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.
Some insight has come from studies aimed at identifying a role for genetic background as a modifier of Me Hg toxicity, which have predominantly focused on factors influencing Me Hg toxicokinetics, notably, polymorphisms in genes related to glutathione (GSH) metabolism.
For example, variants in genes encoding the catalytic and modifier subunits of glutamyl-cysteine ligase (GCLc and GCLm), the rate limiting enzyme for GSH synthesis, have been reported to associate with Hg body burden (Hg levels in blood or hair) in humans.
The underlying role of genetic background as a modifier of Me Hg toxicity has recently received great attention.