Chronic embryonic arsenic and mercury exposure-induced developmental neurotoxicity, neurobehavioral dysfunction and metabolic alteration in zebrafish (Daniorerio F.Hamilton, 1822)

Arsenic and mercury are ubiquitous in the environment. Exposure to these toxicants at low concentrations is unremarkable in developing organism. Nevertheless, their long-term adverse effects are underestimated and their association with cognitive deficits, one of the major criteria for neurodevelopmental disorders (NDD) remains a challenge to understand. This study investigated the long-term effects of embryonic exposure to arsenic and mercury at low environmentally relevant concentrations on developmental neurotoxicity, neurobehavioral dysfunction, and metabolic alteration in the developing zebrafish. Chronic embryonic exposure to arsenic trioxide (As2O3) or mercury chloride (HgCl2) from gastrulation to hatching resulted in developmental neurotoxicity, neurobehavioral dysfunction, and metabolic alteration in the treated larvae. Embryonic exposure to As2O3 or HgCl2 induced hypo-/hyperlocomotion, affecting common metabolic pathways, particularly arachidonic and linoleic acid metabolism. Downregulation of docosahexaenoic acid (DHA) metabolites results in reduction of eyes, lens, and retinas diameter, and impaired microridges for both As2O3 and HgCl2 exposure. Long-term impairment of learning by As2O3 exposure was evident in a lack of directional and color preference responses in adult zebrafish correspond with depletion of both arachidonic acid and DHA metabolites. Lower survivability in HgCl2 exposed larvae compared to As2O3 could be related to the inflammatory response and abnormal inflation of swim bladder. Transcriptional evaluation of adsl, shank3a, tsc1b and nrxn revealed association between embryonic exposure to As2O3 and HgCl2 with autism spectrum disorder (ASD). In this study, zebrafish was successfully developed as an animal model for evaluation of the long-term neurotoxicity effects of toxicants by integrating toxicity, behavior, metabolomics, and gene expression to understand the underlying behavioural disorders associated with NDDs. Thus, highlighting the risk of exposure to low concentrations of As/Hg for long-term duration. Considering the ubiquity of As2O3 and HgCl2 in the environment, this study proves that arsenic and mercury as one of the risk factors for NDDs, especially ASD in the human population

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