Elucidating the behavior of an enzyme

Posted by / 22-Apr-2019 10:46

Our findings have important implications for understanding variation in Me Hg toxic potential on an individual basis and for informing the process of relating a measurement of Hg body burden to the potential for adverse developmental outcome.Methylmercury (Me Hg) is an environmental toxicant and contaminant of seafood that arises from both natural and anthropogenic sources.The underlying role of genetic background as a modifier of Me Hg toxicity has recently received great attention.Studies based in human populations have frequently focused on polymorphisms in genes related to the metabolism of glutathione (GSH) (Llop et al., 2015).We also find that global upregulation of GSH levels, with GCLc trans-gene expression, can induce Me Hg tolerance and reduce Hg body burden.However, we demonstrate that Me Hg tolerance can also be achieved independently of reducing Hg body burden, in both wild-derived strains and with targeted expression of GCLc in developing neuronal and muscle tissue, pointing to a robust toxicodynamic mechanism.These mechanisms predict that polymorphisms affecting GSH synthesis, conjugation, and/or redox status could manifest differences in both Me Hg kinetics and dynamics.Supporting evidence for this comes from studies of fish-eating populations harboring polymorphic variants in genes encoding the catalytic and modifier subunits of the glutamyl-cysteine ligase enzyme (GCLc and GCLm, respectively).

Using a protocol of larval feeding, measurements of Hg body burden, and assays of development to adulthood (pupal eclosion), we identify strain-dependent variation in Me Hg elimination as a potential kinetic determinant of differential tolerance to Me Hg.Sorting out mechanisms of Me Hg toxicity is impingent on characterizing the dose–response relationship, which in turn relies on toxicokinetic principles of absorption, distribution, metabolism, and excretion (ADME).Yet, variability in toxicity can also stem from toxicodynamic mechanisms at the site of action, e.g., affinity for tissue-specific targets and secondary response, such as generation of reactive oxygen species (ROS), both having the potential to vary with genetic background and developmental timing.In several instances, polymorphisms predicting reduced function of GCLc/GCLm show an association with elevated levels of Hg in blood or hair biomarkers (Custodio et al., 2004; Barcelos et al., 2013), consistent with the notion that reduced GSH levels result in slower excretion kinetics and elevated Me Hg body burden.Nonetheless, findings across several studies investigating GCLc/m, and other GSH-related genes, including glutathione S-transferases (GSTs) and GSH-dependent ABCC transporters, have produced conflicting results, whereby associations with both higher and lower Hg levels in blood or hair are seen for the same polymorphic variant (Custodio et al., 2004; Schlawicke Engstrom et al., 2008; Barcelos et al., 2013).

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(D) Rate of eclosion of pupae reared on Me Hg food at the indicated concentration throughout the larval stages.