Acute and Chronic Toxicity of Triphenyl Phosphate in Cervical Epithelial Cells: Involvement of Ferroptosis Dysregulation.

Abstract

The increasing global use of organophosphate esters (OPEs) has raised concerns about their environmental and health impacts, with evidence suggesting adverse effects on reproductive system health. As a widely used OPE, triphenyl phosphate (TPHP) has drawn attention for its endocrine-disrupting properties; however, its effects on cervical epithelial cells and association with cervical diseases remain unclear. In this study, analysis of 12 urinary OPE metabolites (mOPEs) in 116 cervical cancer (CC) cases and 116 controls revealed that multiple exposure biomarkers, particularly those related to TPHP exposure, were significantly positively associated with CC risk, suggesting a potential link between OPE exposure and disease development. In toxicological experiments, acute exposure to TPHP (50 μM, 24 h) induced significant cytotoxicity in human cervical epithelial cells (HcerEpic), characterized by reduced cell viability, cell cycle disruption, apoptosis, and oxidative stress. Conversely, chronic low-dose exposure (100 nM, 30 weeks) conferred a survival advantage to HcerEpic cells and enhanced their epithelial-mesenchymal transition (EMT) capacity, with enhanced tumor formation ability observed in a nude mouse xenograft model. Transcriptomic analysis revealed that ferroptosis was a significantly enriched pathway in both exposure models. Furthermore, experimental validation confirmed that acute TPHP exposure induced ferroptosis in HcerEpic cells, whereas chronically exposed cells exhibited ferroptosis resistance. Collectively, our findings highlight the critical role of ferroptosis dysregulation in TPHP-induced acute and chronic toxicities in HcerEpic cells, suggesting that TPHP may be a potential risk factor for CC and underscoring the need for further attention to the health risks associated with OPE exposure.