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, diabetes, cardiovascular disease, obesity, early puberty, infertility and other reproductive disorders, and childhood and adult cancers.
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.
- 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.]
- 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.]
- 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.]
- 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. ]
- 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. 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]
- 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]
- 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. ]
- 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.]