY), 3-phenoxybenzoic acid (3-PBA), and 2,4-dichlorophenoxyacetic acid (2,4-D) were detected in ≥95% of the urine samples analyzed. Urinary concentrations of IMPY, MDA, PNP, 3-PBA and 2,4-D tended to be higher in younger, non-Hispanic black, nulliparous and less affluent women. IMPY was the most dominant compound in urine followed by PNP and TCPY. When women in the 4th quartile of IMPY and the 2nd quartile of TCPY concentrations (μg/g creatinine) were compared with women in the 1st quartile, the odds ratios (ORs) for diagnosis of endometriosis increased significantly in unadjusted models (IMPY OR = 1.89, 95% confidence interval (Cl) = 1.12–3.20; TCPY OR = 1.65, 95% Cl = 1.02–2.69) for the operative (n = 471) and entire data set (n = 594), respectively. Our results suggest that exposure to elevated concentrations of diazinon (the parent compound of IMPY) and chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY) may be associated with endometriosis.
[Li, A.J., Chen, Z., Lin, T.C., Louis, G.M.B. and Kannan, K., 2020. Environment International, 136, p.105456.] - Early Life Exposure to Environmentally Relevant Levels of Endocrine Disruptors Drive Multigenerational and Transgenerational Epigenetic Changes in a Fish Model
The inland silverside, Menidia beryllina, is a euryhaline fish and a model organism in ecotoxicology. We previously showed that exposure to picomolar (ng/L) levels of endocrine disrupting chemicals (EDCs) can cause a variety of effects in M. beryllina, from changes in gene expression to phenotypic alterations. Here we explore the potential for early life exposure to EDCs to modify the epigenome in silversides, with a focus on multi- and transgenerational effects. EDCs included contaminants of emerging concern (the pyrethroid insecticide bifenthrin and the synthetic progestin levonorgestrel), as well as a commonly detected synthetic estrogen (ethinylestradiol), and a synthetic androgen (trenbolone) at exposure levels ranging from 3 to 10 ng/L. In a multigenerational experiment, we exposed parental silversides to EDCs from fertilization until 21 days post hatch (dph). Then we assessed DNA methylation patterns for three generations (F0, F1, and F2) in whole body larval fish using reduced representation bisulfite sequencing (RRBS). We found significant (α = 0.05) differences in promoter and/or gene body methylation in treatment fish relative to controls for all EDCs and all generations indicating that both multigenerational (F1) and transgenerational (F2) effects that were caused by strict inheritance of DNA methylation alterations and the dysregulation of epigenetic control mechanisms. Using gene ontology and pathway analyses, we found enrichment in biological processes and pathways representative of growth and development, immune function, reproduction, pigmentation, epigenetic regulation, stress response and repair (including pathways important in carcinogenesis). Further, we found that a subset of potentially EDC responsive genes (EDCRGs) were differentially methylated across all treatments and generations and included hormone receptors, genes involved in steroidogenesis, prostaglandin synthesis, sexual development, DNA methylation, protein metabolism and synthesis, cell signaling, and neurodevelopment. The analysis of EDCRGs provided additional evidence that differential methylation is inherited by the offspring of EDC-treated animals, sometimes in the F2 generation that was never exposed. These findings show that low, environmentally relevant levels of EDCs can cause altered methylation in genes that are functionally relevant to impaired phenotypes documented in EDC-exposed animals and that EDC exposure has the potential to affect epigenetic regulation in future generations of fish that have never been exposed.
[Major, K.M., DeCourten, B.M., Li, J., Britton, M., Settles, M.L., Mehinto, A.C., Connon, R.E. and Brander, S.M., 2020. Frontiers in Marine Science, 7, p.471.] - Effects of environmental pyrethroids exposure on semen quality in reproductive-age men in Shanghai, China
Animal experiments have revealed that pyrethroids (PYRs) exposure could affect semen quality, however evidence on humans being is limited and controversial.To explore the potential effects of environmental PYRs exposure on semen quality in reproductive age men. We conducted a cross-sectional study of 346 men who planned to conceive and addressed to hospital for preconception examination. PYRs exposure was assessed by analyzing PYRs urinary metabolites [3-phenoxybenzoic acid (3PBA), trans- and cis-3-(2,2-Dichlorovinyl) −2,2-dimethylcy clopropane carboxylic acid (TDCCA and CDCCA)] levels using gas chromatography-mass spectrometry. Semen quality was assessed by a computer-aided semen analyzer.For a detection rate of 99.7%, 76.6%, and 22.0%, the median levels (μg/g creatinine) of PYRs metabolites were 0.46 for 3PBA, 0.38 for TDCCA and under detection limit for CDCCA. Linear regression models found negative associations between 3PBA and sperm morphology (β = −2.12, 95% CI: −4.02 to −0.22) as well as between TDCCA and log-transformed total sperm count (β = −0.09, 95% CI: −0.16 to −0.01). In logistic regression models, men with the highest quartile of 3PBA had higher risk of poor semen quality (having below-reference semen parameter, OR = 2.40, 95% CI: 1.26 to 4.54; having below-reference sperms morphology, OR = 3.08, 95% CI: 1.10 to 8.60) compared to men in the lowest quartile. Our study suggests that environmental PYRs exposure might adversely affect semen parameters of reproductive age men in Shanghai, China. Further studies are needed to confirm our findings and demonstrate a causal relationship between PYRs exposure and semen quality.
[Hu, Y., Zhang, Y., Vinturache, A., Wang, Y., Shi, R., Chen, L., Qin, K., Tian, Y. and Gao, Y., 2020. Chemosphere, 245, p.125580.] - How fossil fuel-derived pesticides and plastics harm health, biodiversity, and the climate
Three global challenges menace survival as we know it: climate change, loss of biodiversity, and chemical pollution (including endocrine-disrupting chemicals [EDCs]). These threats are more strongly interlinked than previously thought by their common origins in fossil fuels such as coal, oil, or gas, including that derived from fracking. It is well established that accumulation of anthropogenic greenhouse gases (CO2, methane, and N2O) in the atmosphere is the main driver of climate change. However, policy makers and the general public need to better appreciate the links of each of these threats to life.
The foremost threats are chemical pollution, plastic pollution, and loss of biodiversity, as each is largely linked to the fossil fuel industry. The argument is that not only can these threats be averted, but also by reducing our dependence on fossil fuel usage we can simultaneously mitigate and eventually reverse the current climate crisis and improve environmental wellbeing and human health. If we are to embrace these economic transitions which are so urgently required, a deeper understanding of the interlinked mechanisms is needed. These outcomes can be achieved by investing in alternative energies—eg, solar, wind, or geothermic. Development of these renewable energy sources will in turn substantially reduce biodiversity loss, chemical pollution, and plastic pollution.
Although not all chemicals are EDCs, overexploitation of fossil fuels can be linked to atmospheric and chemical pollution, and their closely linked corollary—endocrine disruption. Food contact plastics, some pesticides, flame retardants, perfluorinated compounds, and other endocrine-disrupting compounds are derived from oil, coal, or gas. Moreover, shale gas, obtained by fracking, produces multiple EDCs.
[Demeneix, B. (2020) How fossil fuel-derived pesticides and plastics harm health, biodiversity, and the climate, The Lancet Diabetes & Endocrinology. Available at: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30116-9/fulltext. ] - Incidence of male breast cancer in Scotland over a twenty-five-year period (1992–2017)
Male breast cancer (MBC) accounts for around 1% of all breast cancers diagnosed. There are inconsistent reports on the incidence of MBC which some propose may be rising. Here, for the first time, the incidence of MBC in Scotland over 25 years from 1992 to 2017 was examined through interrogating the Information Services Division Scotland database. Results showed MBC incidence rose with age, peaking in the 65–70 and 75–79 age groups. Both the total number and the age-adjusted incidence of MBC increased in Scotland since 1992. This rising trend was most clear in the North of Scotland. Interestingly a higher MBC incidence in some rural areas was also observed. Our findings emphasise the need for a better understanding of MBC risk factors so that improved prevention policies can be applied for patient benefit.
[Reddington, R., Galer, M., Hagedorn, A., Liu, P., Barrack, S., Husain, E., Sharma, R., Speirs, V. and Masannat, Y., 2020. European Journal of Surgical Oncology.] - Longitudinal association of biomarkers of pesticide exposure with cardiovascular disease risk factors in youth with diabetes
Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: −0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of −0.64 (−1.17, −0.11) for 2,4-D and −0.39 (−0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (−0.11, 3.01) higher and log FCP levels that were −0.28 (−0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up.Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes.
[Kaur, N., Starling, A.P., Calafat, A.M., Sjodin, A., Clouet-Foraison, N., Dolan, L.M., Imperatore, G., Jensen, E.T., Lawrence, J.M., Ospina, M. and Pihoker, C., 2020. Environmental Research, 181, p.108916.] - Neonicotinoid insecticides exposure cause amino acid metabolism disorders, lipid accumulation and oxidative stress in ICR mice
Neonicotinoids are increasingly being used for pest control, and their potential health risks are now receiving attention. In this study, the toxic effects of three neonicotinoids (dinotefuran, nitenpyram and acetamiprid) were evaluated in ICR mice. After 30 days of exposure to neonicotinoids (1/200 LD50), oxidative stress levels, biochemical parameters, free fatty acids contents, and 1H NMR-based hepatic metabolomics were tested. All treatment groups showed signs of amino acid metabolism disorders especially elevated branched chain amino acids and phenylalanine. Furthermore, animals exposed to neonicotinoids had elevated lipid levels, which induced oxidative stress. Overall, we found that oxidative stress is a common toxic effect of exposure to neonicotinoids. In addition, lipid accumulation induced by amino acid metabolism disorder may be the cause of oxidative stress. Our results further our understanding of the toxicological effects of neonicotinoids on mammals.
[Yan, S., Meng, Z., Tian, S., Teng, M., Yan, J., Jia, M., Li, R., Zhou, Z. and Zhu, W., 2020. Chemosphere, 246, p.125661.] - Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease
Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
[Tang, B.L., 2020. Toxics, 8(2), p.21.] - Neurotransmission dysfunction by mixture of pesticides and preventive effects of quercetin on brain, hippocampus and striatum in rats
Epidemiological and toxicological studies in pesticide mixtures show that most neurodegenerative diseases are associated with chronic exposure to pesticides.In this study, we were interested in the evaluation of the neurotoxicity of two pesticides: deltamethrin, a pyrethroid, at a dose of 0.32 mg/kg/day; and acetamiprid, a neonicotinoid, at a dose of 3.14 mg/kg/day, administered chronically orally for 90 days on an animal model, the Wistar rats, as well as the evaluation of the preventive effect of quercetin against this toxicity. The fundamental principle of this experiment is the evaluation of total and regional cerebral neurotransmission (hippocampus and striatum) in control rats and pesticide-treated rats.The analysis of the results of this study shows a very clear perturbation of neurotransmitter levels either regionally or totally in rats exposed to pesticides. On the other hand, the use of quercetin at a dose of 10 mg/kg/day modifies and improves the harmful effects of treatment with both insecticides (AC and DM). These results demonstrated that quercetin corrects the neurotoxicity caused by the mixture of deltamethrin and acetamiprid.
[Gasmi, S., 2020. Toxicology and Environmental Health Sciences, pp.1-10.] - Organochlorine pesticide levels in Greek patients with Parkinson’s Disease
Parkinson’s disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data. To examine the relationship between OC blood concentrations and PD risk. In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p’-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls. All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p’-DDE (n = 214, 100% of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5%, controls 53.5%). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders [Odds Ratio, OR (95% confidence interval, C.I.)]: 2.592,(1.29-5.21)], whilst lower levels of HCB were detect among PD patients [OR,95%CI:0.176(0.09-0.35)]. Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.
[Dardiotis, E., Aloizou, A.M., Sakalakis, E., Siokas, V., Koureas, M., Xiromerisiou, G., Petinaki, E., Wilks, M., Tsatsakis, A., Hadjichristodoulou, C. and Stefanis, L., 2020. Toxicology Reports.] - Persistent organic pollutant exposure and celiac disease: A pilot study
Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p’-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.
[Gaylord, A., Trasande, L., Kannan, K., Thomas, K.M., Lee, S., Liu, M. and Levine, J., 2020. Environmental Research, p.109439.] - Spatial distribution patterns and human exposure risks of polycyclic aromatic hydrocarbons, organochlorine pesticides and polychlorinated biphenyls in Nepal using tree bark as a passive air sampler
Nepal is abutted between the populated Indo-Gangetic Plain (IGP) and Himalayan mountains. Currently, knowledge on the country-wide distribution and cancer risks of atmospheric organic toxicants in Nepal remains limited. In this study, the concentrations, sources, and distributions of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polychlorinated biphenyls (PCBs), along with their cancer risks, were investigated in Nepal by using tree bark as a passive air sampler. After transferring by a bark/air partitioning model, the averaged concentrations of ∑PAHs, ∑DDTs, ∑HCHs, HCB, ∑Endo and ∑PCBs in the atmosphere of Nepal were 3.71 × 104 pg/m3, 1.10 × 103 pg/m3, 2.92 × 102 pg/m3, 4.38 × 102 pg/m3, 4.66 pg/m3 and 65.8 pg/m3, respectively. Source diagnosis suggested that biomass burning is the major source for PAHs, while local application and long-range transport jointly contribute to the high levels of DDT and HCH in the air. The ILCR (incremental lifetime cancer risk) value was used to assess the risks of various chemicals. Adults have a higher risk than other age groups; the major exposure pathway for risk is by inhalation; and PAHs and HCHs are the dominant chemical classes that lead to risk. It was also found that, in certain hotspots in south Nepal, the carcinogenic risks caused by DDT and HCH were particularly high (>1 × 10−4). Given that illegal and disordered use of legacy POPs in south Nepal and the IGP region is common, our results highlight an urgent need for voluntary regulation of the ongoing use of pesticides.
[Wang, X., Gong, P., Wang, C., Wang, X., Pokhrel, B. and Dotel, J., 2020. Environmental Research, p.109510.] - The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity
Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp®, has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as “probably carcinogenic” in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries’ authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.
[Peillex, C. and Pelletier, M. (2020) The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity, Journal of Immunotoxicology. Available at: https://www.tandfonline.com/doi/full/10.1080/1547691X.2020.1804492.] - The Impact of Environmental Chemicals on the Gut Microbiome
Since the surge of microbiome research in the last decade, many studies have provided insight into the causes and consequences of changes in the gut microbiota. Among the multiple factors involved in regulating the microbiome, exogenous factors such as diet and environmental chemicals have been shown to alter the gut microbiome significantly. Although diet substantially contributes to changes in the gut microbiome, environmental chemicals are major contaminants in our food and are often overlooked. Herein, we summarize the current knowledge on major classes of environmental chemicals (bisphenols, phthalates, persistent organic pollutants, heavy metals, and pesticides) and their impact on the gut microbiome, which includes alterations in microbial composition, gene expression, function, and health effects in the host. We then discuss health-related implications of gut microbial changes, which include changes in metabolism, immunity, and neurological function.
[Chiu, K., Warner, G., Nowak, R.A., Flaws, J.A. and Mei, W., 2020.Toxicological Sciences, 176(2), pp.253-284.] - US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects
Breast cancer risk from pesticides may be missed if effects on mammary gland are not assessed in toxicology studies required for registration. Using US EPA's registration documents, we identified pesticides that cause mammary tumors or alter development, and evaluated how those findings were considered in risk assessment. Of 28 pesticides that produced mammary tumors, EPA's risk assessment acknowledges those tumors for nine and dismisses the remaining cases. For five pesticides that alter mammary gland development, the implications for lactation and cancer risk are not assessed. Many of the mammary-active pesticides activate pathways related to endocrine disruption: altering steroid synthesis in H295R cells, activating nuclear receptors, or affecting xenobiotic metabolizing enzymes. Clearer guidelines based on breast cancer biology would strengthen assessment of mammary gland effects, including sensitive histology and hormone measures. Potential cancer risks from several common pesticides should be re-evaluated, including: malathion, triclopyr, atrazine, propylene oxide, and 3-iodo-2-propynyl butylcarbamate (IPBC).
[Cardona, B. and Rudel, R.A., 2020. Molecular and Cellular Endocrinology, p.110927.] - A restatement of the natural science evidence base on the effects of endocrine disrupting chemicals on wildlife
Abstract
Endocrine disrupting chemicals (EDCs) are substances that alter the function of the endocrine system and consequently cause adverse effects to humans or wildlife. The release of particular EDCs into the environment has been shown to negatively affect certain wildlife populations and has led to restrictions on the use of some EDCs. Current chemical regulations aim to balance the industrial, agricultural and/or pharmaceutical benefits of using these substances with their demonstrated or potential harm to human health or the environment. A summary is provided of the natural science evidence base informing the regulation of chemicals released into the environment that may have endocrine disrupting effects on wildlife. This summary is in a format (a 'restatement') intended to be policy-neutral and accessible to informed, but not expert, policy-makers and stakeholders.
[Godfray, H.C. et al. (2019) ‘A restatement of the Natural Science Evidence Base on the effects of endocrine disrupting chemicals on wildlife’, Proceedings of the Royal Society B: Biological Sciences, 286(1897), p. 20182416. doi:10.1098/rspb.2018.2416. ] - Association Between Exposure to Pyrethroid Insecticides and Risk of All-Cause and Cause-Specific Mortality in the General US Adult Population
Widespread exposure to pyrethroid insecticides has been reported among the general population in the United States and worldwide. However, little is known about the association of pyrethroid. To examine the association of pyrethroid exposure with all-cause and cause-specific mortality among adults in the United States. The national representative cohort included 2116 adults aged 20 years and older who participated in the US National Health and Nutrition Examination Survey conducted from 1999 to 2002 and provided urine samples for pyrethroid metabolite measurements. Participants were linked to mortality data from the survey date through December 31, 2015. Data were analyzed from May to August 2019. Urinary levels of 3-phenoxybenzoic acid, a general pyrethroid metabolite and commonly used biomarker for pyrethroid exposure, were determined by using high-performance liquid chromatography coupled with electrospray chemical ionization and tandem mass spectrometry. Mortality from all causes, cardiovascular disease, and cancer. This cohort study of 2116 adults comprised 1145 women (weighted proportion, 51.6%) and 971 men (weighted, 48.4%), with a weighted mean (SE) age of 42.6 (0.5) years; 958 participants (weighted, 68.4%) were of non-Hispanic white ancestry, 646 (weighted, 14.7%) of Hispanic ancestry, 419 (weighted, 11.3%) of non-Hispanic black ancestry, and 93 (weighted, 5.6%) of other ancestry. During a median of 14.4 years (range, 0.1-16.8 years) of observation, 246 deaths occurred, including 41 associated with cardiovascular disease and 52 associated with cancer. Participants with higher urinary 3-phenoxybenzoic acid levels were at a higher risk of death during the follow-up period, with death occurring in 8.5% (unweighted, 75 of 709), 10.2% (unweighted, 81 of 701), and 11.9% (unweighted, 90 of 706) of participants across increasing tertiles of urinary 3-phenoxybenzoic acid levels. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratios for all-cause mortality, cardiovascular disease mortality, and cancer mortality among participants with the highest tertile compared with those with the lowest tertile of urinary 3-phenoxybenzoic acid levels were 1.56 (95% CI, 1.08-2.26), 3.00 (95% CI, 1.02-8.80), and 0.91 (95% CI, 0.31-2.72), respectively. In this nationally representative sample of US adults, environmental exposure to pyrethroid insecticides was associated with an increased risk of all-cause and cardiovascular disease mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.
[Bao, W., Liu, B., Simonsen, D.W. and Lehmler, H.J., 2019. JAMA Internal Medicine. 180(3):367-374.] - Association between urinary triclosan with bone mass density and osteoporosis in the US adult women, 2005-2010.
Laboratory studies have demonstrated that Triclosan (TCS) could result in significant interstitial collagen accumulation and an increase in trabecular bone. However, little is known about the relationship between TCS exposure and human bone health. We used 2005-2010 National Health and Nutrition Examination Survey data to examine the association between urinary TCS concentrations with BMD and osteoporosis in the US adult women (age ≥20 years). After inclusion and exclusion, 1,848 women were finally analyzed. After adjustment for other covariates, we observed significant associations between tertile 3 of TCS concentration and lower BMD in regions of total femur (β=-0.016, 95% CI=-0.032, -0.000), intertrochanter (β=-0.022, 95% CI=-0.042, -0.002), and lumbar spine (β=-0.014, 95% CI=-0.029, 0.001), respectively, relative to tertile 1. Compared with women at tertile 1, those at tertile 3 were more likely to have increased osteoporosis prevalence in intertrochanter [odd ratio (OR)=2.464, 95% CI = 1.190, 5.105]. This is the first epidemiological study to investigate the association between urinary TCS concentration with BMD and osteoporosis in the US adult women. We found urinary TCS concentration was negatively associated with BMD and was positively associated with the prevalence of osteoporosis. The evidence was stronger in postmenopausal women than in premenopausal women. Future prospective studies are needed to validate the findings.
[Cai, S., Zhu, J., Sun, L., Fan, C., Zhong, Y., Shen, Q. and Li, Y., 2019. The Journal of Clinical Endocrinology & Metabolism.] - DDT and Breast Cancer: Prospective Study of Induction Time and Susceptibility Windows
In a previous Child Health and Development Studies report, p, p’-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50–54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure. We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50–54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31–49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1–3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p’-DDT, o, p’-DDT, and p, p’-DDE. Odds ratios (ORs) below are given for doubling of serum p, p’-DDT. All statistical tests were two-sided. For early postmenopausal breast cancer, p, p’-DDT was associated with risk for all women (ORDDT 50–54 = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (ORDDT 50–54 for first exposure after infancy = 2.83, 95% CI = 1.96 to 4.10 vs ORDDT 50–54 for first exposure during infancy = 0.56, 95% CI = 0.26 to 1.19; Pinteraction DDT x age at first exposure = .01). In contrast, for premenopausal breast cancer, p, p’-DDT was associated with risk among women first exposed during infancy through puberty, but not after (ORDDT = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03). p, p’-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause.
[Cohn, B.A., Cirillo, P.M. and Terry, M.B., 2019. 111(8), pp.803-810.] - Endocrine disrupting chemicals: Impact on human health, wildlife and the environment
Abstract
Endocrine disrupting chemicals are a group of pollutants that can affect the endocrine system and lead to diseases and dysfunctions across the lifespan of organisms. They are omnipresent. They are in the air we breathe, in the food we eat and in the water we drink. They can be found in our everyday lives through personal care products, household cleaning products, furniture and in children’s toys. Every year, hundreds of new chemicals are produced and released onto the market without being tested, and they reach our bodies through everyday products. Permanent exposure to those chemicals may intensify or even become the main cause for the development of diseases such as type 2 diabetes, obesity, cardiovascular diseases and certain types of cancer. In recent years, legislation and regulations have been implemented, which aim to control the release of potentially adverse endocrine disrupting chemicals, often invoking the precautionary principle. The objective of this review is to provide an overview of research on environmental aspects of endocrine disrupting chemicals and their effects on human health, based on evidence from animal and human studies. Emphasis is given to three ubiquitous and persistent groups of chemicals, polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides, and on two non-persistent, but ubiquitous, bisphenol A and phthalates. Some selected historical cases are also presented and successful cases of regulation and legislation described. These led to a decrease in exposure and consequent minimization of the effects of these compounds. Recommendations from experts on this field, World Health Organization, scientific reports and from the Endocrine Society are included.
[Encarnação, T. et al. (2019) ‘Endocrine disrupting chemicals: Impact on human health, wildlife and the environment’, Science Progress, 102(1), pp. 3–42. doi:10.1177/0036850419826802. ] - Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data
Plant Protection Products, more commonly referred to as pesticides and biocides, are used to control a wide range of yield-reducing pests including insects, fungi, nematodes, and weeds. Concern has been raised that some pesticides may act as endocrine disrupting chemicals (EDCs) with the potential to interfere with the hormone systems of non-target invertebrates and vertebrates, including humans. EDCs act at low doses and particularly vulnerable periods of exposure include pre- and perinatal development. Of critical concern is the number of pesticides with the potential to interfere with the developing nervous system and brain, notably with thyroid hormone signaling. Across vertebrates, thyroid hormone orchestrates metamorphosis, brain development, and metabolism. Pesticide action on thyroid homeostasis can involve interference with TH production and its control, displacement from distributor proteins and liver metabolism. Here we focused on thyroid endpoints for each of the different classes of pesticides reviewing epidemiological and experimental studies carried out both in in vivo and in vitro. We conclude first, that many pesticides were placed on the market with insufficient testing, other than acute or chronic toxicity, and second, that thyroid-specific endpoints for neurodevelopmental effects and mixture assessment are largely absent from regulatory directives.
[Leemans, M. et al. (2019) Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data, Frontiers in Endocrinology. Available at: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00743/full. ] - One size does not fit all: Caste and sex differences in the response of bumblebees (Bombus impatiens) to chronic oral neonicotinoid exposure
Neonicotinoid insecticides have been implicated in the rapid global decline of bumblebees over recent years, particularly in agricultural and urban areas. While there is much known about neonicotinoid toxicity effects at the colony stage of the bumblebee annual cycle, far less is known about such effects at other stages critical for the maintenance of wild populations. In the present work, individual-based feeding assays were used to show that chronic consumption of the widely used neonicotinoid clothianidin at a field-realistic average rate of 3.6 and 4.0 ng/g·bee/day reduces survival of queen and male bumblebees, respectively, within a 7-day period. In contrast, worker survival was unaffected at a similar consumption rate of 3.9 ng/g·bee/day. To test the hypothesis that males have a lower tolerance for oral clothianidin exposure than workers due to their haploid genetic status, RNAseq analysis was used to compare the transcriptomic responses of workers and males to chronic intake of clothianidin at a sub-lethal dose of 0.37ng/bee/day for 5 days. Surprisingly, clothianidin consumption only altered the expression of 19 putative detoxification genes in a sex-specific manner, with 11/19 genes showing increased expression in workers. Sub-lethal clothianidin exposure also altered the expression of 40 genes associated with other major biological functions, including locomotion, reproduction, and immunity. Collectively, these results suggest that chronic oral toxicity effects of neonicotinoids are greatest during mating and nest establishment phases of the bumblebee life cycle. Chronic oral toxicity testing on males and queens is therefore required in order to fully assess the impact of neonicotinoids on wild bumblebee populations.
[Mobley, M.W. and Gegear, R.J., 2018. PloS one, 13(10).] - Simazine, a triazine herbicide, disrupts swine granulosa cell functions
Abstract
The triazine herbicide simazine is a pesticide commonly detected in surface and ground waters, although banned in most European countries since 2004. Concerns for humans and animal health result from its potential endocrine disrupting action, that can lead to reproductive disorders. The present in vitro study was undertaken to study simazine effects on swine granulosa cell function, namely cell viability, proliferation, steroidogenesis and NO production. Moreover, the ability of this substance to interfere with the angiogenetic process, a crucial event in reproductive function, was taken into account. Our data document that simazine treatment, at 0.1 or 10 μM concentration levels, stimulates granulosa cell proliferation and viability and impairs steroidogenesis, increasing in particular progesterone production. In addition, the in vitro angiogenesis bioassay revealed a significant simazine stimulatory effect on immortalized porcine Aortic Endothelial Cell proliferation. Collectively, these results show that simazine can display disruptive effects on ovarian cell functional parameters, possibly resulting in reproductive dysfunction. This hypothesis is also supported by the observed pro-angiogenetic properties of this herbicide, as already suggested for different endocrine disruptors.
[Grasselli, F. et al. (2018) ‘Simazine, a triazine herbicide, disrupts swine granulosa cell functions’, Animal Reproduction, 15(1), pp. 3–11. doi:10.21451/1984-3143-2017-ar960. ] - Association of reproductive disorders and male congenital anomalies with environmental exposure to endocrine active pesticides.
There is growing evidence that environmental exposure to pesticides may increase the risk of developing reproductive and developmental disorders. This study determined the prevalence and risk of developing gestational disorders and male congenital genitourinary malformations in areas with distinct exposure to pesticides, many of them with potential endocrine disrupting properties. A population-based case-control study was carried out on pregnant women and male children living in ten health districts of Andalusia classified as areas of high and low environmental exposure to pesticides according to agronomic criteria. The study population included 45,050 cases and 950,620 controls matched for age and health district. Data were collected from computerized hospital records between 1998 and 2005. Prevalence rates and risk of miscarriage, low birth weight, hypospadias, cryptorchidism and micropenis were significantly greater in areas with higher use of pesticides in relation to those with lower use, thus supporting and extending previous information.
[García J, Ventura MI, Requena M, Hernández AF, et al. 2017. Reprod Toxicol. 71:95-100.] - Association of serum organochlorine pesticides concentrations with reproductive hormone levels and polycystic ovary syndrome in a Chinese population.
To investigate the serum concentrations of organochlorine pesticides (OCPs) in patients with polycystic ovary syndrome (PCOS), a total of 178 women were studied. The concentrations of hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) in serum were determined using Gas Chromatography Mass-Mass Spectrometer. No differences with statistical significance in the mean HCH, p,p'-DDD, p,p'-DDE concentrations were observed between the patients with PCOS and the control group. Serum p,p'-DDT (P = 0.016) and o,p'-DDT (P = 0.000) levels were significantly higher in patients with PCOS compared with the control group. The results of the association between OCPs levels and hormone levels indicated that o,p'-DDT may play a role in the pathogenesis of PCOS by affecting hormones levels. Further trials should be investigated with the findings in this study to obtain new pathogenesis of PCOS.
[Guo Z, Qiu H, Wang L, Wang L, et al. 2017. Chemosphere. 171:595-600.] - Chronic exposure to the fungicide propiconazole: Behavioral and reproductive evaluation of F1 and F2 generations of male rats.
Several studies have suggested that propiconazole (PROP) may be an endocrine disruptor; possibly altering the activity of the CYP51 enzyme, which is part of the cholesterol biosynthesis pathway required for the production of sexual steroid hormones. Another PROP effect is inhibition of the aromatase enzyme that converts androgens into estrogens, which could lead to negative effects on reproductive parameters. Therefore, the present study evaluated the reproductive and developmental toxicity of PROP by exposing two generations (F1 and F2) of male rats to this fungicide, since a previous study from our lab reported that PROP has anti-estrogenic and anti-androgenic activities (Costa et al., 2015) in the male parental (P) generation. The F1 males were exposed to PROP (4 or 20mg/kg) through germ cells (via the P generation), intra uterus, and lactation, following treatment by gavage from post-natal day (PND) 21 to 120, while the F2 generation was exposed through germ cells, intra uterus, and lactation. The parameters observed in both F1 and F2 generations were: body weight, anogenital distance (PND 0 and 21), ontogenic reflex, testosterone plasmatic levels, testis weight, and testicular histomorphology (PND 21); and in the F1 generation only: preputial separation (PND 40), sexual behavior, organ weights, testosterone and estradiol plasmatic levels (PND 120), sperm count and morphology, and testicular histomorphology at adulthood. In the F1 and F2 generations, PROP (4mg/kg) presented a decrease in testosterone levels, and in the F1 decreases in the vas deferens weight, without hormonal and functional changes of the reproductive organs, either at 4mg/kg or at 20mg/kg, in adulthood. Based on the results of this work, PROP did not alter the gonadal-endocrine parameters under these exposure conditions in rats.
[Vieira ML, Costa NO, Pereira MRF, et al. 2017. Toxicology. 389:85-93.] - Computational study involving identification of endocrine disrupting potential of herbicides: Its implication in TDS and cancer progression in CRPC patients.
Several environmental pollutants, including herbicides, act as endocrine disrupting chemicals (EDCs). They can cause cancer, diabetes, obesity, metabolic diseases and developmental problems. Present study was conducted to screen 608 herbicides for evaluating their endocrine disrupting potential. The screening was carried out with the help of endocrine disruptome docking program, http://endocrinedisruptome.ki.si (Kolsek et al., 2013). This program screens the binding affinity of test ligands to 12 major nuclear receptors. As high as 252 compounds were capable of binding to at least three receptors wherein 10 of them showed affinity with at-least six receptors based on this approach. The latter were ranked as potent EDCs. Majority of the screened herbicides were acting as antagonists of human androgen receptor (hAR). A homology modeling approach was used to construct the three dimensional structure of hAR to understand their binding mechanism. Docking results reveal that the most potent antiandrogenic herbicides would bind to hydrophobic cavity of modeled hAR and may lead to testicular dysgenesis syndrome (TDS) on fetal exposure. However, on binding to T877 mutant AR they seem to act as agonists in castration-resistant prostate cancer (CRPC) patients.
[Ahmad MI, Usman A, Ahmad M. 2017. Chemosphere. 173:395-403.] - Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review.
Human health is beset with a legion of ailments, which is exacerbated by lifestyle errors. Out of the numerous enzymes in human body, aromatase, a cytochrome P450 enzyme is particularly very critical. Occurring at the crossroads of multiple signalling pathways, its homeostasis is vital for optimal health. Unfortunately, medications, hormone therapy, chemical additives in food, and endocrine-disrupting personal care products are oscillating the aromatase concentration beyond the permissible level. As this enzyme converts androgens (C19) into estrogens (C18), its agitation has different outcomes in different genders and age groups. Some common pathologies associated with aromatase disruption include breast cancer, prostate cancer, polycystic ovary syndrome (PCOS), endometriosis, osteoporosis, ovarian cancer, gastric cancer, pituitary cancer, Alzheimer's disease, schizophrenia, male hypogonadism, and transgender issues. Several drugs, cosmetics and pesticides act as the activators and suppressors of this enzyme. This carefully-compiled critical review is expected to increase public awareness regarding the threats resultant of the perturbations of this enzyme and to motivate researchers for further investigation of this field.
[Patel S. 2017. J Steroid Biochem Mol Biol.168:19-25] - Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review.
Human health is beset with a legion of ailments, which is exacerbated by lifestyle errors. Out of the numerous enzymes in human body, aromatase, a cytochrome P450 enzyme is particularly very critical. Occurring at the crossroads of multiple signalling pathways, its homeostasis is vital for optimal health. Unfortunately, medications, hormone therapy, chemical additives in food, and endocrine-disrupting personal care products are oscillating the aromatase concentration beyond the permissible level. As this enzyme converts androgens (C19) into estrogens (C18), its agitation has different outcomes in different genders and age groups. Some common pathologies associated with aromatase disruption include breast cancer, prostate cancer, polycystic ovary syndrome (PCOS), endometriosis, osteoporosis, ovarian cancer, gastric cancer, pituitary cancer, Alzheimer's disease, schizophrenia, male hypogonadism, and transgender issues. Several drugs, cosmetics and pesticides act as the activators and suppressors of this enzyme. This carefully-compiled critical review is expected to increase public awareness regarding the threats resultant of the perturbations of this enzyme and to motivate researchers for further investigation of this field.
[Patel S. 2017. J Steroid Biochem Mol Biol.168:19-25] - Effect of exposure to p,p´-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area.
Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy. To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy we analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models. Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (β=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis.Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy.
[Hernández-Mariano JÁ, Torres-Sánchez L, Bassol-Mayagoitia S, et al. 2017. Environ Res. 156:597-604.] - Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review.
Ovarian cancer (OC) is a relatively fatal female reproductive malignancy. Since the underlying causes are uncertain, it brings us to believe that both genetic and external factors contribute toward development of this lethal disorder. Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, and so on is potentially carcinogenic and their ability to cause epigenetic modifications has led us to hypothesize that they may play a catalytic role in OC progression. In response to synthetic chemicals, animal models have demonstrated disturbances in the development of ovaries and steroid hormonal levels but in humans, more research is required. The present review is an attempt to address the impact of EDCs on the hormonal system and gene methylation levels that may lead to malfunctioning of the ovaries which may consequently develop in the form of cancer. It can be concluded that endocrine disruptors do have a potential carcinogenicity and their high proportions in human body may cause epigenetic modifications, prompting ovarian surface epithelium to grow in an abnormal manner.
[Samtani R, Sharma N, Garg D. 2017. Reprod Sci. 1933719117711261.] - Endocrine Disrupting Chemicals, Transgenerational Epigenetics
and Metabolic Diseases
Exposure to environmental chemicals can produce effects on the endocrine system through epigenetic mechanisms. These can considerably decrease or increase the sensitivity of multiple hormones depending on the dose, route, or time of exposure. The exposure of endocrine disrupting chemicals (EDCs) during the in utero period could be a critical window, altering the epigenome profile. Recently, several researchers suggest a role of EDCs in the obesity epidemic. In this
brief review, we focused on how four EDCs (bisphenol A, dichlorodiphenyltrichloroethane, di-(2-ethylhexyl) phthalate and tributyltin) may underlay transgenerational epigenetic effects. We also discuss the adipogenesis signaling pathway and the impact of exposure to individual or mixtures of EDCs on the developing endocrine system. Understanding the molecular determinants
of epigenetic memory across generations will provide essential insight into how environmental exposure can affect the health of individuals, as well as subsequent generations.
[Feroe, A. et al. (2017) Endocrine disrupting chemicals, transgenerational epigenetics and metabolic diseases, EC Endocrinol Metab Res. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563023/. ] - Endocrine Disruptor Compounds (EDCs) and agriculture: The case of pesticides.
A number of pesticides are suspected or proved to act as endocrine disruptor compounds (EDCs). In the present survey of the literature, we try to define the main issues to be considered to classify individual pesticides as EDC or not.
[Combarnous, Y., 2017. Comptes rendus biologies, 340(9-10), pp.406-409.] - Endocrine Disruptors and Obesity
The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period. In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.
[Darbre PD. 2017. Curr Obes Rep. 6(1):18-27] - Environmental endocrine disruptors: New diabetogens?
The prevalence of type-2 diabetes has dramatically increased worldwide during the last few decades. While lifestyle factors (sedentariness, noxious food), together with genetic susceptibility, are well-known actors, there is accumulating evidence suggesting that endocrine disrupting chemicals (EDCs) may also play a pathophysiological role in the occurrence of metabolic diseases. Both experimental and epidemiological evidence support a role for early and chronic exposure to low doses of chemical pollutants with endocrine and metabolic disrupting effects. Most are present in the food chain and accumulate in the fat mass after absorption. In rodents, bisphenol A stimulates synthesis and secretion of pancreatic β cells and disturbs insulin signaling in liver, muscle and adipose tissue through epigenetic changes leading to insulin resistance and β cell impairment. In humans, epidemiological reports show statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, dioxins or aromatic polycyclic hydrocarbides or heavy metals and DT2 after acute accidental releases or early in life and/or chronic, low doses exposure. More prospective, longitudinal studies are needed to determine the importance of such environmental risk factors.
[Fénichel P, Chevalier N. 2017. C R Biol. pii: S1631-0691(17)30124-5] - Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data.
Because only 25% of cases of premature ovarian insufficiency (POI) have a known etiology, the aim of this review was to summarize the associations and mechanisms of the impact of the environment on this pathology. Eligible studies were selected from an electronic literature search from the PUBMED database from January 2000 to February 2016 and associated references in published studies. The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data have been grouped according to the studied pollutants in order to synthetize their impact on follicular development and follicular atresia and the molecular pathways involved. Ninety-seven studies appeared to be eligible and were included in the present study, even though few directly address POI. Phthalates, bisphenol A, pesticides and tobacco were the most reported substances having a negative impact on ovarian function with an increased follicular depletion leading to an earlier age of menopause onset. These effects were found when exposure occured at different times throughout the lifetime from the prenatal to the adult period, possibly due to different mechanisms. The main mechanism seemed to be an increase in atresia of pre-antral follicles. Environmental pollutants are probably a cause of POI. Health officials and the general public must be aware of this environmental effect in order to implement individual and global preventive actions.
[Vabre P, Gatimel N, Moreau J, Gayrard V, et al. 2017. Environ Health. 16(1):37.] - Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents.
The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. Authors evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (≥10,000 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα predicts a weak and unstable interaction (-4.10 kcal mol-1) compared to estradiol (-25.79 kcal mol-1), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Study reveals that glyphosate, but not other components present in GBHs, can activate ERα in vitro, albeit at relatively high concentrations.
[Mesnage R, Phedonos A, Biserni M, et al. 2017. Food Chem Toxicol. 108(Pt A):30-42.] - Exposure to endocrine disruptors during adulthood: consequences for female fertility.
Endocrine disrupting chemicals are ubiquitous chemicals that exhibit endocrine disrupting properties in both humans and animals. Female reproduction is an important process, which is regulated by hormones and is susceptible to the effects of exposure to endocrine disrupting chemicals. Disruptions in female reproductive functions by endocrine disrupting chemicals may result in subfertility, infertility, improper hormone production, estrous and menstrual cycle abnormalities, anovulation, and early reproductive senescence. This review summarizes the effects of a variety of synthetic endocrine disrupting chemicals during adult life. The chemicals covered in this review are pesticides (organochlorines, organophosphates, carbamates, pyrethroids, and triazines), heavy metals (arsenic, lead, and mercury), diethylstilbesterol, plasticizer alternatives (di-(2-ethylhexyl) phthalate and bisphenol A alternatives), 2,3,7,8-tetrachlorodibenzo-p-dioxin, nonylphenol, polychlorinated biphenyls, triclosan, and parabens. This review focuses on the hypothalamus, pituitary, ovary, and uterus because together they regulate normal female fertility and the onset of reproductive senescence. The literature shows that several endocrine disrupting chemicals have endocrine disrupting abilities in females during adult life, causing fertility abnormalities in both humans and animals.
[Rattan S, Zhou C, Chiang C, Mahalingam S, Brehm E, Flaws J. J Endocrinol. pii: JOE-17-0023. ] - Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.
Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.
[Sifakis S, Androutsopoulos VP, Tsatsakis AM, Spandidos DA. 2017. Environ Toxicol Pharmacol. 51:56-70.] - Investigation of Associations Between Exposures to Pesticides and Testosterone Levels in Thai Farmers
We conducted a cross-sectional study to assess the relationship between pesticide exposures and testosterone levels in 133 male Thai farmers. Urine and serum samples were collected concurrently from participants. Urine was analyzed for levels of specific- and non-specific metabolites of organophosphates (OPs), pyrethroids, select herbicides, and fungicides. Serum was analyzed for total and free testosterone. Linear regression analyses revealed significant negative relationships between total testosterone and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) after controlling for covariates (e.g., age, BMI, smoking status). Positive significant associations were found between some OP pesticides and total testosterone. Due to the small sample size and the observational nature of the study, future investigation is needed to confirm our results and to elucidate the biological mechanisms.
[Panuwet P, Ladva C, Barr DB, Prapamontol T, et al. 2017. Arch Environ Occup Health. doi: 10.1080/19338244.2017.1378606] - Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones.
Use of pesticides results in indirect effects on human health. We aimed to evaluate implications of toxicological effects of subchronic chlorpyrifos exposure on reproductive function in male rats. A total of 48 adult Wistar male rats were separated into four groups (n = 12). Animals were gavaged with 2.5 mg/kg (T1), 5 mg/kg (T2), or 10 mg/kg (T3) body weight of chlorpyrifos (CPF) or distilled water (control) daily for 30 days. Organ weights, epididymal sperm parameters, DNA integrity, sex hormonal (FHS and LH) levels, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and creatinine concentrations were determined on day 31. Another two sets of (four groups/set; n = 10) animals were orally treated with the same doses of CPF, control animal groups were treated with distilled water only for 30 days, and fertility indices and blood plasma acetylcholine esterase (AchE) were determined on day 31. Exposure to CPF resulted in a significant (p < 0.05) decrease in weights of testis and epididymis. An increase in liver weight resulted in reduced sperm counts and sperm motility and an increase in sperm abnormalities. Significant reduction in serum testosterone (p < 0.01), luteinizing hormone (p < 0.05), and follicular stimulating hormone (p < 0.05) levels was evident in animals treated with the highest dose. A significant decrease in the number of viable implantation sites and pups was observed in female rats mated with the T3 (p < 0.01) and T2 (p < 0.05) males. The ALT, AST, GGT, and creatinine contents were significantly increased (p < 0.05 and p < 0.01, respectively) on CPF exposure. A significant (p < 0.01) reduction in blood plasma AchE enzyme was observed with the highest dose. Our results demonstrated that prolonged exposure of CPF induces spermatogenesis damage, possibly through interference with sex hormones and AchE enzyme resulting in reduction of fertility. Therefore, awareness programs on handling CPF (pesticides) to enhance safety warrant minimization of its hazards.
[Peiris DC, Dhanushka T. 2017. Environ Sci Pollut Res Int. doi: 10.1007/s11356-017-9617-x.] - Maternal linuron exposure alters testicular development in male offspring rats at the whole genome level.
Linuron is a widely used herbicide; its toxicity on the male reproductive system has been recognized. The current study was designed to explore the molecular mechanism underlying linuron-induced reproductive toxicity. Pregnant rats received daily oral gavage of linuron at the dose of 120mg/kg/d from gestation day (GD)12 to GD17. Tissues from male offspring rats were collected for pathological examination and microarray gene expression profiling. Changes in gene expression were further verified by quantitative real-time RT-PCR. Data showed that linuron-exposed offspring rats had a decreased sperm count (88% of controls) and disrupted acrosome formation. There were evident damages in seminiferous tubules and abnormal morphology in mesenchymal cells in samples from linuron-exposed animals. Microarray analysis indicated that the expressions of testosterone synthesis-associated genes, i.e., Star, P450scc, 3β-Hsd, Abp, Cox7a2, Pcna, p450c17and17β-Hsd were significantly altered by linuron exposure, along with other genes involving in cell proliferation and apoptosis, such as c-myc, S6K, Apaf1, and TSC1. These data indicate that linuron upon entering male offspring body can directly or indirectly interact with the androgen production and function; linuron-induced alteration in genes encoding testosterone synthesis is likely a major factor in linuron-induced male reproductive toxicity.
[Bai J, Han H, Wang F, Su L, et al. 2017. Toxicology. 389:13-20] - Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.
Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. Study evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. Higher exposure to the insecticide aldrin was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01).Results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators..
[Lerro CC, Beane Freeman LE, DellaValle CT. et al. 2017. Occup Environ Med. pii: oemed-2017-104431.] - Potential short-term neurobehavioral alterations in children associated with a peak pesticide spray season: The Mother’s Day flower harvest in Ecuador
Exposures to cholinesterase inhibitor pesticides (e.g. organophosphates) have been associated with children’s neurobehavioral alterations, including attention deficit and impulsivity. Animal studies have observed transient alterations in neurobehavioral performance in relation to cholinesterase inhibitor pesticide exposures; however, limited evidence exists regarding transient effects in humans. We estimated the associations between neurobehavioral performance and time after Mother’s Day flower harvest (the end of a heightened pesticide usage period) among 308 4-to 9-year-old children living in floricultural communities in Ecuador in 2008 who participated in the ESPINA study. Children’s neurobehavior was examined once (NEPSY-II: 11 subtests covering 5 domains), between 63 and 100 days (SD: 10.8 days) after Mother’s Day harvest (blood acetylcholinesterase activity levels can take 82 days to normalize after irreversible inhibition with organophosphates). The mean (SD) neurobehavioral scaled scores across domains ranged from 6.6 (2.4) to 9.9 (3.3); higher values reflect greater performance. Children examined sooner after Mother’s Day had lower neurobehavioral scores than children examined later, in the domains of (score difference per 10.8 days, 95%CI): Attention/Inhibitory Control (0.38, 0.10–0.65), Visuospatial Processing (0.60, 0.25–0.95) and Sensorimotor (0.43, 0.10–0.77). Scores were higher with longer time post-harvest among girls (vs. boys) in Attention/Inhibitory Control. Our findings, although cross-sectional, are among the first in non-worker children to suggest that a peak pesticide use period may transiently affect neurobehavioral performance, as children examined sooner after the flower harvest had lower neurobehavioral performance than children examined later. Studies assessing pre- and post-exposure measures are needed.
[Suarez-Lopez, J.R., Checkoway, H., Jacobs Jr, D.R., Al-Delaimy, W.K. and Gahagan, S., 2017. Neurotoxicology, 60, pp.125-133.] - Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
[Di Donato M, Cernera G, Giovannelli P, et al. 2017. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ] - Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer.
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
[Di Donato M, Cernera G, Giovannelli P, et al. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ] - Reproductive toxic impact of subchronic treatment with combined butylparaben and triclosan in weanling male rats.
The effect of treatment with combined butylparaben and triclosan on male gonadal toxicity in weanling rats was investigated. All treated groups experienced atrophy in the ventral prostate and seminal vesicle, likewise significant depletion in the number and motility of sperm. Given individually or combined butylparaben and triclosan, significantly decreased testosterone, luteinizing hormone, and follicle‐stimulating hormone levels. Individual treatment with tested compounds caused significant elevation in the E2 level, whereas combined treatment did not alter the E2 level. Testicular DNA damage was recorded in all treated groups. Moreover, the testicular malondialdehyde level was significantly elevated, along with a significant decrease in catalase enzyme activity in all treated groups. Superoxide dismutase enzyme activity was significantly decreased in the butylparaben‐treated group, increased in the triclosan‐treated group, and nonsignificantly changed the butylparaben‐triclosan‐treated group. The combined treatment produced an endocrine disturbance with a concomitant induction of testicular oxidative stress, which may represent a common mechanism of endocrine disruptor‐mediated dysfunction.
[Riad, M et al. 2017. J Biochem Mol Toxicol doi:10.1002/jbt.22037.] - Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: from Mechanisms to Novel Test Methods.
Endocrine disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, e.g., production of common household materials, in resin-based medical supplies, pesticides. Thus, they are environmentally ubiquitous and humans and wildlife are exposed to them on a daily basis. Early life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article is to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs.
[Alavian-Ghavanini A, Rüegg J. 2017. Basic Clin Pharmacol Toxicol. doi: 10.1111/bcpt.12878.] - An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring
The herbicide atrazine, a suspected endocrine disrupting chemical (EDC), frequently contaminates potable water supplies. Studies suggest alterations in the neuroendocrine system along the hypothalamus-pituitary-gonadal axis; however, most studies address either developmental, pubertal, or adulthood exposures, with few investigations regarding a developmental origins hypothesis. In this study, zebrafish were exposed to 0, 0.3, 3, or 30 parts per billion (ppb) atrazine through embryogenesis and then allowed to mature with no additional chemical exposure. Reproductive function, histopathology, hormone levels, offspring morphology, and the ovarian transcriptome were assessed. Embryonic atrazine exposure resulted in a significant increase in progesterone levels in the 3 and 30 ppb groups. A significant decrease in spawning and a significant increase in follicular atresia in the 30 ppb group were observed. In offspring, a decrease in the head length to body ratio in the 30 ppb group, along with a significant increase in head width to body ratio in the 0.3 and 3 ppb groups occurred. Transcriptomic alterations involved genes associated with endocrine system development and function, tissue development, and behavior. This study provides evidence to support atrazine as an EDC causing reproductive dysfunction and molecular alterations in adults exposed only during embryogenesis and morphological alterations in their offspring.
[Wirbisky, S.E. et al. (2016) An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring, Scientific Reports. Available at: https://www.nature.com/articles/srep21337. ] - Effect of methomyl on the biochemical and reproductive parameters in pregnancy rats: the protective role of Pistacia Lentiscus oil
Methomyl (MET) is a carbamate insecticide used worldwide to protect a wide variety of crops from insect nuisances. Besides this beneficial role, it is classified as highly toxic compound for humans and animals by the EPA. Pistacia Lentiscus (PL) is a shrub that grows in the Mediterranean region; plant parts and oil have a long history in folk medicine in healing several diseases by their antioxidant, anti-inflammatory, antimicrobial, antifungal, antiatherogenic and anticancer properties. Hence, this study was undertaken to assess the effect of MET on biochemical, histological and reproductive parameters as well as the possible protective role of Pistacia Lentiscus oil (PLO) against MET-induced toxicity in pregnant female rats. Thirty two pregnant female rats were randomly divided into four equal groups including control, MET group (10 mg/kg/bw), PLO group (0.5 ml/kg/bw) and MET+ PLO group, MET and PLO were administered by oral route. At the eighteenth day of gestation (GD18), the blood samples were taken from retro-orbital sinus to evaluate the biochemical parameters and progesterone level. Then after the parturition, the different reproductive parameters were measured and the ovary and adrenal glands were removed, weighed, fixed and used for histopathological examination.The results show that MET increased significantly the weight of liver and adrenal gland, the level of cholesterol, glucose, creatinin, urea, ASAT and ALAT, meanwhile the level of total protein was reduced. Likewise, MET induced reproductive toxicity pronounced by a decline in the level of progesterone, an alteration in the reproductive index and an increase in the number of ovary atretic follicles and degenerative corpus luteum. The supplementation of the PLO with MET reverses partially and/or completely all adverse effects noted on the biochemical and reproductive parameters as well as on the histopathological changes by their antioxidant activities. We recommended the use of PLO by oral and/or dermal application as protective agent against several diseases related to reproduction dysfunction.
[Mosbah, R., Mokrani, N., Mosbahi, I., Rouabhi, S. and Mantovani, A., 2016. In 18th European Congress of Endocrinology (Vol. 41). BioScientifica.] - Endocrine-Disrupting Chemicals and Reproductive Health.
This review discusses the evidence linking industrial chemicals to a variety of health and reproductive outcomes. Industrial chemical production has increased over the past 30 to 40 years. Basic science, animal models, and epidemiologic data suggest that certain chemicals may act as endocrine disruptors (substances that interfere with normal hormonal action) and may play an etiologic role in a number of conditions whose incidence has also increased during this same period. These include low birth weight, gestational diabetes, obesity, certain cancers, certain birth defects, and neurodevelopmental disorders such as attention deficit disorder and autism. In addition, some environmental chemicals may have epigenetic effects, resulting in transgenerational health impacts. The epidemiologic and experimental evidence that links chemicals such as plasticizers (eg, phthalates and phenols), flame retardants, perfluorinated compounds, and pesticides with adverse reproductive health outcomes is reviewed. Women's health care providers are the liaison between scientific research and their patients; they should educate themselves on the significance of environmental toxins to health. They are ideally positioned, not only to counsel and reassure pregnant women, but also to suggest practicable changes in dietary and lifestyle habits to improve their health. Furthermore, women's health care providers should advocate for regulatory changes that protect women and their families from the health effects of environmental toxins.
[Zlatnik MG. 2016. J Midwifery Womens Health. 61(4):442-55.] - Epidemiological trends of hormone-related cancers in Slovenia.
The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
[Zadnik V, Krajc M. 2016. Arh Hig Rada Toksikol. 67(2):83-92. ] - Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis.
Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison.We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33).The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion).EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention.
[Attina TM, Hauser R, Sathyanarayana S, et al. Lancet Diabetes Endocrinol. 4(12):996-1003] - Exposure to pesticides and mental disorders in a rural population of Southern Brazil.
Exposure to pesticides has been associated with mental disorders, especially in occupationally exposed populations, such as farmers. This effect has been attributed to the neurotoxic and endocrine-disrupting activity of pesticides, as suggested by experimental studies.To determine the prevalence of common mental disorders and self-reported depression, and analyze their association with the exposure to pesticides in a rural population resident in the municipality of Dom Feliciano, Rio Grande do Sul, where tobacco farming is the main economic activity. A cross-sectional study evaluating the prevalence of common mental disorders and self-reported depression in a sample of 869 adult individuals resident in Dom Feliciano, between October 2011 and March 2012 was performed. The evaluation of common mental disorders was performed using the Self-Reporting Questionnaire (SRQ-20), setting a cutoff point of 8 for both genders.The prevalence of common mental disorders and self-reported depression in the sample population were 23% and 21%, respectively. Among individuals who reported depression, an increase of 73% was observed in the odds of pesticide exposure at an age equal to or less than 15 years. There was a positive association between self-reported pesticide poisoning and common mental disorders (OR=2.63; 95% CI, 1.62-4.25) as well as self-reported depression (OR=2.62; 95% CI, 1.63-4.21). Individuals who reported depression had a greater odds of exposure to pyrethroids (OR=1.80; 95% CI, 1.01-3.21) and aliphatic alcohol (OR=1.99; 95% CI, 1.04-3.83). An SRQ-20≥8 was associated with an approximately seven times higher odds of exposure to aliphatic alcohol (95% CI, 1.73-27.53). Self-reported depression positively correlated with a greater period of exposure to dinitroaniline (OR=2.20; 95% CI, 1.03-4.70) and sulphonylurea (OR=4.95; 95% CI, 1.06-23.04).The results suggest that exposure to pesticides could be related mental disorders. However, other common risk factors in tobacco farming, the main local economic activity, cannot be excluded.
[Campos Ÿ, Dos Santos Pinto da Silva V, Sarpa Campos de Mello M, Barros Otero U. 2016. Neurotoxicology. 56:7-16.] - Exposure to pesticides and prostate cancer: systematic review of the literature
Investigations about the association between prostate cancer and environmental and/or occupational pesticide exposure have evidenced a possible role of these chemical substances on tumor etiology, related to their action as endocrine disruptors.To assess the association between pesticide exposure and prostate cancer by conducting a systematic review of the scientific literature.The review included 49 studies published between 1993 and 2015. All studies were in English and analyzed exposure to pesticides and/or agricultural activities. Most studies (32 articles) found a positive association between prostate cancer and pesticides or agricultural occupations, with estimates ranging from 1.01 to 14.10.The evidence provided by the reviewed studies indicates a possible association between the development of prostate cancer and pesticide exposure and/or agricultural occupations.
[Silva JF, Mattos IE, Luz LL, Carmo CN, Aydos RD. Rev Environ Health. 31(3):311-27. ] - Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
[Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.] - Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review
Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes.
[Giulivo M, Lopez de Alda M, Capri E, Barceló D. 2016. Environ Res. 151:251-264.] - Individual and combined effect of chlorpyrifos and cypermethrin on reproductive system of adult male albino rats.
Commercial mixtures of chlorpyrifos and cypermethrin pesticides are widely used to enhance the toxic effects of cypermethrin on target insects. So, the purpose of the current study was to evaluate the individual and combined toxic effects of chlorpyrifos (CPF) and cypermethrin (CYP) on reproductive system of adult male albino rats. Forty adult male albino rats were randomized into main four groups. All treatments were given by oral gavage for 12 weeks. Single CPF and CYP exposures significantly have adverse effects on reproductive function of adult male albino rats manifested by reduced testicular weight, decreased sperm count, motility and viability, significantly increased percent of morphologically abnormal spermatozoa, and significant increments in sperm DNA fragmentation index (DFI) with respect to control group. Furthermore, serum follicle stimulating hormone, luteinizing hormone, and testosterone levels were decreased significantly compared to control group. This was accompanied with histopathological changes in the testis of rats such as necrosis, degeneration, decreasing number of spermatogenic cells in some seminiferous tubules, edema, congested blood vessels, and exudate in interstitial tissue of the testis. Notably, all these changes were exaggerated in rats treated concomitantly with chlorpyrifos and cypermethrin rendering the mixture more toxic than the additive effects of each compound and causing greater damage on the reproductive system of male albino rats than the individual pesticides.
[Alaa-Eldin EA, El-Shafei DA, Abouhashem NS. 2016. Environ Sci Pollut Res. doi:10.1007/s11356-016-7912-6] - Lambda-cyhalothrin disrupts the up-regulation effect of 17β-estradiol on post-synaptic density 95 protein expression via estrogen receptor α-dependent Akt pathway.
Lambda-cyhalothrin (LCT), one of the type II pyrethroids, has been widely used throughout the world. The estrogenic effect of LCT to increase cell proliferation has been well established. However, whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated. In addition, 17β-Estradiol (E2) plays a crucial role in neurodevelopment and induces an increase in synaptic proteins. The post-synaptic density 95 (PSD95) protein, which is involved in the development of the structure and function of new spines and localized with estrogen receptor α (ERα) at the post-synaptic density (PSD), was detected in our study by using hippocampal neuron cell line HT22. We found that LCT up-regulated PSD95 and ERα expression, estrogen receptor (ER) antagonist ICI182,780 and phosphatidylinositol-4; 5-bisphosphate 3-kinase (PI3K) inhibitor LY294,002 blocked this effect. In addition, LCT disrupted the promotion effect of E2 on PSD95. To investigate whether the observed changes are caused by ERα-dependent signaling activation, we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B (PKB/Akt)-eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) pathway. There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment. In addition, LCT could disrupt the activation effect of E2 on the Akt pathway. However, no changes in cAMP response element-binding protein (CREB) activation and PSD95 messenger ribonucleic acid (mRNA) were observed. Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway, and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
[Wang Q, Xia X, Deng X, Li N, et al. 2016. J Environ Sci (China). 41:252-60.] - Negative Role of the Environmental Endocrine Disruptors in the Human Neurodevelopment
The endocrine disruptors (EDs) are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS) the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected by centralization in the last year (2015). More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs), chlorpyrifos and chlorfenvinfos, have been found in seven and three samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers but simply time-deferral mechanisms of absorption.
[Roncati L, Termopoli V, Pusiol T. 2016. Front Neurol. 7:143.] - The Increasing Prevalence in Intersex Variation from Toxicological Dysregulation in Fetal Reproductive Tissue Differentiation and Development by Endocrine-Disrupting Chemicals
An increasing number of children are born with intersex variation (IV; ambiguous genitalia/hermaphrodite, pseudohermaphroditism, etc.). Evidence shows that endocrine-disrupting chemicals (EDCs) in the environment can cause reproductive variation through dysregulation of normal reproductive tissue differentiation, growth, and maturation if the fetus is exposed to EDCs during critical developmental times in utero. Animal studies support fish and reptile embryos exhibited IV and sex reversal when exposed to EDCs. Occupational studies verified higher prevalence of offspring with IV in chemically exposed workers (male and female). Chemicals associated with endocrine-disrupting ability in humans include organochlorine pesticides, poly-chlorinated biphenyls, bisphenol A, phthalates, dioxins, and furans. Intersex individuals may have concurrent physical disorders requiring lifelong medical intervention and experience gender dysphoria. An urgent need exists to determine which chemicals possess the greatest risk for IV and the mechanisms by which these chemicals are capable of interfering with normal physiological development in children.
[Rich AL, Phipps LM, Tiwari S, et al. 2016. Environ Health Insights. 10:163-71. ] - EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
[Gore AC, Chappell VA, Fenton SE, Flaws JA, et al. 2015. Endocr Rev. 36(6):E1-E150.] - Elucidating the Links Between Endocrine Disruptors and Neurodevelopment
Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.
[Schug TT, Blawas AM, Gray K, et al. 2015. Endocrinology. 156(6):1941-51.] - Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect.
This study's aim was to identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias. A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery. In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs.Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias. The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys, especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias. Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys . Association of occupational and environmental exposures increases this risk.This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk.
[Kalfa N, Paris F, Philibert P, Orsini M, et al.2015. Eur Urol.pii: S0302-2838(15)00409-1] - Case-control study of breast cancer and exposure to synthetic environmental chemicals among Alaska Native women.
Exposure to environmental chemicals may impair endocrine system function. Alaska Native (AN) women may be at higher risk of exposure to these endocrine disrupting chemicals, which may contribute to breast cancer in this population. To measure the association between exposure to select environmental chemicals and breast cancer among AN women. A case-control study of 170 women (75 cases, 95 controls) recruited from the AN Medical Center from 1999 to 2002. Participants provided urine and serum samples. Serum was analyzed for 9 persistent pesticides, 34 polychlorinated biphenyl (PCB) congeners, and 8 polybrominated diethyl ether (PBDE) congeners. Urine was analyzed for 10 phthalate metabolites. We calculated geometric means (GM) and compared cases and controls using logistic regression. Serum concentrations of most pesticides and 3 indicator PCB congeners (PCB-138/158; PCB-153, PCB-180) were lower in case women than controls. BDE-47 was significantly higher in case women (GM=38.8 ng/g lipid) than controls (GM=25.1 ng/g lipid) (p=0.04). Persistent pesticides, PCBs, and most phthalate metabolites were not associated with case status in univariate logistic regression. The odds of being a case were higher for those with urinary mono-(2-ethylhexyl) phthalate (MEHP) concentrations that were above the median; this relationship was seen in both univariate (OR 2.16, 95% CI 1.16-4.05, p=0.02) and multivariable (OR 2.43, 95% CI 1.13-5.25, p=0.02) logistic regression. Women with oestrogen receptor (ER)-/progesterone receptor (PR)-tumour types tended to have higher concentrations of persistent pesticides than did ER+/PR+ women, although these differences were not statistically significant. Exposure to the parent compound of the phthalate metabolite MEHP may be associated with breast cancer. However, our study is limited by small sample size and an inability to control for the confounding effects of body mass index. The association between BDE-47 and breast cancer warrants further investigation.
[Holmes AK, Koller KR, Kieszak SM, Sjodin A, et al. 2014. Int J Circumpolar Health. 73:25760.] - Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence.
In this review, authors covered studies of autism and estimates of exposure to tobacco, air pollutants, volatile organic compounds and solvents, metals (from air, occupation, diet, dental amalgams, and thimerosal-containing vaccines), pesticides, and organic endocrine-disrupting compounds such as flame retardants, non-stick chemicals, phthalates, and bisphenol A. Studies include those that had individual-level data on autism, exposure measures pertaining to pregnancy or the 1st year of life, valid comparison groups, control for confounders, and adequate sample sizes. Despite the inherent error in the measurement of many of these environmental exposures, which is likely to attenuate observed associations, some environmental exposures showed associations with autism, especially traffic-related air pollutants, some metals, and several pesticides, with suggestive trends for some volatile organic compounds (e.g., methylene chloride, trichloroethylene, and styrene) and phthalates. Whether any of these play a causal role requires further study. Given the limited scope of these publications, other environmental chemicals cannot be ruled out, but have not yet been adequately studied. Future research that addresses these and additional environmental chemicals, including their most common routes of exposures, with accurate exposure measurement pertaining to several developmental windows, is essential to guide efforts for the prevention of the neurodevelopmental damage that manifests in autism symptoms.
[Kalkbrenner AE, Schmidt RJ, Penlesky AC. 2014. Curr Probl Pediatr Adolesc Health Care. 44(10):277-318.] - Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME study.
Endocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult. Our goal was to identify gestational EDC exposures associated with autistic behaviors. We measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs.Most of the EDCs were associated with negligible absolute differences in SRS scores (≤ 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (β = 2.5; 95% CI: -0.6, 5.6) or trans-nonachlor (β = 4.1; 95% CI: 0.8-7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (β = -3.0; 95% CI: -6.3, 0.2), β-hexachlorocyclohexane (β = -3.3; 95% CI: -6.1, -0.5), or PBDE-85 (β = -3.2; 95% CI: -5.9, -0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (β = -2.0; 95% CI: -4.4, 0.4).Some EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, β-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors.
[Braun JM, Kalkbrenner AE, Just AC, Yolton K, et al. 2014. Environ Health Perspect. 122(5):513-20.] - Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals
Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR - 10mg/kg), perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50 μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25 μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms.
[Sobolewski M, Conrad K, Allen JL, Weston H, et al. 2014. Neurotoxicology. 45:121-30] - Endocrine-Disrupting contaminant mixtures induce adverse developmental effects in pre-weaning rats.
Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine disrupting contaminants, including pesticides, plastic- and cosmetic ingredients, and paracetamol. ll exposures and a vehicle were administered by oral gavage to time-mated Wistar dams rats throughout gestation and lactation, and their offspring were assessed for reproductive effects at birth and in prepuberty.The mixture doses which included the anti-androgenic compounds, affected the male offspring by causing decreased anogenital distance, increased nipple retention and reduced ventral prostate weights, at both medium and high doses. Additionally, the weights of the levator ani/bulbocavernosus muscle (LABC) were decreased at the high anti-androgen mixture dose. No effects were seen after exposure to the estrogenic chemicals alone, whereas males exposed solely to paracetamol showed decreased LABC weights and increased nipple retention. Thus adverse reproductive effects were observed at mixtures reflecting 200 times high end human exposure, which is relatively close to the safety margin covered by the regulatory uncertainty factor of 100. This suggests that highly exposed human population groups may not be sufficiently protected against mixtures of endocrine disrupting chemicals.
[Axelstad M, Christiansen S, Boberg J,et al. 2013. Reproduction. doi: 10.1530/REP-13-0447] - Glyphosate induces human breast cancer cells growth via estrogen receptors.
This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
[Thongprakaisang S, Thiantanawat A, Rangkadilok N, et al. 2013. Food Chem Toxicol.59:129-36] - Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders
Even though high doses of organic pollutants are toxic, relatively low concentrations have been reported to cause long-term alterations in functioning of individual organisms, populations and even next generations. Among these pollutants are dioxins, polychlorinated biphenyls, pesticides, brominated flame retardants, plasticizers (bisphenol A, nonylphenol, and phthalates) as well as personal care products and drugs. In addition to toxic effects, they are able to interfere with hormone receptors, hormone synthesis or hormone conversion. Because these chemicals alter hormone-dependent processes and disrupt functioning of the endocrine glands, they have been classified as endocrine-disrupting chemicals (EDCs). Because certain EDCs are able to alter neural transmission and the formation of neural networks, the term neural-disrupting chemicals has been introduced, thus implicating EDCs in the etiology of neurological disorders. Recently, public concern has been focused on the effects of EDCs on brain function, concomitantly with an increase in neuropsychiatric disorders, including autism, attention deficit and hyperactivity disorder as well as learning disabilities and aggressiveness. Several lines of evidence suggest that exposure to EDCs is associated with depression and could result in neural degeneration. EDCs act via several classes of receptors with the best documented mechanisms being reported for nuclear steroid and xenobiotic receptors. Low doses of EDCs have been postulated to cause incomplete methylation of specific gene regions in the young brain and to impair neural development and brain functions across generations. Efforts are needed to develop systematic epidemiological studies and to investigate the mechanisms of action of EDCs in order to fully understand their effects on wildlife and humans.
[Kajta M, Wójtowicz AK. 2013. Pharmacol Rep. 65(6):1632-9.] - Late life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters
This study examined late life effects of perinatal exposure of rats to a mixture of endocrine disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, UV-filters, bisphenol A, parabens and the drug paracetamol.Onset of puberty and estrous cyclicity at 9 and 12 months of age was assessed. Significantly fewer females showed regular estrus cyclicity at 12 months of age in the 2 exposure groups compared to controls. In 19 months old male offspring, epididymal sperm counts were lower than controls and in ventral prostate, an over-representation of findings related to hyperplasia was observed in exposed groups compared to controls particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the high dose group. Developmental exposure of rats to the highest dose of a human relevant mixture of endocrine disrupters induced adverse effects late in life manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.
[Isling LK, Boberg J, Jacobsen PR, et al. 2013. Reproduction. doi: 10.1530/REP-13-0448] - Physiology and toxicology of hormone-disrupting chemicals in higher plants
Higher plants are exposed to natural environmental organic chemicals, associated with plant–environment interactions, and xenobiotic environmental organic chemicals, associated with anthropogenic activities. The effects of these chemicals result not only from interaction with metabolic targets, but also from interaction with the complex regulatory networks of hormone signaling. Purpose-designed plant hormone analogues thus show extensive signaling effects on gene regulation and are as such important for understanding plant hormone mechanisms and for manipulating plant growth and development. Some natural environmental chemicals also act on plants through interference with the perception and transduction of endogenous hormone signals. In a number of cases, bioactive xenobiotics, including herbicides that have been designed to affect specific metabolic targets, show extensive gene regulation effects, which are more in accordance with signaling effects than with consequences of metabolic effects. Some of these effects could be due to structural analogies with plant hormones or to interference with hormone metabolism, thus resulting in situations of hormone disruption similar to animal cell endocrine disruption by xenobiotics. These hormone-disrupting effects can be superimposed on parallel metabolic effects, thus indicating that toxicological characterisation of xenobiotics must take into consideration the whole range of signaling and metabolic effects. Hormone-disruptive signaling effects probably predominate when xenobiotic concentrations are low, as occurs in situations of residual low-level pollutions. These hormone-disruptive effects in plants may thus be of importance for understanding cryptic effects of low-dosage xenobiotics, as well as the interactive effects of mixtures of xenobiotic pollutants.
[Couée, I. et al. (2013) Physiology and toxicology of hormone-disrupting chemicals in higher plants, Plant Cell Reports. Available at: https://link.springer.com/article/10.1007/s00299-013-1428-z. ] - Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine-disrupting pesticides.
The present study investigated whether a mixture of low doses of five environmentally relevant endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, would cause adverse developmental toxicity effects in rats. In rat dams, a significant increase in gestation length was seen, while in male offspring increased nipple retention and increased incidence and severity of genital malformations were observed. Severe mixture effects on gestation length, nipple retention and genital malformations were seen at dose levels where the individual pesticides caused no or smaller effects when given alone. Generally, the mixture effect predictions based on dose-additivity were in good agreement with the observed effects. The results indicate that there is a need for modification of risk assessment procedures for pesticides, in order to take account of the mixture effects and cumulative intake, because of the potentially serious impact of mixed exposure on development and reproduction in humans.
[Hass U, Boberg J, Christiansen S, Jacobsen PR, et al. 2012. Reprod Toxicol.34(2):261-74] - Characterization of endocrine-disrupting chemicals based on hormonal balance disruption in male and female adult rats.
Reproductive functions are controlled by a finely tuned balance between estrogens and androgens. To further characterize the gonadal pathways leading to hormonal balance disruption by atrazine, vinclozolin, methoxychlor, and bisphenol A in rat, study investigated their effects in male and female young adult animals. Specifically, reproductive tract alterations, sex hormone balance in serum and gonads, tissue dosimetry, and mRNA expression were assessed. Study observed different aromatase regulation profiles between animals with similar estrogen-to-androgen ratios but with different chemical treatments. For example, increased estrogen-to-androgen ratios in atrazine-treated females could be partly linked to aromatase upregulation, while in methoxychlor- and bisphenol A-treated females, peripheral mechanisms such as conjugation/deconjugation processes might be more likely to elevate estrogen levels. In vinclozolin-treated animals, the decreased estrogen-to-androgen ratios reported might be due to an increase of peripheral (adrenal) steroidogenesis. Thus, measurement of many endpoints is necessary for good risk assessment.
[Quignot N, Arnaud M, Robidel F, Lecomte A, et al. 2012. Reprod Toxicol. 33(3):339-52.] - Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review.
This study provides an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited.
[de Cock M, Maas YG, van de Bor M. 2012. Acta Paediatr. 101(8):811-8] - Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses
Here, a team of researchers review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. They review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, they explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. Authors illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. Authors conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.
[Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, et al. 2012. Endocr Rev.33(3):378-455.] - Effect of Endocrine Disruptor Pesticides: A Review
Endocrine disrupting chemicals (EDC) are compounds that alter the normal functioning of the endocrine system of both wildlife and humans. A huge number of chemicals have been identified as endocrine disruptors, among them several pesticides. Pesticides are used to kill unwanted organisms in crops, public areas, homes and gardens, and parasites in medicine. Human are exposed to pesticides due to their occupations or through dietary and environmental exposure (water, soil, air). For several years, there have been enquiries about the impact of environmental factors on the occurrence of human pathologies. This paper reviews the current knowledge of the potential impacts of endocrine disruptor pesticides on human health.
[Mnif, W. et al. (2011) Effect of endocrine disruptor pesticides: A Review, International Journal of Environmental Research and Public Health. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC3138025/. ] - Estrogenic and androgenic activities in total plasma measured with reporter-gene bioassays: Relevant exposure measures for endocrine disruptors in epidemiologic studies?
The objective of this study was to explore the effects of a variety of sources of potential endocrine disruptors on estrogenic and androgenic activities in total plasma measured by Chemically Activated LUciferase gene eXpression (CALUX®). Plasma samples and interview data on sources of potential endocrine disruptors were collected from 108 men with different exposures profiles. Mean differences (beta) in 17ß-estradiol equivalents (EEQs) and dihydrotestosterone equivalents (AEQs) between exposure groups were estimated using general linear models. Mean plasma AEQs and EEQs were 9.1×10(-1)ng/ml and 12.0pg/ml, respectively. Elevated AEQs were found in smokers and heavy drinkers, and in men occupationally exposed to disinfectants or welding/soldering fumes. Occupational exposure to pesticides, disinfectants, and exhaust fumes seemed to be associated with increased plasma EEQs: 1.5 (-0.2-3.2)pg/ml, 2.1 (0.2-3.9)pg/ml, and 2.9 (0.6-5.2)pg/ml, respectively. Moderate to high plasma dioxin levels, measured in a subgroup by the dioxin-responsive CALUX®, were accompanied by a 20% increase in AEQs. Although the results are not yet readily interpretable, they indicate that these measurements can be valuable for epidemiologic studies on endocrine disruptors and give direction for further research.
[Brouwers MM et al. 2011. Environ Int.;37(3):557-64] - An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells.
Fenvalerate (Fen), widely used for its high insecticidal potency and low mammalian toxicity, is classified as an endocrine-disrupting chemical. Recently, Fen has received great attention for its adverse effects on human reproductive health. In this study, we found that Fen (10 microM) had a stimulatory effect on the growth of both cell lines at 24 h compared with controls by MTS (p < 0.01) and BrdU (p < 0.01) assays in hormonally responsive uterine leiomyoma (UtLM) cells and normal uterine smooth muscle cells (UtSMC). Data shows that Fen can stimulate the growth of both UtLM cells and UtSMC, which involves a combination of enhanced cell cycle progression and inhibition of apoptosis. Also this compound can increase collagen I expression, at both mRNA and protein levels. Results also indicate that Fen exposure could be considered a novel risk factor for uterine fibroids through molecular mechanisms that do not directly involve the ERs.
[Gao X, Yu L, Castro L, Moore AB, et al. 2010. Toxicol Lett. 196(3):133-41] - Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis)
The herbicide atrazine is one of the most commonly applied pesticides in the world. As a result, atrazine is the most commonly detected pesticide contaminant of ground, surface, and drinking water. Atrazine is also a potent endocrine disruptor that is active at low, ecologically relevant concentrations. Previous studies showed that atrazine adversely affects amphibian larval development. The present study demonstrates the reproductive consequences of atrazine exposure in adult amphibians. Atrazine-exposed males were both demasculinized (chemically castrated) and completely feminized as adults. Ten percent of the exposed genetic males developed into functional females that copulated with unexposed males and produced viable eggs. Atrazine-exposed males suffered from depressed testosterone, decreased breeding gland size, demasculinized/feminized laryngeal development, suppressed mating behavior, reduced spermatogenesis, and decreased fertility. These data are consistent with effects of atrazine observed in other vertebrate classes. The present findings exemplify the role that atrazine and other endocrine-disrupting pesticides likely play in global amphibian declines.
[Hayes, T. et al. (2010) Atrazine induces complete feminization and chemical castration in male African clawed frogs (xenopus laevis), Proceedings of the National Academy of Sciences. Available at: https://www.pnas.org/doi/10.1073/pnas.0909519107. ] - A mode of action for induction of thyroid gland tumors by Pyrethrins in the rat.
Prolonged treatment with high doses of pyrethrins results in thyroid gland tumors in the rat. To elucidate the mode of action for tumor formation, the effect of pyrethrins on rat thyroid gland, thyroid hormone levels and hepatic thyroxine UDPglucuronosyltransferase activity was investigated. Treatment with pyrethrins and NaPB increased hepatic microsomal thyroxine UDPglucuronosyltransferase activity and serum thyroid stimulating hormone levels (TSH), but reduced serum levels of either thyroxine (T4) and/or triiodothyronine (T3). The effects of pyrethrins in female rats were dose-dependent, with 100 ppm being a no-effect level, and on cessation of treatment were essentially reversible in both sexes. The concordance between the effects of pyrethrins and NaPB suggests that the mode of action for Pyrethrins-induced rat thyroid gland tumors is similar to that of some other non-genotoxic inducers of hepatic xenobiotic metabolism.
[Finch JM, Osimitz TG, Gabriel KL, et al. 2006. Toxicol Appl Pharmacol.214(3):253-62] - Differential Effects of Glyphosate and Roundup on Human Placental Cells and Aromatase
Roundup is a glyphosate-based herbicide used worldwide, including on most genetically modified plants that have been designed to tolerate it. Its residues may thus enter the food chain, and glyphosate is found as a contaminant in rivers. Some agricultural workers using glyphosate have pregnancy problems, but its mechanism of action in mammals is questioned. Here we show that glyphosate is toxic to human placental JEG3 cells within 18 hr with concentrations lower than those found with agricultural use, and this effect increases with concentration and time or in the presence of Roundup adjuvants. Surprisingly, Roundup is always more toxic than its active ingredient. We tested the effects of glyphosate and Roundup at lower nontoxic concentrations on aromatase, the enzyme responsible for estrogen synthesis. The glyphosate-based herbicide disrupts aromatase activity and mRNA levels and interacts with the active site of the purified enzyme, but the effects of glyphosate are facilitated by the Roundup formulation in microsomes or in cell culture. We conclude that endocrine and toxic effects of Roundup, not just glyphosate, can be observed in mammals. We suggest that the presence of Roundup adjuvants enhances glyphosate bioavailability and/or bioaccumulation.
[Richard S., et al. 2005. Environmental Health Perspectives, 113(6).] - Environmental risk factors and male fertility and reproduction
Several environmental substances and pesticides exert a direct, cytotoxic effect on male germ cells. However, an increasing concern has been raised by compounds that may act through more subtle mechanisms, for example, specific pesticides that are potentially capable of modulating or disrupting the endocrine system. Overall, exposure to pesticides with endocrine-disrupting potential raise a particular concern for male fertility because of the possible occurrence of both effects at low concentrations and additive interactions with other environmental risk factors. Delayed reproductive problems deserve special attention, since experimental data consistently indicate a high vulnerability in the developing male reproductive system. Epidemiologic studies have confirmed an increased risk of conception delay associated with occupational exposure to pesticides. Moreover, an increased risk of spontaneous abortion has been noted among wives of exposed workers.
[Petrelli, G and Mantovani, A. 2001. Contraception. 65(4):297–300] - Environmental risk factors and male fertility and reproduction
Several environmental substances and pesticides exert a direct, cytotoxic effect on male germ cells. However, an increasing concern has been raised by compounds that may act through more subtle mechanisms, for example, specific pesticides that are potentially capable of modulating or disrupting the endocrine system. Overall, exposure to pesticides with endocrine-disrupting potential raise a particular concern for male fertility because of the possible occurrence of both effects at low concentrations and additive interactions with other environmental risk factors. Delayed reproductive problems deserve special attention, since experimental data consistently indicate a high vulnerability in the developing male reproductive system. Epidemiologic studies have confirmed an increased risk of conception delay associated with occupational exposure to pesticides. Moreover, an increased risk of spontaneous abortion has been noted among wives of exposed workers.
[Petrelli, G and Mantovani, A. 2001. Contraception. 65(4):297–300] - Effects of Pesticides and Toxic Substances On Behavioral and Morphological Reproductive Development: Endocrine Versus Nonendocrine Mechanisms
Exposure to toxic substances or pesticides during critical perinatal developmental periods can alter reproductive and central nervous system (CNS)function in a manner that does not compromise the growth and viability of the fetus but causes functional alterations that become apparent later in life. While some "CNS/behavioral teratogens" are mutagenic or alter cell division, other chemicals produce alterations of CNS development via endocrine-mediated mechanisms. This discussion focuses on studies conducted primarily in our laboratory that describe how pesticides and toxic substances alter development of the reproductive and central nervous systems as a consequence of organizational or activational exposures. Abnormal behavior and morphology can result from exposure to endocrine-disrupting toxicants by altering organization of the CNS during critical stages of life or activation of behavior after puberty. Some of the toxicants that alter rodent sexual differentiation include xenoestrogens, antiandrogenic pesticides, and dioxin-like toxic substances. Chemicals that alter sex-linked nonreproductive and reproductive CNS development via nonhormonal mechanisms are also discussed in order to demonstrate that multiple mechanisms of action are involved in the development of behavioral abnormalities in pre- and perinatally exposed offspring. The fact that reproductive function (behavioral, biochemical, and morphological) can be altered via such a wide variety of mechanisms indicates that hazard identification in this area cannot rely solely on the detection of endocrine activity.
[Gray, LE and Ostby, J. 1998. Toxicol Ind Health 14(1-2): 159-184] - Developmental effects of endocrine-disrupting chemicals in wildlife and humans.
Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.
[Colborn, T, vom Saal, FS, and Soto, AM. 1993. Environ Health Perspect. 101(5): 378–384]
Metabolic Disorders
- Environmental Obesogens and Their Perturbations in Lipid Metabolism
Abstract
Epidemiological data show that obesity is now a pandemic. Lipid homeostasis requires the coordination of multiple tissues and organs, including the liver, kidney, cardiovascular system, and adipose tissues, to maintain bodily homeostasis. As increasing amounts of chemicals are being synthesized, applied, and released into the environment, their obesogenic effects have triggered serious concern. Currently, more than 50 types of chemicals with high human exposure levels have been identified as environmental obesogens that can interfere with lipid metabolism and induce obesity. Experimental studies have shown that the lipid metabolism interference effects of obesogens have multiple targets, including nuclear receptors, transcription factors, cytokines, and hormones. The interfering factors of environmental obesogen-induced obesity include transgenerational effects, susceptibility windows, gender differences, structure–effect relationships, and diet habits. Various research approaches have been established to conduct obesogenic effect research. This comprehensive review summarizes the mechanisms underlying obesogen actions and the research progress on obesogen-disrupted lipid metabolism, along with the influencing factors and research approaches, aiming to provide a framework for understanding the effects of environmental obesogens on lipid metabolism.
[Wang, X. et al. (2024) ‘Environmental obesogens and their perturbations in lipid metabolism’, Environment & Health [Preprint]. doi:10.1021/envhealth.3c00202. ] - Science evolves but outdated testing and static risk management in the US delay protection to human health
There is increasing concern amongst public health professionals, environmental health scientists, and medical organizations about exposures to synthetic chemicals via polluted air and water, consumer products such as cosmetics, fabrics and upholstery, and food and packaging. These organizations’ concerns are based on the overwhelming evidence showing associations between chemical exposures and adverse health outcomes in human populations.
[Maffini, M. and Vandenberg, L. (2024) Science evolves but outdated testing and static risk management in the US delay protection to human health, Frontiers. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1444024/full.] - Association of Lifetime Exposure to Glyphosate and Aminomethylphosphonic Acid (AMPA) with Liver Inflammation and Metabolic Syndrome at Young Adulthood: Findings from the CHAMACOS Study
We aimed to assess whether lifetime exposure to glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), is associated with elevated liver transaminases and metabolic syndrome among young adults. We conducted a prospective cohort study (lowercase italic n equals 480n=480 mother–child dyads) and a nested case–control study (lowercase italic n equals 60n=60 cases with elevated liver transaminases and 91 controls) using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We measured glyphosate and AMPA concentrations in urine samples collected during pregnancy and at child ages 5, 14, and 18 y from cases and controls. We calculated glyphosate residue concentrations: [glyphosate plus open parenthesis 1.5 times uppercase a m p a close parenthesisglyphosate + (1.5×AMPA)]. We estimated the amount of agricultural-use glyphosate applied within a 1 kilometer1−km radius of every residence from pregnancy to age 5 y for the full cohort using California Pesticide Use Reporting data. We assessed liver transaminases and metabolic syndrome at 18 y of age. Urinary AMPA at age 5 y was associated with elevated transaminases [relative risk (RR) per two-fold increase equals 1.272−fold increase=1.27, 95% confidence interval (CI): 1.06, 1.53] and metabolic syndrome (relative risk equals 2.07RR=2.07, 95% CI: 1.38, 3.11). Urinary AMPA and glyphosate residues at age 14 y were associated with metabolic syndrome [relative risk equals 1.80RR=1.80 (95% CI: 1.10, 2.93) and relative risk equals 1.88RR=1.88 (95% CI: 1.03, 3.42), respectively]. Overall, a 2-fold increase in urinary AMPA during childhood was associated with a 14% and a 55% increased risk of elevated liver transaminases and metabolic syndrome, respectively. Living near agricultural glyphosate applications during early childhood (birth to 5 y of age) was also associated with metabolic syndrome at age 18 y in the case–control group (relative risk equals 1.53RR=1.53, 95% CI: 1.16, 2.02). Childhood exposure to glyphosate and AMPA may increase risk of liver and cardiometabolic disorders in early adulthood, which could lead to more serious diseases later in life.
[Eskenazi, B., Gunier, R.B., Rauch, S., Kogut, K., Perito, E.R., Mendez, X., Limbach, C., Holland, N., Bradman, A., Harley, K.G. and Mills, P.J., 2023. Environmental Health Perspectives, 131(3), p.037001.] - Effect of Pesticides on Peroxisome Proliferator-Activated Receptors (PPARs) and Their Association with Obesity and Diabetes
Obesity and diabetes mellitus are considered the most important diseases of the XXI century. Recently, many epidemiological studies have linked exposure to pesticides to the development of obesity and type 2 diabetes mellitus. The role of pesticides and their possible influence on the development of these diseases was investigated by examining the relationship between these compounds and one of the major nuclear receptor families controlling lipid and carbohydrate metabolism: the peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ; this was possible through in silico, in vitro, and in vivo assays. The present review aims to show the effect of pesticides on PPARs and their contribution to the changes in energy metabolism that enable the development of obesity and type 2 diabetes mellitus.
[Hernández-Valdez, J., Velázquez-Zepeda, A. and Sánchez-Meza, J.C., 2023. PPAR research, 2023.] - Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
[Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.] - Investigating the Acute Metabolic Effects of the N-Methyl Carbamate Insecticide, Methomyl, on Mouse Liver
Many pesticides have been identified as endocrine and metabolism-disrupting chemicals with hepatotoxic effects. However, data are limited for insecticides in the n-methyl carbamate class, including methomyl. Here, we investigate the liver and systemic metabolic effects of methomyl in a mouse model. We hypothesize that methomyl exposure will disrupt xenobiotic and intermediary metabolism and promote hepatic steatosis in mice. Male C57BL/6 mice were exposed daily to 0–5 mg/kg methomyl for 18 days. Mice were fed water and regular chow diet ad libitum. Metabolic phenotyping was performed, and tissue samples were collected. Effects were generally greatest at the highest methomyl dose, which induced Cyp1a2. Methomyl decreased whole body weight while the liver:body weight and testes:body weight ratios were increased. Hepatic steatosis increased while plasma LDL decreased. Fasting blood glucose and the glucose tolerance test area under the curve decreased along with hepatic glycogen stores. Methomyl, however, did not increase liver oxidative stress or injury. Collectively, these data demonstrate that methomyl disrupts hepatic xenobiotic and intermediary metabolism while increasing the testes:body weight ratio, suggesting that it may be an endocrine disrupting chemical. Besides methomyl’s known action in cholinesterase inhibition, it may be involved in aryl hydrocarbon receptor activation. The potential impact of n-methyl carbamate insecticides on metabolic health and diseases, including toxicant-associated steatotic liver disease (TASLD), warrants further investigation.
[Groswald, A.M. et al. (2023) Investigating the acute metabolic effects of the N-methyl carbamate insecticide, methomyl, on Mouse Liver, Metabolites. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10456691/. ] - Metabolic Consequences of the Water We Drink: A Study Based on Field Evidence and Animal Model Experimentation
The effect of the chronic consumption of water contaminated with residual concentrations of DDT's metabolites (DDD-dichlorodiphenyldichloroethane and DDE-dichlorodiphenyldichloroethylene) found in the environment were evaluated on the biometric, hematological and antioxidant system parameters of the hepatic, muscular, renal and nervous tissues of Wistar rats. The results showed that the studied concentrations (0.002 mg.L-1 of DDD plus 0.005 mg.L-1 of DDE) could not cause significant changes in the hematological parameters. However, the tissues showed significant alteration in the activity of the antioxidant system represented by the increase in the activity of the enzymes gluthathione S-transferases in the liver, superoxide dismutase in the kidney, gluthathione peroxidase in the brain, and several changes in enzymatic activity in muscle (SOD, GPx and LPO). The enzymes alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) were also evaluated for the amino acids' metabolism in the liver, with ALT showing a significant increase in the exposed animals. In the integrative analysis of biomarkers (Permanova and PCOA), the studied concentrations showed possible metabolic changes and damage to cellular structures evidenced by increased oxidative stress and body weight gain among the treated animals. This study highlights the need for further studies on the impact of banned pesticides still present in soils that may induce adverse effects in organisms that may prevail in future generations and the environment.
[Wolfart, J.C., Theodoro, J.L., Silva, F.C., de Oliveira, C.M.R., Ferreira, N.G. and Bittencourt Guimarães, A.T., 2023. Toxics, 11(4), p.315.] - Pesticides and insulin resistance-related metabolic diseases: Evidences and mechanisms.
The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented.
[Arab, A. and Mostafalou, S., 2023. Pesticide Biochemistry and Physiology, p.105521.] - Sex-specific effects of acute chlordane exposure in the context of steatotic liver disease, energy metabolism, and endocrine disruption.
Chlordane is an organochlorine pesticide (OCP) that is environmentally persistent. Although exposures to OCPs including chlordane have been associated with elevated liver enzymes, current knowledge on OCPs’ contribution to toxicant-associated steatotic liver disease (TASLD) and underlying sex-specific metabolic/endocrine disruption are still widely limited. Therefore, the objective of this study was to investigate the sex-dependent effects of chlordane in the context of TASLD. Age-matched male and female C57BL/6 mice were exposed to chlordane (20 mg/kg, one-time oral gavage) for two weeks. Female mice generally exhibited lower bodyfat content but more steatosis and hepatic lipid levels, consistent with increased hepatic mRNA levels of genes involved in lipid synthesis and uptake. Surprisingly, chlordane-exposed females demonstrated lower hepatic cholesterol levels. With regards to metabolic disruption, chlordane exposure decreased expression of genes involved in glycogen and glucose metabolism (Pklr, Gck), while chlordane-exposed females also exhibited decreased gene expression of HNF4A, an important regulator of liver identity and function. In terms of endocrine endpoints, chlordane augmented plasma testosterone levels in males. Furthermore, chlordane activated hepatic xenobiotic receptors, including the constitutive androstane receptor, in a sex-dependent manner. Overall, chlordane exposure led to altered hepatic energy metabolism, and potential chlordane-sex interactions regulated metabolic/endocrine disruption and receptor activation outcomes.
[Luo, J., Watson, W.H., Gripshover, T.C., Qaissi, Z. and Wahlang, B., 2023. Food and Chemical Toxicology, 180, p.114024.] - Widespread use of toxic agrochemicals and pesticides for agricultural products storage in Africa and developing countries: Possible panacea for ecotoxicology and health implications
Chemicals used for storage majorly possess insecticidal activities - deterring destructive insect pests and microorganisms from stored agricultural produce. Despite the controversy about their safety, local farmers and agro-wholesalers still predominantly use these chemicals in developing countries, especially Africa, to ensure an all-year supply of agriproducts. These chemicals could have short- or long-term effects. Despite the state-of-the-art knowledge, factors such as poor education and awareness, limited agricultural subventions, quests for cheap chemicals, over-dosage, and many more are the possible reasons for these toxic chemicals' setback and persistent use in developing countries. This paper provides an up-to-date review of the environmental and ecological effects, as well as the health impacts arising from the indiscriminate use of toxic chemicals in agriproducts. Existing data link pesticides to endocrine disruption, genetic mutations, neurological dysfunction, and other metabolic disorders, apart from the myriad of acute effects. Finally, this study recommended several naturally sourced preservatives as viable alternatives to chemical counterparts and emphasized the invaluable role of education and awareness programs in mitigating the use in developing nations for a sustainable society.
[Anaduaka, E.G., Uchendu, N.O., Asomadu, R.O., Ezugwu, A.L., Okeke, E.S. and Ezeorba, T.P.C., 2023. Heliyon.] - Pesticides and Their Impairing Effects on Epithelial Barrier Integrity, Dysbiosis, Disruption of the AhR Signaling Pathway and Development of Immune-Mediated Inflammatory Diseases
The environmental and occupational risk we confront from agricultural chemicals increases as their presence in natural habitats rises to hazardous levels, building a major part of the exposome. This is of particular concern in low- and middle-income countries, such as Brazil, known as a leading producer of agricultural commodities and consumer of pesticides. As long as public policies continue to encourage the indiscriminate use of pesticides and governments continue to support this strategy instead of endorsing sustainable agricultural alternatives, the environmental burden that damages epithelial barriers will continue to grow. Chronic exposure to environmental contaminants in early life can affect crucial barrier tissue, such as skin epithelium, airways, and intestine, causing increased permeability, leaking, dysbiosis, and inflammation, with serious implications for metabolism and homeostasis. This vicious cycle of exposure to environmental factors and the consequent damage to the epithelial barrier has been associated with an increase in immune-mediated chronic inflammatory diseases. Understanding how the harmful effects of pesticides on the epithelial barrier impact cellular interactions mediated by endogenous sensors that coordinate a successful immune system represents a crucial challenge. In line with the epithelial barrier hypothesis, this narrative review reports the available evidence on the effects of pesticides on epithelial barrier integrity, dysbiosis, AhR signaling, and the consequent development of immune-mediated inflammatory diseases.
[Lima, C., Falcão, M.A.P., Rosa, J.G.S., Disner, G.R. and Lopes-Ferreira, M., 2022. International Journal of Molecular Sciences, 23(20), p.12402.] - Risk of Parkinson disease associated with pesticide exposure and protection by probiotics
Neurodegenerative disease is very harmful to human health. Some common neurodegenerative disease is; Parkinson s disease (PD), Alzheimer disease (AD), Multiple sclerosis (MS). Their cause is associated with various environmental and genetic factors. Several environmental toxins have been involved in the onset of PD. Some of them increase the risk of PD such as agriculture, and handling pesticides and heavy metals, cause death of dopamine producing neurons. Pesticides are primary class of environmental factor associated with PD. These contain various class and subclass of herbicides, insecticides, fungicides, rodenticides, and fumigants. Rotenone, paraquat, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, among the most popular toxicants used to imitate PD. These toxicants have expressed their interaction with different genes associated with PD like alpha-synuclein. In short, a common understanding of genetic and environmental pathways is essential for early diagnosis and successful translation of potential treatments. Other than these, newer classes of pesticides can cause genetic alterations in humans which leads to illness. Environmental factors are important to note in order to detect prodromal phase of Parkinson disease. In order to treat the neurodegenerative disease, the gut microbiota should be healthy. Their present a microbiota gut brain axis (MGBA) which joins the brain to gut via a vagus nerve, which is a bidirectional nerve. Under normal condition the MGBA help in regulating digestive system and also responsible for maintaining homeostasis in metabolic activities. Due to environmental factors constitution of gut microbiome can be disturbed which leads to dysregulation of enteric nervous system. Hence, MGBA function gets disrupt and causes progressive neurodegeneration disease. To reduce the symptoms of neurodegenerative disease the probiotics can be useful as they contain good or healthy microbes such as Lactobacillus, Blautia, Roseburia, Lachnospiraceae, Prevotellaceae, and Akkermansia. In order to treat the neurodegenerative disease various microbes can be used as probiotics. Therefore, this review article gives a detailed description about various pesticides and their association with neurodegeneration and information regarding neuroprotective role of probiotics.
[Rajawat, N. K., Bhardwaj, K., & Mathur, N. (2022). Risk of Parkinson disease associated with pesticide exposure and protection by probiotics. Materials Today: Proceedings, 69, A1-A11. https://www.sciencedirect.com/science/article/pii/S2214785322075253 ] - Gestational and childhood exposure to per- and polyfluoroalkyl substances and cardiometabolic risk at age 12 years
Background
Per- and polyfluoroalkyl substances (PFAS) may adversely influence cardiometabolic risk. However, few studies have examined if the timing of early life PFAS exposure modifies their relation to cardiometabolic risk. We examined the influence of gestational and childhood PFAS exposure on adolescents’ cardiometabolic risk.Methods
We quantified concentrations of four PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorononanoate [PFNA], and perfluorohexane sulfonate [PFHxS]) in sera collected during pregnancy, at birth, and at ages 3, 8, and 12 years from 221 mother–child pairs in the HOME Study (enrolled 2003–06, Cincinnati, Ohio). We measured cardiometabolic risk factors using physical examinations, fasting serum biomarkers, and dual-energy X-ray absorptiometry scans at age 12 years. Cardiometabolic risk summary scores were calculated by summing age- and sex-standardized z-scores for individual cardiometabolic risk factors. We used multiple informant models to estimate covariate-adjusted associations of serum PFAS concentrations (log2-transformed) at each visit with cardiometabolic risk scores and their individual components, and tested for differences in associations across visits.Results
The associations of serum PFOA concentrations with cardiometabolic risk scores differed across visits (P for heterogeneity = 0.03). Gestational and cord serum PFOA concentrations were positively associated with cardiometabolic risk scores (βs and 95% confidence intervals [95% CIs]: gestational 0.8 [0.0, 1.6]; cord 0.9 [-0.1, 1.9] per interquartile range increase). These positive associations were primarily driven by homeostatic model assessment for insulin resistance index (β = 0.3 [0.1, 0.5]) and adiponectin to leptin ratio (β = -0.5 [-1.0, 0.0]). Other individual cardiometabolic risk factors associated with gestational PFOA included insulin and waist circumference. Gestational and cord PFHxS were also associated with higher cardiometabolic risk scores (βs: gestational 0.9 [0.2, 1.6]; cord 0.9 [0.1, 1.7]).Conclusion
In this cohort of children with higher gestational PFOA exposure, fetal exposure to PFOA and PFHxS was associated with unfavorable cardiometabolic risk in adolescence.
[Li, N. et al. (2021) Gestational and childhood exposure to per- and polyfluoroalkyl substances and cardiometabolic risk at age 12 years, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412020322996?via%3Dihub. ] - Microplastics from food packaging: An overview of human consumption, health threats, and alternative solutions
Highlights
- Regularly used plastic packaging materials are releasing MPs into our food and drinks.
- Humans from infants to oldsters are consuming MPs released from plastic packaging.
- Interaction of MPs with human cells increased acute inflammation and cell damage.
- High temperature, age of material and mechanical stress triggers the flaking of MPs.
- Edible bioplastic packaging can be the most feasible solution to overcome health hazards.
Abstract
Microplastic (MP) accumulation in the environment and its contamination in food products has become a global threat to both environmental and human health. But nowadays, the heavy use of plastic food containers, plastic packaging, plastic bottles, disposable cups, infant feeders, plastic-coated metal, and paper cartons has provoked the issue with direct contact and release of plastic flaking into food items. People store, transport, prepare, and consume food in plastic containers, but they aren't aware of the leaching plastic from containers into their foods and drinks and consequently, they are directly consuming MPs. In this article, we focus on revealing the release of MPs from such plastic packaging materials into our food and drinks with the factors influencing their release. The consumption of such plastic particles damages the human systems and impairs the normal metabolism processes. Therefore, this study also enlightens the possible impacts of these hazardous micro-sized particles on human health. Further, we provide an overview of the alternatives that can replace plastic packaging and aid to overcome the direct consumption of microplastics with safe food packaging.
[Jadhav, E.B. et al. (2021) ‘Microplastics from Food Packaging: An overview of human consumption, health threats, and alternative solutions’, Environmental Nanotechnology, Monitoring & Management, 16, p. 100608. doi:10.1016/j.enmm.2021.100608. ] - Agrochemicals disrupt multiple endocrine axes in amphibians
Concern over global amphibian declines and possible links to agrochemical use has led to research on the endocrine disrupting actions of agrochemicals, such as fertilizers, fungicides, insecticides, acaricides, herbicides, metals, and mixtures. Amphibians, like other species, have to partition resources for body maintenance, growth, and reproduction. Recent studies suggest that metabolic impairments induced by endocrine disrupting chemicals, and more particularly agrichemicals, may disrupt physiological constraints associated with these limited resources and could cause deleterious effects on growth and reproduction. Metabolic disruption has hardly been considered for amphibian species following agrichemical exposure. As for metamorphosis, the key thyroid hormone-dependent developmental phase for amphibians, it can either be advanced or delayed by agrichemicals with consequences for juvenile and adult health and survival. While numerous agrichemicals affect anuran sexual development, including sex reversal and intersex in several species, little is known about the mechanisms involved in dysregulation of the sex differentiation processes. Adult anurans display stereotypical male mating calls and female phonotaxis responses leading to successful amplexus and spawning. These are hormone-dependent behaviours at the foundation of reproductive success. Therefore, male vocalizations are highly ecologically-relevant and may be a non-invasive low-cost method for the assessment of endocrine disruption at the population level. While it is clear that agrochemicals disrupt multiple endocrine systems in frogs, very little has been uncovered regarding the molecular and cellular mechanisms at the basis of these actions. This is surprising, given the importance of the frog models to our deep understanding of developmental biology and thyroid hormone action to understand human health. Several agrochemicals were found to have multiple endocrine effects at once (e.g., targeting both the thyroid and gonadal axes); therefore, the assessment of agrochemicals that alter cross-talk between hormonal systems must be further addressed. Given the diversity of life-history traits in Anura, Caudata, and the Gymnophiona, it is essential that studies on endocrine disruption expand to include the lesser known taxa. Research under ecologically-relevant conditions will also be paramount. Closer collaboration between molecular and cellular endocrinologists and ecotoxicologists and ecologists is thus recommended.
[Trudeau, V. et al. (2020) Agrochemicals disrupt multiple endocrine axes in amphibians, Molecular and Cellular Endocrinology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0303720720301611. ] - Association between organic food consumption and metabolic syndrome: cross-sectional results from the NutriNet-Santé study.
Metabolic syndrome (MetS), a multicomponent condition, is a cardiovascular disease predictor. Although exposure to agricultural pesticides has been suggested as a potential contributor to the rising rates of obesity, type 2 diabetes, and other features of metabolic disorders, no studies have focused on the association between consumption of organic food (produced without synthetic pesticides) and MetS. We aimed to investigate the cross-sectional association between organic food consumption and MetS in French adults to determine whether it would be worth conducting further studies, particularly large prospective and randomised trials.A total of 8174 participants from the NutriNet-Santé study who attended a clinical visit and completed an organic food frequency questionnaire were included in this cross-sectional analysis.Higher organic food consumption was negatively associated with the prevalence of MetS: adjusted prevalence ratio was 0.69 (95% CI 0.61, 0.78) when comparing the third tertile of proportion of organic food in the diet with the first one (p value <0.0001). Higher consumption of organic plant-based foods was also related to a lower probability of having MetS. In addition, when stratifying by lifestyle factors (nutritional quality of the diet, smoking status, and physical activity), a significant negative association was detected in each subgroup (p values <0.05), except among smokers. Our results showed that a higher organic food consumption was associated with a lower probability of having MetS. Additional prospective studies and randomised trials are required to ascertain the relationship between organic food consumption and metabolic disorders.
[Baudry J, Lelong H, Adriouch S, Julia C, et al. 2017. Eur J Nutr. doi: 10.1007/s00394-017-1520-1. ] - Early-life chemical exposures and risk of metabolic syndrome.
The global prevalence of obesity has been increasing at a staggering pace, with few indications of any decline, and is now one of the major public health challenges worldwide. While obesity and metabolic syndrome (MetS) have historically thought to be largely driven by increased caloric intake and lack of exercise, this is insufficient to account for the observed changes in disease trends. There is now increasing evidence to suggest that exposure to synthetic chemicals in our environment may also play a key role in the etiology and pathophysiology of metabolic diseases. Importantly, exposures occurring in early life (in utero and early childhood) may have a more profound effect on life-long risk of obesity and MetS. This narrative review explores the evidence linking early-life exposure to a suite of chemicals that are common contaminants associated with food production (pesticides; imidacloprid, chlorpyrifos, and glyphosate) and processing (acrylamide), in addition to chemicals ubiquitously found in our household goods (brominated flame retardants) and drinking water (heavy metals) and changes in key pathways important for the development of MetS and obesity.
[De Long NE, Holloway AC. 2017. Diabetes Metab Syndr Obes. 10:101-109. ]
Thyroid Function
- Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study
Background
Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive.
Objectives
This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function.
Methods
The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function.
Results
The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (β = -6.21, 95 % confidence interval [CI]: −12.21, −0.21), with more pronounced associations observed among girls (β = -9.57, 95 % CI: −18.33, −0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ.
Conclusions
Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.
[Zhang, B. et al. (2024) Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412024003064. ] - Science evolves but outdated testing and static risk management in the US delay protection to human health
There is increasing concern amongst public health professionals, environmental health scientists, and medical organizations about exposures to synthetic chemicals via polluted air and water, consumer products such as cosmetics, fabrics and upholstery, and food and packaging. These organizations’ concerns are based on the overwhelming evidence showing associations between chemical exposures and adverse health outcomes in human populations.
[Maffini, M. and Vandenberg, L. (2024) Science evolves but outdated testing and static risk management in the US delay protection to human health, Frontiers. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2024.1444024/full.] - Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function
Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds that interfere with the endocrine system, inducing harmful effects on organisms depending on the dose and period of exposure. Numerous studies have identified concerning amounts of EDCs in environmental and human samples. The thyroid gland is essential for thyroid hormone production and controls several body functions. Several EDCs have been classified as thyroid disruptors, impairing thyroid hormone production, synthesis, metabolism, transport, and/or actions. Notably, thyroid disorders are the second most prevalent endocrine disease worldwide, with incidence increasing significantly in recent years. Some studies have correlated this rise in thyroid dysfunctions and cancers with increased exposure to EDCs. Although many EDCs are linked to thyroid dysfunction, this review focuses on the deleterious effects of plasticizers, organochlorine pesticides, and per- and poly-fluoroalkyl substances on thyroid function. These contaminants are commonly found in food, water, and everyday products. Although the impact of human exposure to these EDCs is controversial, numerous epidemiological, in vivo, and in vitro studies have indicated their harmful effects on thyroid function. Given the critical role of thyroid function and hormone production in growth, metabolism, and development, this review summarizes the consequences of exposure to thyroid disruptors for human health.
[Rodrigues, V.G. et al. (2024) Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function, Endocrines. Available at: https://www.mdpi.com/2673-396X/5/3/32.] - Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis
There are increased concerns about the thyroidal effects of many anthropogenic substances in the environment. These substances include agricultural pesticides and industrial and pharmaceutical chemicals among others. Their potential thyroidal effects are of serious health and ecological concerns, as thyroid hormones mediate numerous physiological processes, including growth regulation, general metabolism and metamorphosis in metamorphic animals. This study assessed thyroidal activities of Arsenal formulation (Imazapyr) at environmentally relevant concentrations of 0.5, 2.0 and 3.5 mg/L following a Xenopus metamorphosis assay (XEMA). The result shows that the Arsenal formulation significantly delayed the tadpole development, reduced the hind-limb length (HLL) and increased the whole-body mass (WBM) at a concentration of 3.5 mg/L relative to the control exposure. In histopathology, the formulation increased the epithelium height, at all exposure concentrations, but reduced the colloidal area at 0.5 and 2 mg/L, respectively, and the gland area at 2 mg/L relative to the control. Consequently, the Arsenal formulation is thyroid-active at environmentally relevant concentrations and poses a threat to both human and wildlife, especially metamorphic organisms. With this exposure impact, more studies are imperative to further characterise other endocrine-disrupting potential of this formulation.
[Babalola, O.O. and van Wyk, J.H. (2021) Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis, Environmental Science and Pollution Research. Available at: https://link.springer.com/article/10.1007/s11356-021-14227-4. ] - Genetic Polymorphisms of Pesticide-Metabolizing Enzymes and Transporters in Agricultural Workers and Thyroid Hormone Levels
Chronic exposure to pesticides has been associated with thyroid dysfunction owing to their endocrine disruption ability. Genetic variations in genes encoding phase I and II enzymes and phase III transporters are partly responsible for individual responses to chemical pesticides. This study investigated the association between variations in genes involved in pesticide metabolism and altered thyroid hormone concentrations. The study assessed thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in organic agriculture workers (n = 216) and workers who used chemical pesticides (n = 229). A questionnaire was used to collect sociodemographic, pesticide exposure, and health status data. Blood samples were analyzed for TSH, FT3, and FT4. Genomic DNA was extracted and genotyped using the TaqMan real-time PCR genotyping assay and restriction fragment length polymorphism method for 15 metabolically related genes. Results: Significant differences in the TSH (1.58 vs 1.12 µIU/mL) and FT3 (0.34 vs 0.31 ng/dL) concentrations between the chemical and organic worker groups were observed. The frequencies of all single nucleotide polymorphisms were in Hardy–Weinberg equilibrium and were mostly consistent with Asian populations. The findings showed the association between SNPs of enzymes and transporters and TSH, FT3, and FT4. The odd ratio and adjusted odd ratio (with sex, age, smoking status, alcohol consumption and exposure parameters) for subclinical thyroid disease by the variant alleles CYP1A1 rs1048943, CYP2B6 rs2279343, CYP2C19 rs4244285, NAT2 rs1799931, and PON1 rs662 in the chemical workers compared with the organic workers were found (P values < 0.05). This is the first study to assess gene–environment interactions in Thai agricultural workers by investigating disruptions of the hypothalamic–pituitary–thyroid axis. The investigated SNP profiles revealed several gene–thyroid hormone associations in which even low levels of pesticide exposure could disturb thyroid homeostasis. These findings provide a foundation for planning future studies investigating associations between complex diseases and occupational pesticide exposure
[Sirivarasai, J., Chanprasertyothin, S., Kongtip, P. and Woskie, S. Risk Management and Healthcare Policy, 14, p.3435.] - Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid hormones, and infant neurodevelopment
Background
Per- and polyfluoroalkyl substances (PFAS) are believed to impair early neurodevelopment and disrupt thyroid hormone (TH) levels. However, there are limited epidemiological data on the neurodevelopmental effects in infancy of prenatal PFAS exposure and the potential mediating effects of TH.
Objectives
To evaluate potential associations between prenatal PFAS exposure and early neurodevelopmental deficiencies, and assess mediator effects of TH.
Methods
From 2010 to 2013, 274 mother-infant pairs were recruited to the Laizhou Wan Birth Cohort in China. Ten PFAS and five TH were measured in cord serum. Developmental quotient (DQ) from 5 domains (adaptive, social, language, gross and fine motor) was assessed using Gesell Developmental Schedules for each child at 1 year of age. The associations between PFAS and DQs were evaluated using multivariable linear regressions. TH-mediated effects of PFAS on DQs were calculated by mediation analyses.
Results
Among our study population, PFAS exposures were common and associated with DQ decrement in infants. For each 10-fold increase in PFBS concentrations, gross motor and adaptive DQ decreased by 8.56 (95%CI: −15.15, −1.97) and 5.87 (95%CI: −8.07, −3.67) points, respectively. TSH mediated 12.90% of the association of PFBS with gross motor DQ and FT4 explained 19.63% of the association of PFBS with adaptive DQ. The negative association was also found between PFHxS exposure and gross motor DQ (β = 8.14, 95%CI: −15.39, −0.98).
Conclusions
PFBS and PFHxS were negatively associated with early neurodevelopment, especially consistent in gross motor domain. The associations were partly explained by TSH and FT4.
[Yao, Q. et al. (2021) Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid hormones, and infant neurodevelopment, Environmental Research. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0013935121018624. ] - The pyriproxyfen metabolite, 4′–OH–PPF, disrupts thyroid hormone signaling in neural stem cells, modifying neurodevelopmental genes affected by ZIKA virus infection
North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by the Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. Thyroid hormone (TH) represses MSI1. PPF is a suspected TH disruptor. We hypothesized that co-exposure to the main metabolite of PPF, 4′–OH–PPF, could exacerbate ZIKV effects through increased MSI1 expression. Exposing an in vivo reporter model, Xenopus laevis, to 4′–OH–PPF decreased TH signaling and increased msi1 mRNA and protein, confirming TH-antagonistic properties. Next, we investigated the metabolite's effects on mouse subventricular zone-derived neural stem cells (NSCs). Exposure to 4′–OH–PPF dose-dependently reduced neuroprogenitor proliferation and dysregulated genes implicated in neurogliogenesis. The highest dose induced Msi1 mRNA and protein, increasing cell apoptosis and the ratio of neurons to glial cells. Given these effects of the metabolite alone, we considered if combined infection with ZIKV worsened neurogenic events. Only at the fourth and last day of incubation did co-exposure of 4′–OH–PPF and ZIKV decrease viral replication, but viral RNA copies stayed within the same order of magnitude. Intracellular RNA content of NSCs was decreased in the combined presence of 4′–OH–PPF and ZIKV, suggesting a synergistic block of transcriptional machinery. Seven out of 12 tested key genes in TH signaling and neuroglial commitment were dysregulated by co-exposure, of which four were unaltered when exposed to 4′–OH–PPF alone. We conclude that 4′–OH–PPF is an active TH-antagonist, altering NSC processes known to underlie correct cortical development. A combination of the TH-disrupting metabolite and ZIKV could aggravate the microcephaly phenotype.
[Vancamp, P., Spirhanzlova, P., Sébillot, A., Butruille, L., Gothié, J.D., Le Mével, S., Leemans, M., Wejaphikul, K., Meima, M., Mughal, B.B. and Roques, P. Environmental Pollution, 285, p.117654.] - Agrochemicals disrupt multiple endocrine axes in amphibians
Concern over global amphibian declines and possible links to agrochemical use has led to research on the endocrine disrupting actions of agrochemicals, such as fertilizers, fungicides, insecticides, acaricides, herbicides, metals, and mixtures. Amphibians, like other species, have to partition resources for body maintenance, growth, and reproduction. Recent studies suggest that metabolic impairments induced by endocrine disrupting chemicals, and more particularly agrichemicals, may disrupt physiological constraints associated with these limited resources and could cause deleterious effects on growth and reproduction. Metabolic disruption has hardly been considered for amphibian species following agrichemical exposure. As for metamorphosis, the key thyroid hormone-dependent developmental phase for amphibians, it can either be advanced or delayed by agrichemicals with consequences for juvenile and adult health and survival. While numerous agrichemicals affect anuran sexual development, including sex reversal and intersex in several species, little is known about the mechanisms involved in dysregulation of the sex differentiation processes. Adult anurans display stereotypical male mating calls and female phonotaxis responses leading to successful amplexus and spawning. These are hormone-dependent behaviours at the foundation of reproductive success. Therefore, male vocalizations are highly ecologically-relevant and may be a non-invasive low-cost method for the assessment of endocrine disruption at the population level. While it is clear that agrochemicals disrupt multiple endocrine systems in frogs, very little has been uncovered regarding the molecular and cellular mechanisms at the basis of these actions. This is surprising, given the importance of the frog models to our deep understanding of developmental biology and thyroid hormone action to understand human health. Several agrochemicals were found to have multiple endocrine effects at once (e.g., targeting both the thyroid and gonadal axes); therefore, the assessment of agrochemicals that alter cross-talk between hormonal systems must be further addressed. Given the diversity of life-history traits in Anura, Caudata, and the Gymnophiona, it is essential that studies on endocrine disruption expand to include the lesser known taxa. Research under ecologically-relevant conditions will also be paramount. Closer collaboration between molecular and cellular endocrinologists and ecotoxicologists and ecologists is thus recommended.
[Trudeau, V. et al. (2020) Agrochemicals disrupt multiple endocrine axes in amphibians, Molecular and Cellular Endocrinology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0303720720301611. ] - Anthropogenic stressors impact fish sensory development and survival via thyroid disruption
Larval metamorphosis and recruitment represent critical life-history transitions for most teleost fishes. While the detrimental effects of anthropogenic stressors on the behavior and survival of recruiting fishes are well-documented, the physiological mechanisms that underpin these patterns remain unclear. Here, we use pharmacological treatments to highlight the role that thyroid hormones (TH) play in sensory development and determining anti-predator responses in metamorphosing convict surgeonfish, Acanthurus triostegus. We then show that high doses of a physical stressor (increased temperature of +3 °C) and a chemical stressor (the pesticide chlorpyrifos at 30 µg L−1) induced similar defects by decreasing fish TH levels and affecting their sensory development. Stressor-exposed fish experienced higher predation; however, their ability to avoid predation improved when they received supplemental TH. Our results highlight that two different anthropogenic stressors can affect critical developmental and ecological transitions via the same physiological pathway. This finding provides a unifying mechanism to explain past results and underlines the profound threat anthropogenic stressors pose to fish communities.
[Besson, M., Feeney, W.E., Moniz, I., François, L., Brooker, R.M., Holzer, G., Metian, M., Roux, N., Laudet, V. and Lecchini, D., 2020. Nature communications, 11(1), pp.1-10.] - Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data
Plant Protection Products, more commonly referred to as pesticides and biocides, are used to control a wide range of yield-reducing pests including insects, fungi, nematodes, and weeds. Concern has been raised that some pesticides may act as endocrine disrupting chemicals (EDCs) with the potential to interfere with the hormone systems of non-target invertebrates and vertebrates, including humans. EDCs act at low doses and particularly vulnerable periods of exposure include pre- and perinatal development. Of critical concern is the number of pesticides with the potential to interfere with the developing nervous system and brain, notably with thyroid hormone signaling. Across vertebrates, thyroid hormone orchestrates metamorphosis, brain development, and metabolism. Pesticide action on thyroid homeostasis can involve interference with TH production and its control, displacement from distributor proteins and liver metabolism. Here we focused on thyroid endpoints for each of the different classes of pesticides reviewing epidemiological and experimental studies carried out both in in vivo and in vitro. We conclude first, that many pesticides were placed on the market with insufficient testing, other than acute or chronic toxicity, and second, that thyroid-specific endpoints for neurodevelopmental effects and mixture assessment are largely absent from regulatory directives.
[Leemans, M. et al. (2019) Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data, Frontiers in Endocrinology. Available at: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00743/full. ] - Pesticide Exposure and Thyroid Function in Elementary School Children Living in an Agricultural Area, Brebes District, Indonesia.
Children living in agricultural areas are at risk of exposure to pesticides due to their involvement in agricultural activities. Pesticides are one of the chemicals classified as endocrine disrupting chemicals.To examine the association between exposure to organophosphate pesticides and the occurrence of thyroid dysfunction in children.This cross-sectional study was conducted on 66 children in two elementary schools located in an agricultural area in Brebes District, Indonesia, in 2015. To determine the pesticide exposure history, we analyzed urine samples and completed a questionnaire. Meanwhile, thyroid function tests were performed. Organophosphate pesticide metabolites were detected in urine samples of 15 (23%) of 66 children. Thyroid stimulating hormone (TSH) levels >4.5 μIU/mL were detected in 24 (36%) children. Free thyroxine (FT4) levels of all participants were normal. The mean TSH level in children with positive urinary organophosphate pesticide metabolites (7.74 μIU/ mL) was significantly (p=0.005) higher than that in those who were negative (4.34 μIU/mL). The prevalence of hypothyroidism in children with positive urinary organophosphate pesticide metabolites (67%) was significantly higher than that in those who were negative (27%; PR 2.4, 95% CI 1.4 to 4.3).A history of pesticide exposure could be used as a risk factor for the occurrence of thyroid dysfunction in children living in agricultural areas.
[Suhartono S, Kartini A, Subagio HW, et al. 2018. Int J Occup Environ Med. 9(3):137-144.] - Direct quantification of gamma H2AX by cell-based high throughput screening for evaluation of genotoxicity of pesticides in a human thyroid cell lines.
Genotoxicity is thought to be the cause of many cancers. Genotoxicity due to environmental toxins may be partly responsible for the dramatic increase in the incidence of papillary thyroid cancer over the past two decades. Study presents a fully automatable assay platform that directly quantifies the phosphorylation of nuclear histone gamma H2AX (γH2AX), a specific cellular marker for DNA double strand breaks (DSBs) via immunohistochemistry and laser scanning cytometry. It multiplexes γH2AX with total cell number measured as propidium iodide and calculates the percentage of cells with DSBs. Validation of this assay using NTHY-ori-3-1 human thyroid cells and etoposide showed that it was an excellent choice for high throughput applications. Study used the assay to test the genotoxic effects of the EPA Toxcast Phase 1 pesticide library of 309 compounds. Compounds were evaluated in dose response and the DSB was quantified. 19 pesticides induce DSB in vitro, highlighting a need to further assess these pesticides for their long-term oncogenic effects on the thyroid gland.
[Hershman JM, France B, Hon K, Damoiseaux R. 2017. Environ Mol Mutagen. doi: 10.1002/em.22103. ] - Effect of exposure to p,p´-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area.
Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy. To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy we analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models. Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (β=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis.Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy.
[Hernández-Mariano JÁ, Torres-Sánchez L, Bassol-Mayagoitia S, et al. 2017. Environ Res. 156:597-604.] - Environmental Issues in Thyroid Diseases.
Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves' disease and Graves' ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction.
[Ferrari SM, Fallahi P, Antonelli A, Benvenga S. 2017. Front Endocrinol (Lausanne). 8:50.] - Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.
Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. Study evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. Higher exposure to the insecticide aldrin was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01).Results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators..
[Lerro CC, Beane Freeman LE, DellaValle CT. et al. 2017. Occup Environ Med. pii: oemed-2017-104431.] - EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
[Gore AC, Chappell VA, Fenton SE, Flaws JA, et al. 2015. Endocr Rev. 36(6):E1-E150.] - Serum Biomarkers of Exposure to Perfluoroalkyl Substances in Relation to Serum Testosterone and Measures of Thyroid Function among Adults and Adolescents from NHANES 2011–2012
Perfluoroalkyl substances (PFASs) are a group of environmentally-persistent chemicals that have been widely used in many industrial applications. There is human and animal evidence that PFASs may alter levels of reproductive and thyroid-related hormones. However, human studies on the potential age-related effects of PFASs on these outcomes among males and females are limited. We explored the relationship between serum PFASs and serum total testosterone (T), thyroid stimulating hormone (TSH), and free and total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4) among males and females 12 to 80 years of age from the 2011–2012 cycle of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models that were stratified on sex and age categories. Effect estimates from the majority of the adjusted models were not statistically significant. However, exposure to PFASs may be associated with increases in FT3, TT3, and FT4 among adult females, but during adolescence, PFASs may be related to increases in TSH among males and decreases in TSH among females. No significant relationships were observed between PFASs and T in any of the models. These findings suggest that exposure to PFASs may disrupt thyroid hormone homeostasis.
[Lewis, R.C., Johns, L.E. and Meeker, J.D. (2015) Serum biomarkers of exposure to perfluoroalkyl substances in relation to serum testosterone and measures of thyroid function among adults and adolescents from NHANES 2011-2012, International journal of environmental research and public health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483690/. ] - Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study
Objective: Thyroid dysfunction is associated with impaired cognitive development. Perchlorate decreases thyroidal iodine uptake, potentially reducing thyroid hormone production. It is unclear whether perchlorate exposure in early life affects neurodevelopment.Design: Historical cohort analysis.
Patients: From 2002 to 2006, 21,846 women at gestational age
Main outcome measures: Maternal urinary perchlorate, offspring IQ.
Results: Urine perchlorate was detectable in all women (median 2.58 μg/L); iodine levels were low (median 72 μg/L). Maternal perchlorate levels in the highest 10% of the population increased the odds of offspring IQ being in the lowest 10% OR = 3.14 (95% CI 1.38, 7.13) P = .006 with a greater negative impact observed on verbal OR = 3.14 (95% CI 1.42, 6.90) P = .005 than performance IQ. Maternal levothyroxine therapy did not reduce the negative impact of perchlorate on offspring IQ.
Conclusions: This is the first study using individual-level patient data to study maternal perchlorate exposure and offspring neurodevelopment and suggests that high-end maternal perchlorate levels in hypothyroid/hypothyroxinemic pregnant women have an adverse effect on offspring cognitive development, not affected by maternal levothyroxine therapy. These results require replication in additional studies, including in the euthyroid population.
[Taylor, P. et al. (2014) Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study, The Journal of Clinical Endocrinology and Metabolism. Available at: https://pubmed.ncbi.nlm.nih.gov/25057878/.] - Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review.
This study provides an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited.
[de Cock M, Maas YG, van de Bor M. 2012. Acta Paediatr. 101(8):811-8] - Autism: Transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents
The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8–12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus–pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism.
[Román, G, C. 2007. Journal of the Neurological Sciences; 262(1-2), pp 15-26]