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The risks of methylmercury (Me Hg) toxicity are greatest during early life where it has long been appreciated that the developing nervous system is an especially sensitive target.
Yet, understanding the discrete mechanisms of Me Hg toxicity have been obscured by the wide variation in the nature and severity of developmental outcomes that are typically seen across individuals in Me Hg exposed populations.
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).
Studies based in human populations have frequently focused on polymorphisms in genes related to the metabolism of glutathione (GSH) (Llop et al., 2015).Furthermore, associations of GSH-related gene polymorphisms with neurodevelopmental outcomes are also reported that are independent of association with Hg levels in biomarkers (Engstrom et al., 2016; Wahlberg et al., 2018), pointing to roles for toxicodynamic mediators of Me Hg toxicity.These variable findings have highlighted the need to discern fundamental toxicokinetic versus toxicodynamic mediators of Me Hg toxicity.However, GSH can facilitate both toxicokinetics and toxicodynamics of Me Hg by forming Me Hg-GSH conjugates, which are readily transported and excreted, and by acting indirectly as an anti-oxidant.
In this study, we refine a model to distinguish kinetic and dynamic traits of Me Hg toxicity using a paradigm of Drosophotoxicolgy.
First, we identify that the pupal stage is selectively sensitive to Me Hg toxicity.