Triphenyl phosphate exposure at physiologically/environmentally relevant concentrations promotes malignant progression of breast cancer: Insights from metabolomics and lipidomics.

Triphenyl phosphate (TPHP) is one of the main alternatives to brominated flame retardants and a typical environmental endocrine disruptor. Although the in vitro tumor-promoting effect of TPHP has been partially emphasized in previous studies, its impact on breast cancer, particularly at physiological/environmental relevant concentrations, had received inadequate attention. To investigate the pro-breast cancer effects of TPHP, both three-dimensional cancer cell spheroids models and chronic murine exposure models were established. Spheroid growth analysis, bioluminescent imaging, and multi-omics analysis were employed to elucidate the molecular mechanisms underlying TPHP induced malignant progression of breast cancer. The results indicated that exposure to physiological/environmental relevant concentrations of TPHP might induce the growth of breast tumor cell spheres in vitro (0.08 and 0.27 μM) and the proliferation and metastasis of breast tumors in mice (120.39 μg/kg/day) by enhancing the energy supply and storage of tumor cells (biosynthesis of glycerophospholipids and glycerolipids, fatty acid β-oxidation, and the tricarboxylic acid cycle). The observed metabolic rewiring diverged from classical Warburg phenotypes typically associated with cancer metabolism. This study provided valuable insights into the pro-carcinogenic effects associated with TPHP exposure and offered a reference for the development of early intervention strategies for high-risk populations and the formulation of environmental regulations.