miR-184/ hamp -Mediated Cardiotoxicity and Hepatotoxicity in Offspring Zebrafish Following Paternal Exposure to Environmentally Relevant Concentrations of Tris(1,3-dichloro-2-propyl) Phosphate

Recently, increasing attention has been focused on the intergenerational toxicity of environmental contaminants. Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a widely detected contaminant in aquatic environments, but its paternally mediated intergenerational toxicity in vertebrates has remained insufficiently elucidated. In this study, zebrafish at 50 days postfertilization (dpf) were exposed to environmentally relevant concentrations (55, 550, and 5500 ng/L) of TDCIPP for 150 days. Following exposure, the males were paired with unexposed females, and cardiotoxicity and hepatotoxicity were assessed in the offspring larvae. It was found that TDCIPP accumulated in F0 testes but not in the offspring embryos. Furthermore, paternal exposure to TDCIPP led to an increased heart rate, abnormal cardiac morphology, and significantly elevated ventricular wall thickness in the offspring zebrafish. Additionally, lipid metabolism disorders, abnormal liver morphology, and functional impairment were also observed in the offspring. Moreover, paternal exposure to TDCIPP down-regulated the expression of the hepcidin antimicrobial peptide gene ( hamp ) in the offspring larvae, leading to iron overload, which might contribute to the observed cardiotoxicity and lipid metabolism disorders in the offspring, as well as the subsequent development of hepatotoxicity. Furthermore, the up-regulation of miR-184 in F0 testes and offspring larvae accounted for the suppression of hamp expression following paternal exposure to TDCIPP. Our findings reveal that paternal exposure to TDCIPP induces up-regulation of miR-184 in F0 testes, and this overexpressed microRNA can be transmitted to the offspring, subsequently inhibiting hamp expression, leading to iron overload and consequently contributing to cardiotoxicity and hepatotoxicity in the offspring.