Genes Plus Organochlorine Pesticides Equals Higher PD Risk
ARTICLE IN BRIEF
Investigators reported that farmers who had higher organochlorine exposure combined with mutant G267 had increased risk for PD.
In discussing etiology of neurodegenerative diseases, it is often said that genes load the gun, and the environment pulls the trigger. The truth of that statement is reinforced by a new discovery that shows the risk of Parkinson disease (PD) in French farmers is highest for those with long exposure to organochlorine pesticides who also possess an allele that encodes a poorer functioning protein at the blood-brain barrier. At the same time, the discovery may indicate how challenging it will be to identify all the different causes of PD.
Pesticides have been suspected from the earliest days of PD epidemiology, when rural living and drinking of well water were identified as risk factors. Two common pesticides, rotenone and paraquat, are used to induce parkinsonism in animal models.
“But we know that not everyone who is exposed to pesticides develops Parkinson disease,” said Alexis Elbaz, MD, PhD, senior author on the study in the June Archives of Neurology, and a researcher in the Neuroepidemiology unit of the Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, France. “It is more and more clear that susceptibility to pesticides may be in part genetic,” he said.
Previous work by Dr. Elbaz's group has shown that a poorer-functioning allele of the detoxification enzyme CYP2D6 was associated with PD among those exposed to pesticides, and another study implicated specific alleles of another gene, glutathione transferase, again only in those with pesticide exposure.
But much of the literature on pesticides and PD has been equivocal, Dr. Elbaz said, in part perhaps because it has been difficult to separate exposure to specific classes of compounds, and because of the lack of control groups in many studies.
Organochlorines are a powerful, and now largely banned, group of pesticides that include DDT and lindane. Some evidence suggests they may increase risk of parkinsonism through increasing free radicals or promoting protein aggregation. Organochlorines are substrates for P-glycoprotein, a transmembrane transporter that acts as an active efflux pump for a wide range of endogenous molecules and xenobiotics. P-glycoprotein is found on the luminal surface of blood capillaries in the blood-brain barrier and regulates intracerebral penetration of these compounds.
Previous work has linked poor P-glycoprotein function to PD, so Dr. Elbaz wondered whether the combination of organochlorine exposure and alleles for a less-functional form of P-glycoprotein might increase the risk of PD.
The study, led by Fabien Dutheil, PhD, drew 207 PD patients and 482 matched controls from a nationwide health expense reimbursement agency for agricultural workers in France. PD diagnosis was confirmed by a neurologist, and all subjects were genotyped for two alleles of the ABCB1 gene, which encodes P-glycoprotein. They found no association with PD for either allele, indicating that gene variation by itself was not enough to increase PD risk.
Next they assessed pesticide exposure among 101 PD patients and 234 controls. They administered a detailed questionnaire about occupational history and pesticide use both professionally and in home gardening. Data were gathered on types of pesticides, number of hours spent applying them, and application methods. Pesticides were grouped into one of 50 chemical families for analysis.
They found that regardless of genotype, professional exposure to organochlorines increased the risk of PD, with an odds ratio of 2.2 (95 percent confidence interval 1.1-4.5, p=0.02). There was no effect from exposure through home gardening.
Next they asked whether the combination of organochlorine exposure and possession of the less functional transporter alleles increased the risk of PD. One of the sites of variance on the gene is called G2677[A,T], with the G allele encoding a more active form of the protein and either the A or T allele encoding a less active form. Among farmers professionally exposed to organochlorines, possessing one copy of either the A or T allele was associated with an increased PD risk. Possessing two copies increased risk of PD by three and a half times compared to those with two copies of the G allele.
“Pesticides are a problem in people without either of the less functional alleles,” Dr. Elbaz said, “but the association is stronger in persons with the alleles.”
Among PD cases only, higher organochlorine exposure combined with the less functional alleles further increase PD risk.
For a second site of variance, called C3435T, which may also affect function of the transporter, the relationship was not as strong.
The results, Dr. Elbaz said, “add some plausibility to the idea that organochlorines may be involved in the cause of Parkinson disease, and it also explains a little bit better why some persons are more at risk.” But he cautioned that these results only apply directly to a small population. “It is important to realize that the people in this study have had very high levels of exposure, and were using pesticides for years and years at very high doses, in many instances without using protection,” he said. “These findings mean something for persons exposed professionally, but do not really apply to those who have used organochlorines for gardening,” or who have consumed them in food.
“This is a very interesting finding,” said Caroline Tanner, MD, director of clinical research at the Parkinson's Institute in Sunnyvale, CA, who was not involved with the study. “It illustrates why different individuals exposed to the same toxicant may not show the same effect. That's always been a concern for those who are skeptical about the role of toxic exposure — why doesn't everybody who is exposed develop PD?”
“It also illustrates the possible complexity of figuring this all out,” she said, given the large number of possible combinations of individual genes and individual toxicants.
However, she said, it is likely that some individual chemicals, and some genes, will be more important than others. Finding the genes, she suggested, may best be done by focusing on metabolic pathways known to be involved in pesticide handling.
Dr. Elbaz suggested that new pathways might be identified through a two-step process: a genomewide scan to find genes associated with PD, and then looking at the function of those genes in the lab to elucidate disease-related pathways.
Dr. Tanner noted that prior to this study, the evidence for an organochlorine role in PD has not been as robust as for some other pesticides. “Hopefully papers like this will push forward additional basic research,” both to identify gene-pesticide interactions, and to generate ideas about common mechanisms in other forms of PD.
Finally, she said, with the advent of personalized genotyping, “it may well be that, just like heart disease risk, you would get a genotype for metabolic processing genes to assess your risk of PD,” the results of which might be used to assess how careful the patient might need to be about exposure to known toxins.