Decabromodiphenyl Ethane Sensitizes Zebrafish to Alcoholic Liver Injury by Compromising NAD+-Mediated Multicellular Responses

Abstract

Epidemiological evidence has confirmed an association between environmental contaminants and elevated risk of liver injury in alcohol consumers. Decabromodiphenyl ethane (DBDPE) is a novel brominated flame retardant that can accumulate in the liver. Given the widespread environmental distribution of DBDPE and rising burden of alcohol abuse, this study investigated the impact of DBDPE on alcoholic liver injury progression by preexposing male zebrafish to DBDPE followed by an acute ethanol challenge. The results showed that DBDPE induced tissue damage and lipid accumulation, which correlated with mitochondrial dysfunction and oxidative stress. DBDPE pre-exposure significantly impaired recovery from ethanol-induced liver injury, as evidenced by delayed normalization of serum transaminase activities. Single-cell transcriptomics further revealed that DBDPE disrupted the tight junction pathway in cholangiocytes and suppressed alcohol metabolism-related pathways in hepatocytes, which correlated with subsequent cholestasis and impaired liver recovery after alcohol challenge. Notably, these adverse effects were driven by NAD+ deficiency, as supplementation with nicotinamide riboside to restore NAD+ levels effectively mitigated DBDPE-induced impairments. Our findings suggest that DBDPE increases zebrafish susceptibility to and impedes recovery from alcoholic liver injury through NAD+ suppression, identifying it as an environmental risk factor for the progression of alcoholic liver disease.