How Pesticides May Boost Parkinson's Risk

 

 

 

 

 

 

 

 

How Pesticides May Boost Parkinson's Risk

 

Pauline Anderson

February 06, 2014

 

Researchers have identified a mechanism by which exposure to pesticides might increase the risk for Parkinson's disease (PD).

Their new study shows that pesticides that inhibit aldehyde dehydrogenase (ALDH) activity can raise PD risk by up to 6-fold and that having a particular genetic predisposition also raises that risk.

"What's new about this report is that we have identified several pesticides currently being used that were previously unknown to inhibit ALDH activity, and we also identified variations in the ALDH gene, which helps determine sensitivity to these pesticides," said lead author Jeff M. Bronstein, MD, PhD, professor, neurology, and director, Movement Disorders, David Geffen School of Medicine, University of California at Los Angeles.

The authors stress the importance of protection for those who must be exposed to pesticides but also argue for removing toxic pesticides from the market. They also suggest possible therapeutic approaches to modulate ALDH enzyme activity that might reduce PD occurrence.

The study was published in the February 4 issue of Neurology.

 

PEG Study

The Parkinson's Environment & Genes (PEG) Study enrolls incident PD cases diagnosed within the previous 3 years as well as population controls from 3 rural California counties (Fresno, Tulare, and Kern). The current analysis included 360 cases and 816 controls who were interviewed by phone to collect demographic data and information on risk factors and history of where they had lived and worked.

The researchers had previously developed an assay that allows them to observe cellular activity of pesticide metabolites, which, according to Dr. Bronstein, are in many cases responsible for ALDH inhibition. Using neurons from the substantia nigra of newborn rats, the researchers tested neuronal activity upon exposure to 26 pesticides in this assay. They noted that several pesticides inhibited ALDH activity.

The ALDH-inhibiting pesticides fell into 4 structural classes.

Among the dithiocarbamates that coordinate as metal complexes, ziram was the most potent, inhibiting 20% of ALDH activity.

Of the imidazoles, benomyl inhibited ALDH by 30% and triflumizole by 13%.

The dicarboxymides captan and folpet inhibited ALDH activity by 18% and 17%, respectively, and the organochlorine dieldrin inhibited it by 8%. None of the screened carbamates, organophosphates, or triazines inhibited ALDH, nor did paraquat or propargite.

 

It's believed that ALDH inhibition occurs through a chemical called dihydroxyphenylacetaldehyde (DOPAL), which is made from dopamine.

 

The researchers calculated human pesticide exposure using a computer model that incorporates Pesticide Use Reporting records, mandated in California since 1974. The reporting system tracks the location, date, type, and amount of active ingredients in each commercial pesticide application.

 

 

"We know through validation studies we did some years ago that if you're within 500 meters of where a pesticide was sprayed, you show significant exposure, through inhalation or ingestion," said Dr. Bronstein.

 

The investigators totaled the number of pesticides to which participants were exposed either at work or at home or both. They assigned the participants to 1 of 3 groups: exposed to 3 or more pesticides, exposed to 1 or 2 pesticides, or unexposed to all ALDH-inhibiting pesticides.

 

Every ALDH-inhibiting pesticide identified in the screen and applied in the study area was found to be associated with increased PD risk. Exposure to an ALDH-inhibiting pesticide at both workplace and residential addresses was associated with a 65% (in the case of benomyl) to a 6-fold (in the case of dieldrin) increase in PD risk.

 

 

Exposure-Dependent Trend

 

When all ALDH-inhibiting pesticides and both workplace and residential addresses were considered, there was an exposure-dependent trend of increasing PD risk compared with participants not exposed to any of these pesticides. PD risk increased 3.5-fold (95% confidence interval, 1.51 - 8.30) with exposure to 3 or more pesticides.

"The more of these pesticides that people were exposed to, or the cumulative amount, the higher the risk," said Dr. Bronstein. "So if you were exposed to 6 of them, your risk was much higher than if you were exposed to 1 or 2 of them."

 

Although it would be "intriguing" to attribute causation to 1 or more specific ALDH-inhibiting pesticides, this would be "overreaching" because very few participants were exposed to only 1 ALDH-inhibiting pesticide and exposures to the pesticides were highly correlated, the authors write.

 

There were also associations between PD and presence of at least 1 copy of clade 2 in the ALDH2 gene, but only when considered along with the environmental factor. "When we looked at the polymorphisms in the ALDH gene, we found that by themselves, without exposure, they didn't confer any additional risk, but if you were exposed, it made a big difference," said Dr. Bronstein. "If you were exposed to a lot of pesticides, and you had one of these polymorphisms, your risk would be up to 6-fold higher than if you weren't exposed."

 

A 6-fold increase in risk is "huge," added Dr. Bronstein.

 

This observation goes a long way toward cementing the much-discussed but not yet proven theory that genes and the environment — in this case pesticide exposure — interact to contribute to PD pathogenesis.

 

 

Potential Targets

 

The authors indicate several potential targets for lowering PD risk, one of which is to inhibit the enzyme that makes DOPAL. Existing drugs on the market protect against pesticide toxicity. But only "fraction," perhaps 6%, of persons exposed to pesticides will get PD, said Dr. Bronstein.

"If we could identify that 6% and put those people on that [a drug that protects against pesticide toxicity], that might make a lot of sense," said Dr. Bronstein.

There are far too many variables to suggest that workers exposed to pesticides be tested for their genetic susceptibility to pesticide toxicity, he said.

 

Reducing pesticide exposure through such measures as enforcing regulations pertaining to handling of pesticides and wearing gloves and masks, for example, is "the most immediate and obvious thing to do" to reduce PD risk, said Dr. Bronstein.

 

Spraying techniques and approaches to farming that don't involve pesticides should also be investigated, he said. As well, he added, "we should systematically go through the pesticides and see which ones are the most dangerous based on modern studies and work to take them off the market," as has already been accomplished in some cases.

 

Samuel Frank, MD, associate professor, neurology, Boston University School of Medicine, Massachusetts, and member of the American Academy of Neurology, agrees. "I would hope that if there is evidence in the scientific literature about any type of toxin available anywhere, it would be removed from the market, but it doesn't always work that way."

As an example, he pointed to rotenone, produced naturally in roots of certain plant species, such as the jicama vine, which he said is considered an organic pesticide but is still sold in nurseries. "If you go into PubMed, you'll find that it's a toxin used to induce Parkinson models."

Dr. Frank praised the study for "tying together" past research on the contribution of both pesticide exposure and genetics, and for "putting very specific information on the framework" underlying the theory of a gene–environment connection in PD.

 

 

Study a "Milestone"

 

Medscape Medical News also invited Emanuele Cereda, MD, PhD, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, who has extensively studied pesticide exposure in PD, to comment on this study. Dr. Cereda said it can be considered a "milestone" in explaining the relationship between pesticide exposure and the risk for PD.

 

"There is now convincing evidence on a detrimental gene–environment interaction leading to PD neurodegeneration," he said.

 

In a recent unpublished study, Dr. Cereda and his colleagues assessed the effect of exposure to pesticides in the presence of a low- or high-risk genotype. "Interestingly, when pooling data from all studies focusing on a gene–environment interaction, regardless of the gene involved, we found a 1.5-fold and a 3-fold increase in risk in subjects carrying a low-risk and a high-risk genotype, respectively."

 

Dr. Cereda praised the new study for providing additional and important information on the role of cumulative pesticide exposure on PD risk. And he found the system the researchers used to estimate exposure of workers and residents and to assess genetic vulnerability "really helpful in clarifying the issue of a dose-response relationship."

As well, he added that the study "opens a new field of research" because it's clear now that pesticides have different mechanisms of action and don't just inhibit mitochondrial functions.

 

"There is still much work to be done, but the road taken is promising."

 

The study was funded in part by the National Institute of Environmental Health Science, the National Institute of Neurologic Disorders and Stroke, the Veterans Administration Healthcare System, the Michael J. Fox Foundation, the Levine Foundation, and the Parkinson Alliance. The authors and commentators have disclosed no relevant financial relationships.

 

Neurology. 2014;82:419-426. Abstract

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