Selenomethionine mitigation of methylmercury-induced epigenetic and transcriptomic alterations in rainbow trout brain: A toxicogenomic survey

Methylmercury (MeHg) is a pervasive neurotoxicant threatening aquatic ecosystems. Selenium (Se) has been reported to protect fish against the adverse MeHg toxicity, yet molecular investigations of their interaction in the brain remain scarce. This study investigated the molecular effects of dietary MeHg and whether organic Se, in the form of selenomethionine (SeMet), could mitigate MeHg-induced change in the brain of rainbow trout (Oncorhynchus mykiss). A 6-month feeding trial was conducted with diets containing low basal Se (0.3 mg/kg) and no mercury (Hg), supplemented with 2 mg Hg/kg diet as MeHg, alone or combined with 1.5 mg Se/kg diet as SeMet. Gene methylation (reduced representation bisulfite sequencing) and expression (RNA sequencing) were assessed, alongside biochemical quantification of DNA methylation-related metabolites (S-adenosylmethionine, SAM, and S-adenosylhomocysteine, SAH) and oxidative stress-related metabolites (reduced glutathione, GSH, and oxidized glutathione, GSSG). SeMet did not prevent MeHg-induced changes in SAM/SAH levels but mitigated MeHg-induced alterations in DNA methylation of genes related to the glutamatergic system, inflammation, and immune response. Transcriptomic analysis revealed antagonistic effects of MeHg and SeMet on energy metabolism pathways, with hypoxia-inducible factor 1 subunit alpha-like 2 identified as a potential key regulator. Although this molecular interaction may reflect SeMet-mediated attenuation of oxidative stress, biochemical data did not confirm changes in GSH/GSSG levels. These findings provide novel insights into the molecular mechanisms underlying MeHg neurotoxicity and its modulation by SeMet in fish brain, highlighting a potential protective role of organic Se against MeHg-induced molecular alterations.