Parkinson's disease, pesticides and individual vulnerability

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Abstract

Current theories suggesting that degeneration of the nigrostriatal pathway following pesticide exposure could be a cause of Parkinson's disease (PD) are supported by epidemiological data linking environmental factors to an increased risk of parkinsonism. PD in humans is therefore thought to be a function of genetic predisposition, potentially associated with how efficiently an individual is able to metabolize dopamine-related neurotoxins. However, meta-analyses of susceptibility studies have failed to demonstrate clear-cut links between polymorphisms of xenobiotic-metabolizing enzymes (XMEs) and PD. We hypothesize that PD-related vulnerability to pesticides is linked to a strictly personal ‘chemico–genetic XME blend’ involving many variables. Innate XME genetic fingerprints undergo acquired ‘modulations’, which in turn are influenced by a myriad of individual exposures to chemical mixtures of environmental pollutants. We make a series of suggestions for the design of susceptibility studies focusing on persistent exposure to a specific pesticide in genetically defined population subsets of workers and gardeners within a geographically defined area.

Section snippets

Chemical aspects: the dual nature of all XMEs and the wide variety of alternative metabolic pathways

XMEs constitute a battery of enzymes (or enzyme-related systems) that play a central role in the response of cells to ‘stress’ chemicals by catalysing detoxicating or toxicating reactions. Unfortunately, the complexity of their molecular mechanisms is often ignored. The conventional distinction between universally harmful ‘activating’ (i.e. phase I) XMEs and universally beneficial ‘detoxificating’ (phase II or III) XMEs is now irrevocably dated. Any XME can either activate or detoxify different

Innate genetic aspects: individual combinations of XME polymorphisms

Another important set of variables in the metabolism of xenobiotics is related to the infinite number of possible combinations of human genetic XME polymorphisms that contribute to our so-called ‘metabolic fingerprint’.

Polymorphic phase I human XMEs include many cytochrome P450 enzymes (CYP1A1, 1A2, 1B1, 2A6, 2A13, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5, 3A7, 4B1, 5A1, 8A1 and 21), flavin-containing monooxygenase 3, MAO, paraoxonase, epoxide hydrolase, NAD(P)H:quinone oxido-reductase,

Acquired aspects: individual XME gene expression

The acquisition of modifications to the expression of individual genes encoding XMEs also inevitably affects the metabolism of different xenobiotics. Within the cell, xenobiotics can bind to specific cytosolic ‘xenosensors’ and induce (either specifically or nonspecifically) signal transduction events that can lead to different physiological and pharmacological responses, including cell homeostasis, proliferation, differentiation, apoptosis or necrosis [39]. The function of XMEs is highly

A preliminary working model

Taken together, the three sets of variables (chemical, innate and acquired) outlined above suggest a preliminary model that can help to explain the almost infinite variety of personal XME modulations present in real-life situations. Acquired modulation of XME gene expression will be determined by both lifestyle and dietary factors (e.g. smoking, drinking, consumption of meat and vegetables and consumption of drugs) and characteristic environmental and workplace exposures (including rural-living

Implications for susceptibility studies

We have advanced the hypothesis that PD-related vulnerability to pesticides is linked to a strictly personal ‘chemico–genetic XME blend’. In summary, our innate XME genetic fingerprints undergo acquired ‘modulations’, which in turn are influenced by an almost infinite variety of individual exposures to chemical mixtures of environmental pollutants. These modulations will occur in relation to the dual detoxicant–toxicant nature of each XME. Eventual biotransformation outcomes will also be

Prospects for the future

Analysis of complete individual XME phenotypes is not currently feasible. However, the effects of potential up- and downregulators of genes encoding XMEs in addition to typical direct XME inhibitors (e.g. grapefruit juice toward CYPs or alcohol toward GSTP1) make measurement of functional parameters (the phenotype of interest) highly desirable. The few available multiple analyses (e.g. cocktail strategy) seem to be inadequate for this purpose. Nevertheless, advances in biotechnology should

Acknowledgements

This work was supported by an Alma Mater Studiorum–University of Bologna grant. We are grateful to Robin M.T. Cooke for scientific editing.

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