High-throughput zebrafish screening reveals cardiotoxic effects of organophosphate flame retardants

The toxicity of organophosphorus flame retardants (OPFRs) remains poorly understood, despite their widespread environmental presence and potential risks to human and ecological health. This study aimed to characterize the cardiovascular developmental toxicity of OPFRs using a high-throughput zebrafish screening model. Over thirty representative OPFRs, classified into three major groups-alkyl, aryl, and halogenated-were evaluated. Our results demonstrated that aryl-substituted OPFRs, such as triphenyl phosphate (TPHP) and tris(3,5-dimethylphenyl) phosphate (TXP), exhibit significantly more potent cardiotoxic effects compared to alkyl- and halogenated-substituted OPFRs. Specifically, heart rate of zebrafish increased by 8.3% and 11.9%, and cardiac output increased by 30.8% and 39.9% for TPHP and TXP, respectively, at a concentration of 160 μg/L. Additionally, exposure to aryl-substituted compounds like TPHP resulted in notable developmental abnormalities, including pericardial edema and skeletal bending. Molecular descriptor analysis further identified a series of essential structural features, including estrogen receptor agonist activity and bioconversion rates, which are closely linked to the observed cardiotoxicity, thus providing a mechanistic explanation for these effects. These findings offer valuable insights into the molecular mechanisms underlying OPFRs toxicity, which could inform the development of safer flame retardant alternatives. Moreover, addressing the research gaps in translating zebrafish findings to other species and real-world ecological scenarios should be further concerned.