Association of organophosphate flame retardant exposure with female infertility: Cross-sectional and mechanistic evidence.

Abstract

Female infertility is an increasing global public health concern. Growing evidence suggests that exposure to organophosphate flame retardants (OPFRs) may contribute to reproductive dysfunction. However, the OPFRs most strongly associated with female infertility and the potential molecular pathways underlying these associations remain unclear. This study employed an integrated framework combining epidemiological analysis, network toxicology, molecular docking, and adverse outcome pathway (AOP) construction to investigate the association between OPFR exposure and female infertility and to explore plausible underlying mechanisms. Cross-sectional data from 1044 women in the National Health and Nutrition Examination Survey (NHANES) 2013-2018 cycles were analyzed using multivariable logistic regression, restricted cubic spline (RCS), Quantile g-computation (Qgcomp), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Diphenyl phosphate (DPhP) was consistently identified as the OPFR metabolite most strongly positively associated with female infertility and showed the greatest relative influence across the mixture models. Network toxicology prioritized six steroidogenic enzymes (CYP11A1, CYP17A1, CYP19A1, HSD3B1, HSD17B1, and HSD17B2) as candidate molecular targets, and molecular docking predicted favorable interactions of DPhP and its parent compound triphenyl phosphate (TPhP) with these proteins. Integration of these computational findings with existing AOPs suggested a plausible mechanistic framework involving perturbation of steroidogenesis, altered estradiol biosynthesis, and disruption of androgen-estrogen homeostasis, which may contribute to impaired female reproductive function. These findings provide cross-sectional evidence for an association between DPhP exposure and female infertility and generate mechanistic hypotheses regarding TPhP/DPhP-associated reproductive effects that warrant further experimental and prospective validation.