Inhibition of aldehyde detoxification in CNS mitochondria by fungicides

Leiphon, Laura J.; Picklo, Matthew J.

doi:10.1016/j.neuro.2006.08.008

Cited by 40 publications

(34 citation statements)

References 37 publications

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“…Several reports have indicated that exposed workers showed an incidence of various neurologic effects and of Parkinson-like symptoms significantly increased respect to control group [134,135]. Recently, it has been evidenced that maneb and mancozeb inhibited the activity of rat aldheyde dehydrogenates ALDH2 and ALDH5, enzymes found in brain mitochondria and involved in the detoxification of lipid peroxidation [136]. In addition, Domico and coworkers [137] demonstrated that both maneb and mancozeb produced toxic effects in cultured rat GABA and DA neurons [137].…”

Section: Ebctds: Mancozeb Maneb Zinebmentioning

confidence: 99%

The Effects of the Endocrine Disruptors Dithiocarbamates on the Mammalian Ovary with Particular Regard to Mancozeb

Cecconi

Paro²,

Rossi³

et al. 2007

CPD

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Many human-made chemicals are called endocrine disruptors (EDs) because they have the potential to disrupt endocrine functions in exposed organisms. Many EDs can disrupt hormonal homeostasis by interfering with hormone receptor recognition, binding and activation, while others act by still unknown mechanisms. Among the EDs specifically affecting the female reproductive system, those with steroidogenic/antisteroidogenic effects have been extensively studied and the mechanisms of toxicity clarified also at molecular level. For many others, information is restricted to few epidemiological data and in vivo/in vitro experiments with animal models. This is the case of the dithiocarbamates, and in particular of the fungicide mancozeb, an ethylenedithiocarbamate widely used to protect fruit and vegetables, ginseng included, because of its low acute toxicity in humans. Although the mechanism(s) by which mancozeb may specifically act on female reproductive organs are largely unknown, data on experimental animals in vivo have demonstrated that the fungicide can induce several disturbances on estrus cycle. When used in vitro at concentrations considered too low to cause human health injuries, the fungicide impairs mouse embryo development and meiotic spindle assembly. The possibility that the female germ cell (the oocyte) could be a specific target of mancozeb suggests a role for this fungicide as probable inductor of infertility also in exposed human populations.

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Section: Ebctds: Mancozeb Maneb Zinebmentioning

confidence: 99%

The Effects of the Endocrine Disruptors Dithiocarbamates on the Mammalian Ovary with Particular Regard to Mancozeb

Cecconi

Paro²,

Rossi³

et al. 2007

CPD

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“…Microtubule inhibitors disrupt the ubiquitin-proteasome system (UPS) (17) and cause selective dopaminergic cell damage and aggregation of α-synuclein, the predominant component of an intracytosolic Lewy body, which is the pathologic hallmark of PD (16). Furthermore, benomyl inhibits aldehyde dehydrogenase (ALDH) activity in liver and brain mitochondria (18,19), although ALDH inhibition has not been measured directly in brains in vivo. The mitochondrial-associated ALDH2 is of particular interest because it metabolizes toxic aldehydes in brain tissue, including the dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) (Fig.…”

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confidence: 99%

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Fitzmaurice

Rhodes²,

Lulla³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

178

141

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Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

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“…21−23 The catecholaldehyde hypothesis predicts straightforwardly that inhibition of MAO should attenuate pesticide-evoked cytotoxicity. This has been demonstrated for the insecticide rotenone with pathophysiological mechanisms involving mitochondrial dysfunction and oxidative stress 1−3 and for benomyl as an ALDH inhibitor.…”

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confidence: 99%

Benomyl, Aldehyde Dehydrogenase, DOPAL, and the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease

Casida

Ford

Jinsmaa

et al. 2014

Chem. Res. Toxicol.

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The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is detoxified mainly by aldehyde dehydrogenase (ALDH). We find that the fungicide benomyl potently and rapidly inhibits ALDH and builds up DOPAL in vivo in mouse striatum and in vitro in PC12 cells and human cultured fibroblasts and glial cells. The in vivo results resemble those noted previously with knockouts of the genes encoding ALDH1A1 and 2, a mouse model of aging-related Parkinson’s disease (PD). Exposure to pesticides that inhibit ALDH may therefore increase PD risk via DOPAL buildup. This study lends support to the “catecholaldehyde hypothesis” that the autotoxic dopamine metabolite DOPAL plays a pathogenic role in PD.

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Inhibition of aldehyde detoxification in CNS mitochondria by fungicides

Cited by 40 publications

References 37 publications

The Effects of the Endocrine Disruptors Dithiocarbamates on the Mammalian Ovary with Particular Regard to Mancozeb

The Effects of the Endocrine Disruptors Dithiocarbamates on the Mammalian Ovary with Particular Regard to Mancozeb

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

Benomyl, Aldehyde Dehydrogenase, DOPAL, and the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease

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