Mechanism for pesticide effect on PD risk uncovered

By Eleanor McDermid, Senior medwireNews Reporter

Some pesticides may contribute to Parkinson’s disease (PD) risk by inhibiting neuronal aldehyde dehydrogenase (ALDH) activity, a study suggests.

Furthermore, genetic variation in the ALDH2 gene may mediate the level of risk associated with exposure to these chemicals, show the findings published in Neurology.

The researchers found that dithiocarbamates, specifically those that exist as metal coordination complexes, significantly inhibited ALDH activity in suspensions of rat neuronal cells. Six of seven dithiocarbamates tested inhibited ALDH activity, by up to 20%. The only one that had no effect is not a metal coordination complex.

An additional five pesticides from three other structural classes (imidazole, dicarboxymide and organochlorine), of a total 26 chemicals and eight classes tested, also inhibited ALDH activity.

Jeff Bronstein (David Geffen School of Medicine at UCLA, Los Angeles, USA) and team then used Pesticide Use Reporting records and lifetime address histories to calculate cumulative exposure to the 11 ALDH-inhibiting pesticides among 360 cases and 816 controls from the Parkinson’s Environment & Genes Study (PEG).

Exposure was associated with increased risk of PD for most pesticides individually, and the risk rose with exposure to increasing numbers of ALDH-inhibiting pesticides, with exposure to three or more pesticides at home as well as at the workplace associated with a 3.54-fold risk increase.

“Although it would be intriguing to attribute causation to one or more specific ALDH-inhibiting pesticides, this would be overreaching because very few subjects were exposed to only one ALDH-inhibiting pesticide, and exposures to the pesticides in our epidemiologic study were highly correlated,” the researchers comment.

This association was strongly linked to ALDH2 variation, which the team assessed by determining ALDH2 haplotypes for all participants and grouping these into two clades, based on shared ancestry. They found that the association between PD risk and pesticide exposure disappeared among participants who were homozygous for one of the clades, but was strengthened among those homozygous or heterozygous for the other clade.

Variation in ALDH2 was not associated with PD in the absence of ALDH-inhibiting pesticide exposure, the team notes.

Bronstein et al say the various chemical structures of the pesticides that inhibit ALDH “suggest several mechanisms through which pesticides might contribute to PD pathogenesis via ALDH inhibition, revealing multiple possible therapeutic targets to reverse disease progression.”

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