Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease.
OBJECTIVE
The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study.


METHODS
A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation.


RESULTS
All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides.


CONCLUSIONS
ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression.
From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles; Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles; Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles; and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
Arthur G
AG
Fitzmaurice
Shannon L
SL
Rhodes
Myles
M
Cockburn
Beate
B
Ritz
Jeff M
JM
Bronstein
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000831:Animals, Newborn; D016022:Case-Control Studies; D004781:Environmental Exposure / Q000009:adverse effects*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D010575:Pesticides / Q000009:adverse effects* / Q000633:toxicity; D011159:Population Surveillance / Q000379:methods*; D051381:Rats
D010575:Pesticides; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial