Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease

Abstract

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.Conclusion: 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. Parkinson disease (PD) is characterized primarily by death of dopaminergic neurons in the substantia nigra pars compacta, 1 although the reason(s) for this selective vulnerability remains the subject of research. Rare mendelian and high-risk genes as well as common but low-risk genetic variants detected by genome-wide association studies account for only a small percentage of cases, 2 so environmental factors almost certainly have an important role. Pesticide exposure has surfaced as a prominent environmental risk factor in PD, [3][4][5][6] and possible modifications of pesticide associations by genetic variants have been reported, 7-10 but the mechanisms through which pesticides contribute to PD pathogenesis remain to be elucidated. We recently reported that the fungicide benomyl was associated with increased PD risk and damaged dopaminergic neurons by inhibiting aldehyde dehydrogenase (ALDH) enzyme activity in vitro and in vivo. 11Because ALDH detoxifies the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), its inhibition offers a potential mechanism for the preferential loss of dopaminergic neurons in PD. The present work investigates this mechanism further by identifying several ALDH-inhibiting *These authors contributed equally to this work.

Reactive dopamine metabolites and neurotoxicity

“…In 2014, Fitzmaurice et al concluded that individuals who expressed a variant of the ALDH2 and ALDH2 genes 159 were associated with exacerbated PD risk when exposed to ALDH-inhibiting compounds, 67 However, benomyl bioaccumulates within tissues, and workers exposed to benomyl at multiple work and home locations had an increased PD risk than exposure at just one location. The link between benomyl exposure and PD was attributed to alteration of DA homeostasis and ALDH inhibition 70 (Scheme 5.1).…”