Methylmercury (MeHg) is an environmental contaminant linked to many neurological defects. Disrupted redox homeostasis is a crucial event in MeHg-induced neurotoxicity. The thioredoxin system is a key redox regulator affected by MeHg, however the mechanism and consequences of this process are not completely understood. Caenorhabditis elegans (C. elegans) is a valuable tool in studying the thioredoxin system, since in worms, unlike in other model organisms, thioredoxin null mutants do not lead to embryonic lethality. Therefore, we used this model to evaluate the role of the thioredoxin system in MeHg-induced neurotoxicity. Synchronized worms at different developmental stage (L1, L4 and adult) were exposed for 1hr to MeHg in M9 buffer. The survival of wild type (wt) and mutant worms with disrupted homologs of the thioredoxin system (
trx-1,
trxr-1,
trx-2,
trxr-2,
trx-3) was evaluated 24hr after exposure. Deficiency of the cytoplasmic thioredoxin system led to higher susceptibility to MeHg, as
trx-1 and
trxr-1 mutants showed significantly higher lethality in response to MeHg than wt worms, especially when treated at L4 stage. Susceptibility of other mutants (
trx-2,
trxr-2,
trx-3) remained unaffected. Still, similarly to the wt, the lifespan of mutants (
trx-1,
trxr-1,
trx-2,
trxr-2,
trx-3) was unchanged for worms which survived MeHg treatment when at L1 or L4 stage. The expression of thioredoxins TRX-1, TRXR-1, TRX-2, TRXR-2 was evaluated 24 and 48hr after MeHg exposure in L1 and L4 worms with corresponding GFP constructs. MeHg downregulated the expression of TRXR-1 in hermaphrodites treated at L1 and L4 stage, both 24 and 48hr after exposure, but not in L4 males. The expression of TRX-1, TRX-2 and TRXR-2 remained unaffected by MeHg, however the TRX-1, which is exclusively expressed in a pair of ASJ sensory neurons, was significantly higher in males when compared with hermaphrodites. Sex-specific differences in response of the
trx-1/trxr-1 system were previously reported in mice brain and were linked to differential susceptibility to developmental MeHg exposure. Therefore, further studies addressing the role of the
trx-1/
trxr-1 system in sex-specific response, especially neurodegeneration upon MeHg treatment, might help to understand this effect. To date, our findings indicate that the cytoplasmic thioredoxin system
trx-1/trxr-1 is not only a sex-specific target, but also an important protectant against MeHg toxicity in C. elegans. Supported by NIEHS R01 ES07331 to MA and ABB.