Association of organophosphate flame retardants exposure with liver function and the contrasting mediating roles of inflammatory and oxidative stress pathways.

Organophosphate flame retardants (OPFRs) have been widely used as alternatives to traditional halogenated flame retardants, resulting in their pervasive environmental presence and significant human exposure. While animal studies using high doses of individual OPFRs have demonstrated hepatotoxicity, evidence of hepatic effects from chronic and low-dose exposure to OPFRs in humans is scarce, and the underlying mechanisms remain largely unknown. In this study, we evaluated the association between urinary metabolites of OPFRs (mOPFRs) and liver function biomarkers in a population aged 1-79 years from the Guangzhou Human Biomonitoring Program. Urinary concentrations of diphenyl phosphate exhibited a significant decreasing trend with increasing age across four age groups (≤12, 13-17, 17-59, ≥60 years), while bis(1-chloro-2-propyl) phosphate concentrations showed a significant positive association with age. Urinary mOPFRs were positively associated with alanine aminotransferase, gamma-glutamyl transferase, and aspartate aminotransferase, and negatively associated with indirect bilirubin levels. Urinary mOPFRs were significantly correlated with total bilirubin, which was consistent with that observed in the National Health and Nutrition Examination Survey database, while other associations were inconsistent. Moreover, we evaluated the roles of inflammatory and oxidative stress markers in the association between urinary mOPFRs and liver function biomarkers by mediation analysis. The results demonstrated that the mediation effects of inflammatory markers were consistent with the total and direct effects of mOPFRs on liver function biomarkers, whereas the mediation effects of oxidative stress markers were discrepant. Inflammation likely exacerbates the adverse effects of OPFRs on liver function, while oxidative stress may play a protective role. We further searched the comparative toxicogenomics database for genes associated with OPFRs and liver function biomarkers to understand the potential regulatory mechanisms.