03
May
Parkinson’s Disease Explodes as Researchers Find Connection to Pesticide Exposure and Genes
(Beyond Pesticides, May 3, 2024) Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer’s. Genetic factors account for only a fraction of PD cases, and for decades scientists have been aware of associations between pesticide exposures and PD. Yet, not everyone exposed to pesticides gets PD. Consequently, neither the genetic nor the environmental hypothesis is fully satisfactory; both may be involved. Thus, there has been great interest in identifying gene variants that affect the risks of PD associated with pesticide exposure.
Now a team of University of California at Los Angeles researchers led by neurologist Brent Fogel, MD, PhD has traced a connection between certain gene variants and the occurrence and severity of PD in a cohort of central California PD patients who have had long-term exposure to pesticides. The genes are related to autophagy, the process by which cells organize, degrade, recycle or eject molecules to maintain healthy chemical balance. Autophagy is an essential process throughout the body, including regulation of mitochondria, which are also vital for healthy cellular function. The study supports other research suggesting that autophagy is disturbed in neurodegenerative diseases.
As Beyond Pesticides discussed in its April 19 Daily News, PD features the accumulation of Lewy bodies in dopaminergic neurons, the nervous system cells most dysfunctional in PD. Lewy bodies are clumps of alpha-synuclein, a protein that, if not removed from neurons when no longer useful, may impede their signaling. This can lead to motor, sleep, behavioral, and other disorders. Lewy bodies are just the kind of problem autophagy should correct, so malfunctioning autophagy could contribute to PD progression.
In the current study, the researchers started with the Parkinson’s Environment and Genes (PEG) data from 757 PD patients who have been followed for decades. The participants in PEG are from California’s Central Valley. Sixty-two percent of the PEG cohort are male; the average age at diagnosis is 67.7 years. PEG includes the details of the patients’ disease onset, progression and severity, as well as their residential and work locations throughout their lives. The patients have also been screened for genetic mutations in genes known to be associated with PD.
The researchers combined the PEG data with land use data and the California Pesticide Use Report (PUR) system, which requires commercial agricultural pesticide users to report the details of pesticide applications, including date, method, location, poundage, type of crop and acreage.
This enabled the researchers to identify a subset of PD patients with known long-term pesticide exposures. They further refined their patient pool to select a group that had been exposed to the “cotton cluster” of pesticides. The cotton cluster includes organoarsenic pesticides, organophosphorus pesticides, and n-methyl carbamates, all of which have “strong epidemiologic association with Parkinson’s disease,” according to the researchers.
The authors single out cacodylic acid, a pesticide in the cotton cluster. This pesticide is an example of the EPA’s regulatory negligence. It is an arsenic compound. Arsenic, an element, is never good for living organisms, but is very common in the Earth’s crust. Cacodylic acid was first used as a pesticide in 1867 in a compound called Paris green, which was also used as a pigment in wallpaper and clothing, resulting in thousands of illnesses and deaths. Its carcinogenicity was suspected as early as 1887. Under the name “Agent Blue,” cacodylic acid was a principal means of killing rice during the Vietnam War—part of the “rainbow” of chemicals, along with Agent Orange, that defoliated much of Vietnam and led to generations of health problems in military veterans.
Despite a long historical record of arsenic compounds’ toxicity, most research has focused on its carcinogenicity rather than its neurological effects. Usage in agriculture has decreased, but EPA declined in its 2006 reregistration review to evaluate one of the still-used arsenic compounds for carcinogenicity. In 2009 EPA canceled registrations for organic arsenical herbicides but continued registration for monosodium methanearsonate (MSMA) on cotton, sod farms, golf courses and highway verges.
Progress has been made against other arsenic compounds. In 2015, after a lawsuit filed by the Center for Food Safety (CFS) and eight other organizations, FDA removed the last of three arsenic drugs from the market; the first two had been voluntarily removed by manufacturers in 2013. The three drugs had been used on chickens, turkeys and pigs to induce “faster weight gain” and create a “healthy color in meat from chickens and turkeys,” according to the CFS. Chromated arsenical manufacturers phased out those chemicals’ use as wood preservatives in 2003, but EPA still allows them to be used on certain wooden parts of buildings.
However, these improvements do not solve the problem with arsenic. Arsenic compounds do not sequester quickly in the environment (as an element, arsenic never breaks down). They are common in air; about two-thirds of atmospheric arsenic derives from human sources such as burning fossil fuels, ore smelting, and pesticides. Thus the legacy of arsenic pesticides is like that of lead, DDT and PCBs—it keeps giving generation after generation.
Arsenic promotes the aggregation of proteins such as alpha-synuclein into Lewy bodies in PD patients’ neurons. In a healthy cell, autophagy would remove Lewy bodies by engulfing them in lysosomes, where they would be taken apart and ejected from the cell. Because lysosomes are crucial to the process, genes known to be important for lysosomal function are of particular interest. If autophagy is inhibited and lysosomes are faulty, PD and other neurodegenerative diseases may progress.
For the current study, the researchers selected 85 genes associated with PD risk in the cotton cluster-exposed group. Of these, they focused on lysosomal genes because they knew such genes are overrepresented in the neurons of patients exposed to the cotton cluster pesticides and might be a locus of disease.
The researchers found that, in fact, nearly three quarters of the PD-associated gene variants in the cotton cluster-exposed PD patients were involved in lysosomal processes, including autophagy, and were not functioning properly. They interpreted this to mean that people carrying these gene variants have an “underlying susceptibility” to exposure to pesticides which, in turn, raises their risk of developing PD. Their neurons would not be able to properly clear Lewy bodies.
The authors also expressed concern about the other pesticides in the cotton cluster. Some are already linked to mitochondrial dysfunction and the proliferation of reactive oxygen species, which itself may trigger autophagy. For example, in laboratory studies the herbicide trifluralin interfered with mitochondria in neurons descended from those in PD patients, and its toxicity is enhanced when applied with other pesticides. Prometryn, a persistent herbicide harmful to fish, and phorate, an insecticide, damage mitochondria and have been associated with PD risk.
Organophosphorus compounds are associated with many health effects ranging from cancer to asthma and diabetes; both organophosphates and n-methyl carbamates are severe neurological toxins, interrupting the acetylcholinesterase signaling pathways in the nervous systems of everything from insects to humans. But they may have a more direct influence on PD induction: a 2024 Alzheimer’s study found that TDCIPP, an organophosphorus flame retardant, disrupts the proper formation of lysosomes.
Because some research shows that the organophosphorus pesticides chlorpyrifos and malathion, as well as the bipyridylium herbicide paraquat, affect lysosomes, the UCLA researchers also recommend further analysis of gene variants’ relationship with exposure to these pesticides.
One of the UCLA study’s coauthors, Kimberly Paul, PhD notes in a press release that Parkinson’s disease is the fastest-growing neurodegenerative disease in the world. Considering this growing prevalence, and the emerging evidence that pesticides are major contributors to it, regulation of the pesticides considered in the current study should be dramatically increased. In fact, elimination of pesticides would reduce the risk of not only neurodegenerative diseases but a wide range of modern human afflictions. The cost of managing chronic and degenerative diseases that are preventable, or at least mitigable, by transition to organic agriculture will certainly exceed the costs of growing food, livestock, and plant and animal materials without pesticides. Beyond Pesticides notes, “There is no conceivable economic rationale that outweighs the burdens suffered by exposed populations—a group that includes everyone.”
All unattributed positions and opinions in this piece are those of Beyond Pesticides.
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