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Increased Risk of Parkinson's Disease with PON1 Gene Variant and Pesticide Exposure

By Laura Hall
January 2010

Beate Ritz, M.D., Ph.D.
"Studying genetics alone or environment alone is like looking through only one eye — you have limited depth perception," explained Ritz. "What you observe is simpler because there are only two dimensions, but it is not an accurate representation of the world."
(Photo courtesy of Georges Mollon)

University of California, Los Angeles (UCLA) researchers report that study participants with two copies of a common gene variant showed an increased risk of Parkinson's disease (PD) when exposed to pesticides used in agriculture. NIEHS partially funded the epidemiologic study that focused on the paraoxonase 1 (PON1) gene, which codes for an enzyme that metabolizes organophosphate pesticides.

"Our research suggests that the impact of organophosphate exposure depends on the activity of a detoxifying enzyme produced by the body," said senior author Beate Ritz( Exit NIEHS, M.D., Ph.D. Ritz, professor and vice chair of the UCLA Epidemiology Department, co-directs the NIEHS-funded UCLA Center for Gene-Environment Studies in Parkinson's Disease.

The authors assessed pesticide exposure in a new way and showed that understanding gene-environment interaction is necessary to explain PD etiology.

PD etiology

PD is a progressive neurological movement disorder. Both genetic and environmental factors probably cause PD but usually are studied separately. The insecticides measured in the UCLA study( Exit NIEHS — the organophosphates diazinon, chlorpyrifos, and parathion — are neurotoxic and implicated in PD by earlier studies.

Pesticide exposure

The UCLA study used participants from three rural California counties known for extensive agricultural pesticide application. A large percentage of participants were exposed to the pesticides from living near agricultural areas.

After application, pesticides can drift in the air, be volatilized, and settle in water or soil. Humans and pets can bring pesticides into houses on clothing and fur. Although organophosphate pesticides have short half lives of a few days on foliage, other studies have shown they can concentrate 10 to 100 times higher indoors than outdoors and persist for months in the soil.

New approach to assess exposure

The authors used a novel, improved approach to determine agricultural exposure from different organophosphate pesticides. They assessed participant pesticide exposure using a geographic information system (GIS) tool, data from California Pesticide Use Reports, land-use maps, and geocoded residential historical locations. This approach allowed time-specific average exposure estimates for each participant and each study pesticide. The researchers determined agricultural exposure to diazinon, chlorpyrifos, and parathion between 1974 and 1999 separately for each subject.

"This GIS tool for determining exposure to pesticides is a vast and important improvement over the more traditional method of asking study participants to recall past exposure — a notoriously biased method of collecting exposure data that has been used by almost all previous studies of pesticides," Ritz explained.

Genetic variant and increased risk of PD

The genetic variant studied is fairly common in the Caucasian population. The variant has a methionine substitution for leucine at the amino acid position 55 of the PON1 protein. This substitution is known to decrease the protein's ability to metabolize certain pesticides. In the study group, 14 percent of the pesticide-exposed subjects and 10 percent of the control subjects had the genotype with two copies of the methionine PON1 variant — the MM PON1-55 genotype.

Individuals with the variant genotype have an increased risk of Parkinson's disease with exposure to specific insecticides. Participants with the MM PON1-55 genotype and exposed to diazinon or chlorpyrifos showed a twofold increased risk of Parkinson's disease (PD) compared to exposed subjects with wildtype genotype or only one variant copy or non-pesticide exposed subjects. The authors found no increased risk of PD with parathion exposure regardless of genotype.

Finding susceptible subpopulations

"Our findings highlight the importance of considering gene variants when studying the risk of environmental exposures," said first author Angelika Manthripragada, Ph.D., now an epidemiologist at the U.S. Food and Drug Administration. "More research is needed to examine the combined effect of environmental exposures with other PON1 gene mutations or variants of other genes involved in xenobiotic metabolism to gain further insight into PD etiology."

The authors pointed out that human genetic variations can cause some individuals to be more vulnerable to environmental exposures. Identifying these vulnerable subpopulations raises awareness of the potential need to protect these groups.

Citation: Manthripragada AD, Costello S, Cockburn MG, Bronstein JM, Ritz B( Exit NIEHS. 2010. Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease. Epidemiology 21(1):87-94.

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)

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