Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease
Identifieur interne : 000C14 ( Main/Exploration ); précédent : 000C13; suivant : 000C15Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease
Auteurs : Arthur G. Fitzmaurice [États-Unis] ; Shannon L. Rhodes [États-Unis] ; Myles Cockburn [États-Unis] ; Beate Ritz [États-Unis] ; Jeff M. Bronstein [États-Unis, Canada]Source :
- Neurology [ 0028-3878 ] ; 2014.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Pesticide.
English descriptors
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.
Affiliations:
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Bronstein</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Department of Neurology, David Geffen School of Medicine at UCLA</s1><s2>Los Angeles</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Molecular Toxicology, University of California</s1><s2>Los Angeles</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Parkinson's Disease Research, Education, and Clinical Center, Greater Los Angeles Veterans Affairs Medical Center</s1><s2>Los Angeles</s2><s3>CAN</s3><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Nervous system diseases</term><term>Parkinson disease</term><term>Pesticides</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Maladie de Parkinson</term><term>Pathologie du système nerveux</term><term>Pesticide</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Pesticide</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Californie</li></region><settlement><li>Los Angeles</li></settlement></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Fitzmaurice, Arthur G" sort="Fitzmaurice, Arthur G" uniqKey="Fitzmaurice A" first="Arthur G." last="Fitzmaurice">Arthur G. Fitzmaurice</name></region><name sortKey="Bronstein, Jeff M" sort="Bronstein, Jeff M" uniqKey="Bronstein J" first="Jeff M." last="Bronstein">Jeff M. Bronstein</name><name sortKey="Bronstein, Jeff M" sort="Bronstein, Jeff M" uniqKey="Bronstein J" first="Jeff M." last="Bronstein">Jeff M. Bronstein</name><name sortKey="Cockburn, Myles" sort="Cockburn, Myles" uniqKey="Cockburn M" first="Myles" last="Cockburn">Myles Cockburn</name><name sortKey="Fitzmaurice, Arthur G" sort="Fitzmaurice, Arthur G" uniqKey="Fitzmaurice A" first="Arthur G." last="Fitzmaurice">Arthur G. Fitzmaurice</name><name sortKey="Rhodes, Shannon L" sort="Rhodes, Shannon L" uniqKey="Rhodes S" first="Shannon L." last="Rhodes">Shannon L. Rhodes</name><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name><name sortKey="Ritz, Beate" sort="Ritz, Beate" uniqKey="Ritz B" first="Beate" last="Ritz">Beate Ritz</name></country><country name="Canada"><region name="Californie"><name sortKey="Bronstein, Jeff M" sort="Bronstein, Jeff M" uniqKey="Bronstein J" first="Jeff M." last="Bronstein">Jeff M. Bronstein</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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