Functional Assessment of Genetic Factors That Moderate Methylmercury Toxicity in Humans

Glutathione (GSH) is a major first line of defense against MeHg toxicity. Several genes are involved in the synthesis and metabolism of GSH, which, in the realm of MeHg metabolism, we refer to collectively as the “GSH axis”. Both direct and indirect activities of GSH are implicated in offsetting MeHg toxicity.  First, the MeHg-GSH conjugate is a pre-requisite complex in direct mechanisms of excretion. Next, GSH plays an indirect role with its well-known activity in combating the consequences of oxidative stress, a by-product of MeHg toxicity. Factors controlling the synthesis and fates of GSH are therefore predicted to be major determinants in MeHg tolerance and susceptibility.

We are assessing the function of enzymes and transporters known to modulate GSH levels and its activity in facilitating MeHg excretion.  Specifically, we are characterizing glutamyl-cysteine ligase subunits (GCLm\GCLc), transferase enzymes (e.g., glutathione-S-transferase pi, GSTP1), and transporters (multi-drug resistance like protein MRP\ABCC). With flies, we are investigating an organ-specific role (e.g. neurons vs. muscle) for these gene products during development in the context of MeHg toxicity.  Our studies are being conducted in parallel with collaborators at the Karolinska Institute, Sweden, and at the University of Rochester who are investigating genetic polymorphisms in human subjects within the Seychelles Child Development Study (SCDS).  The SCDS has investigated developmental outcomes of prenatal MeHg exposure in more than 1500 mother-child pairs.  Through a multi-investigator initiative genotypes of both the mothers and children in this cohort are being probed for polymorphic variants in numerous genes in the GSH axis and correlated with developmental outcomes in neurological domains.  In a recent study, using the expression of polymorphic variants of human GSTP1 in transgenic Drosophila, we find that GST activity can rescue flies against MeHg toxicity, however, the polymorphic variants show a lower specific activity.  Such studies are advancing our ability to identify people predisposed for susceptibility to MeHg toxicity.

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