Sex-specific accumulation and oxidative stress of tris(1,3-dichloro-2-propyl) phosphate and its metabolite bis(1,3-dichloro-2-propyl) phosphate in rats after 90-day exposure.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate ester (OPE), but sex-dependent differences in tissue distribution and toxicity in mammals remain unclear. In this study, male and female SD rats were orally dosed with TDCIPP (0-360 mg/kg bw/day) for 90 days. We quantified TDCIPP and its metabolite bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) in serum, urine, liver, and kidney, assessed glutathione (GSH) homeostasis and lipid peroxidation, and employed network toxicology with molecular docking for target prediction. Male rats exhibited significantly higher BDCIPP accumulation and elevated BDCIPP/TDCIPP ratios in most matrices (P < 0.05), suggesting possible differences in parent/metabolite disposition. Hepatic malondialdehyde (MDA) increased dose-dependently in both sexes (dose main effect, P < 0.001), with an overall higher level in females (sex main effect, P < 0.001) but no significant sex × dose interaction. In kidney, males exhibited significant MDA elevation at 360 mg/kg bw/day despite preserved GSH reserves, suggesting that lipid peroxidation may occur independently of GSH depletion. Human-based network toxicology predicted that pathways associated with liver and kidney injury may be affected by TDCIPP/BDCIPP and involve multiple common signaling pathways, including endocrine disruption, suggesting that sex-specific oxidative responses may involve CYP450 and hormone-receptor crosstalk. In addition, pathway enrichment suggested that oxidative stress pathways were more prominently enriched in the predicted liver injury network, whereas receptor-inflammation pathways were more prominently enriched in the predicted kidney injury network. PIK3R1 and PTK2 emerged as common core nodes shared between organs, while liver-specific targets (EGFR, ERBB2, SRC) and kidney-specific targets (PIK3CB, PIK3CD, JAK2, FYN, PTPN11) revealed distinct organ-specific signaling networks. Collectively, these findings suggest sex-dependent toxicokinetics are associated with organ-specific oxidative responses and may potentially contribute to injury via CYP450 and hormone crosstalk, emphasizing the necessity of incorporating sex- and metabolite-specific oxidative stress and predicted toxicity into OPE risk assessment.