Gene-pesticide interactions linked to Parkinson’s disease

Date:03-12-2009

Pesticide exposure and genetic variability in the dopamine transporter (DAT), a protein that plays a central role in dopaminergic neurotransmission of the brain, interact to significantly increase the risk factor for Parkinson’s disease, according to a new study by University of California, Los Angeles (UCLA) researchers. The population based case-control study, “Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease,” builds on the existing body of evidence of animal data and epidemiological studies that link exposure to pesticides, including gene-pesticide interactions, to Parkinson’s disease. The UCLA researchers, looking at incident Parkinson’s disease cases in three rural counties in Central California, find DAT increases the risk of Parkinson’s when individuals have occupational or residential exposure to pesticides. This is the first epidemiologic study of Parkinson’s disease that relies on pesticide data that is from a record-based source versus recall-based data relying on individuals’ memory.

The second most common neurodegenerative disease affecting more than one million people in the U.S., Parkinson’s disease occurs when nerve cells in the substantia nigra region of the brain are damaged or destroyed and can no longer produce dopamine, a nerve-signaling molecule that helps control muscle movement.

The new UCLA study is based on 324 cases and 334 control subjects that contributed risk factor and genetic data and genotyped for the DAT variants. For residential exposures, the researchers used a GIS computer model based on California state required Pesticide Use Reporting data, land use maps, and residential histories, estimating both maneb and paraquat exposure near study subjects’ homes. Estimates were also calculated for agricultural occupational maneb and paraquat exposure. Fifteen percent of the study subjects are considered both occupationally and residentially highly exposed to maneb and paraquat.

According to the study, an individual can have up to four DAT susceptibility alleles, two copies of the A clade 5’ region and two copies of the 9-repeat 3’VNTR. After assessing the interactions between exposure to both pesticide measures and the number of DAT susceptibility alleles, the researchers find that Parkinson’s patients are more likely to have been exposed to pesticides. High residential exposure to both paraquat and maneb between 1974 and 1999 more than doubled the risk of the disease, while occupational exposure increased the risk around 50 percent. When assessing the cumulative effect of susceptibility alleles, the researchers find a 50 percent increase in risk for carriers of more than two DAT susceptibility alleles as well as an allele dosage effect with increasing number of susceptibility alleles. High residential exposure to maneb and paraquat increased risk almost 3-fold in individuals who have one DAT susceptibility allele and 4.5 fold in those with two or more susceptibility alleles. Researchers do not believe that DAT susceptibility allele(s) are impacting risk for those not exposed to maneb and paraquat.

Paraquat and maneb have previously been linked to Parkinson’s disease. University of Rochester scientists discovered that the synergistic effects of paraquat and maneb target the nigrostriatal dopamine system and indicate progressive neurotoxicity with continuing exposure. Their findings show that while there are no or only marginal effects when these chemicals are administered individually, together they produce synergistic effects when given in combination. In another study, these researchers again chronically expose mice to a low-level combination of paraquat and maneb, resulting in significant reductions in locomotor activity, levels of striatal dopamine and dopaminergic neurons in the substantia nigra, more so than when exposed individually.

 laboratory study finds that “prenatal exposure to the pesticide maneb produces selective, permanent alterations of the nigrostriatal dopaminergic system and enhances adult susceptibility to paraquat exposure.” Additional studies show that exposure to maneb and paraquat during the post-natal and juvenile period causes Parkinson-like declines in dopaminergic neurons and makes the substantia nigra more susceptible to additional exposures in adulthood, “suggesting that developmental exposure to neurtoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.”