Isomer-specific cardiotoxicity induced by tricresyl phosphate in zebrafish embryos/larvae

Tricresyl phosphate (TCP) has received extensive attentions due to its potential adverse effects, while the toxicological information of TCP isomers is limited. In this study, 2 h post-fertilization zebrafish embryos were exposed to tri-o-cresyl phosphate (ToCP), tri-m-cresyl phosphate (TmCP) or tri-p-cresyl phosphate (TpCP) at concentrations of 0, 100, 300 and 600 μg/L until 120 hpf, and the cardiotoxicity and mechanism of TCP isomers in zebrafish embryos/larvae were evaluated. The results showed that ToCP or TmCP exposure induced cardiac morphological defects and dysfunction in zebrafish, characterized by increased distance between sinus venosus and bulbus arteriosis, increased atrium and pericardial sac area, trabecular defects, and decreased heart rate and blood flow velocity, while no adverse effects of TpCP on zebrafish heart were found. Transcriptomic results revealed that extracellular matrix (ECM) and motor proteins, as well as PPAR signaling pathways, were included in the cardiac morphological defects and dysfunction induced by ToCP and TmCP. Co-exposure test with D-mannitol indicated that the inhibition of energy metabolism by ToCP and TmCP affected cardiac morphology and function by decreasing osmoregulation. This study is the first to report the cardiotoxicity induced by TCP in zebrafish from an isomer perspective, providing a new insight into the toxicity of TCP isomers and highlighting the importance of evaluating the toxicity of different isomers. TCP is extensively distributed in various environmental matrices and might pose a serious threat to humans and wildlife. This study, for the first time, reveals the cardiotoxicity induced by TCP in zebrafish from an isomer perspective. Our findings indicate that ToCP and TmCP induced abnormal cardiac development and function in zebrafish embryos/larvae, while TpCP had no significant adverse effect on the heart function. This study broadens the view of environmental toxicology of TCP isomers, emphasizes the importance of evaluating the toxicity of different isomers, and provides a reference for toxicity prediction and classification of aryl phosphate ester isomers.