Abstract
Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant, with human exposures predominantly resulting from fish consumption. Developmental exposure of zebrafish to MeHg is known to alter their neurobehavior. The current study investigated the direct exposure and transgenerational effects of MeHg, at tissue doses similar to those detected in exposed human populations, on sperm epimutations (i.e., differential DNA methylation regions [DMRs]) and neurobehavior (i.e., visual startle and spontaneous locomotion) in zebrafish, an established human health model. F0 generation embryos were exposed to MeHg (0, 1, 3, 10, 30, and 100 nM) for 24 hours ex vivo. F0 generation control and MeHg-exposed lineages were reared to adults and bred to yield the F1 generation, which was subsequently bred to the F2 generation. Direct exposure (F0 generation) and transgenerational actions (F2 generation) were then evaluated. Hyperactivity and visual deficit were observed in the unexposed descendants (F2 generation) of the MeHg-exposed lineage compared to control. An increase in F2 generation sperm epimutations was observed relative to the F0 generation. Investigation of the DMRs in the F2 generation MeHg-exposed lineage sperm revealed associated genes in the neuroactive ligand-receptor interaction and actin-cytoskeleton pathways being effected, which correlate to the observed neurobehavioral phenotypes. Developmental MeHg-induced epigenetic transgenerational inheritance of abnormal neurobehavior is correlated with sperm epimutations in F2 generation adult zebrafish. Therefore, mercury can promote the epigenetic transgenerational inheritance of disease in zebrafish, which significantly impacts its environmental health considerations in all species including humans.
Highlights
Heavy metals are among the top ten chemicals or groups of chemicals of global public health concern identified by the World Health Organization due to their known neurotoxicity [1]
The zebrafish is a powerful model of human development and disease due its similar physiological, morphological, and genetic characteristics with humans [11]. This laboratory has previously demonstrated that direct developmental exposure of F0 generation zebrafish to MeHg leads to deficits in learning and memory, startle reflex responses, and retinal electrophysiology in adulthood [12, 13]
Weber et al [12] showed that direct developmental exposure of F0 generation zebrafish embryos to MeHg (10, 30, 60, 100, and 300 nM) yielded abnormal vision-related phenotypes in adult F0 generation zebrafish analogous to those observed in the F0 and F2 generations in the current study, compared to control
Summary
Heavy metals (e.g., lead [Pb], and mercury [Hg]) are among the top ten chemicals or groups of chemicals of global public health concern identified by the World Health Organization due to their known neurotoxicity [1]. MeHg enters the food web through the consumption of the Hg-converting bacteria by zooplankton [7], and is strongly biomagnified accumulating at high levels in large predatory fishes and other top predators including humans [8]. The zebrafish is a powerful model of human development and disease due its similar physiological, morphological, and genetic characteristics with humans [11]. This laboratory has previously demonstrated that direct developmental exposure of F0 generation zebrafish to MeHg leads to deficits in learning and memory, startle reflex responses, and retinal electrophysiology in adulthood [12, 13]. Knowledge as to how direct developmental MeHg may impact future generations via epigenetics is severely lacking
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