Trichloroethylene and Parkinson’s disease: dissolving the puzzle

Goldman, Samuel

doi:10.1586/ern.10.61

Cited by 27 publications

(16 citation statements)

References 32 publications

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“…In fact, there is an association of Parkinson’s Disease in humans with TCE exposure 84–88 with up to a six-fold increased risk in one study 89 . TCE exposure studies using animal models provide further evidence for a toxicological role for CYP2E1 activtiy 87, 90 .…”

Section: Exogenous Substrates Of Cyp2e1 That Damage Mitochondriamentioning

confidence: 95%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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Cytochrome P450 2E1 (CYP2E1) metabolizes an extensive array of pollutants, drugs, and other small molecules, often resulting in bioactivation to reactive metabolites. Therefore, it is unsurprising that it has been the subject of decades of research publications and reviews. However, while CYP2E1 has historically been studied in the endoplasmic reticulum (erCYP2E1), active CYP2E1 is also present in mitochondria (mtCYP2E1). Relatively few studies have specifically focused on mtCYP2E1, but there is growing interest in this form of the enzyme as a driver in toxicological mechanisms given its activity and location. Many previous studies have linked total CYP2E1 to conditions that involve mitochondrial dysfunction (fasting, diabetes, non-alcoholic steatohepatitis, and obesity). Furthermore, a large number of reactive metabolites that are formed by CYP2E1 through metabolism of drugs and pollutants have been demonstrated to cause mitochondrial dysfunction. Finally, there appears to be significant inter-individual variability in targeting to the mitochondria, which could constitute a source of variability in individual response to exposures. This review discusses those outcomes, the biochemical properties and toxicological consequences of mtCYP2E1, and highlights important knowledge gaps and future directions. Overall, we feel that this exciting area of research is rich with new and important questions about the relationship between mtCYP2E1, mitochondrial dysfunction, and pathology.

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Section: Exogenous Substrates Of Cyp2e1 That Damage Mitochondriamentioning

confidence: 95%

Toxicological implications of mitochondrial localization of CYP2E1

2017

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“…1 Exposure to pesticides and industrial agents has been associated with an increased risk for PD [17, 18], but to date none of these agents have been consistently identified as a causal factor for PD [19]. It is known that exposure to inhibitors of mitochondrial respiration [20–25] are sufficient to induce PD symptoms in humans and DA neurodegeneration in animal models.…”

Section: Neurodegeneration In Parkinson’s Disease Arises From Dysregumentioning

confidence: 99%

Integrating Pathways of Parkinson's Disease in a Molecular Interaction Map

et al. 2013

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Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at http://minerva.uni.lu/pd_map.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-013-8489-4) contains supplementary material, which is available to authorized users.

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“…Solvents have most often been examined epidemiologically as a single, aggregate category, and the effects of particular solvents have rarely been assessed; given that solvents represent a very large group of disparate compounds, any true association between PD and a particular agent (e.g. TCE) could be obscured (Goldman 2010 ;Goldman et al 2012a ). Exposure assessment methods are very limited, and are likely to misclassify exposed individuals.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

“…Exposure misclassifi cation also presents a problem, as recognition and/or recollection of exposures may be poor. Estimation of dose can also be challenging (Goldman 2010 ), limiting our ability to detect any dose-response effects. In addition, solvent exposures are unlikely to occur in isolation, making it diffi cult to tease apart effects specifi cally attributable to TCE.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Role of Trichloroethylene in Parkinson’s Disease

Goldman

Cash

2014

Trichloroethylene: Toxicity and Health Risks

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, primarily affecting older adults. Given the projected growth and aging trend of the population, the prevalence of PD is expected to double by the year 2040, highlighting the imperative need for a better understanding of the disease. It is generally accepted that the development of idiopathic PD is multifactorial, involving both genetic and environmental factors; however, relatively little is known about specifi c exposures. An association between TCE exposure and increased PD risk has been suggested by several case reports/clusters, and recently, the fi rst epidemiologic study found a signifi cant six-fold increased risk of PD associated with occupational TCE exposure. Data from animal studies also support a plausible mechanistic pathway, with rodent models demonstrating TCE-induced neurotoxic effects similar to those occurring in PD. Given that TCE is ubiquitous, even a modest increased risk could have enormous population-level neurological health implications.

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Trichloroethylene and Parkinson’s disease: dissolving the puzzle

Cited by 27 publications

References 32 publications

Toxicological implications of mitochondrial localization of CYP2E1

Toxicological implications of mitochondrial localization of CYP2E1

Integrating Pathways of Parkinson's Disease in a Molecular Interaction Map

Role of Trichloroethylene in Parkinson’s Disease

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