Triphenyl phosphate induces cardiotoxicity through myocardial fibrosis mediated by apoptosis and mitophagy of cardiomyocyte in mice.

Triphenyl phosphate (TPHP) is an organophosphorus flame retardant, but its cardiac toxicity has not been adequately investigated. Therefore, in the current study, the effect of TPHP on the heart and the underlying mechanism involved was evaluated. C57BL/6 J mice were administered TPHP (0, 5, and 50 mg/kg/day) for 30 days. In addition, H9c2 cells were treated with three various concentrations (0, 50, and 150 μM) of TPHP, with and without the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine or the mitochondrial fusion promoter M1. TPHP caused cardiac fibrosis and increased the levels of CK-MB and LDH in the serum. TPHP increased the levels of ROS, malondialdehyde (MDA), and decreased the level of superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px). Furthermore, TPHP caused mitochondrial damage, and induced fusion and fission disorders that contributed to mitophagy in both the heart of C57BL/6 J mice and H9c2 cells. Transcriptome analysis showed that TPHP induced up- or down-regulated expression of various genes in myocardial tissue and revealed enriched apoptosis pathways. It was also found that TPHP could remarkably increase the expression levels of Bax, cleaved Caspase-9, cleaved Caspase-3, and decreased Bcl-2, thereby causing apoptosis in H9c2 cells. Taken together, the results suggested that TPHP promoted mitophagy through mitochondria fusion dysfunction resulting from oxidative stress, leading to fibrosis by inducing myocardial apoptosis.