Phthalate mixtures and pregnancy loss: Linking MCNP exposure with placental dysfunction via epidemiologic and in vivo evidence.

Pregnancy loss is an increasingly serious global health concern driven by complex genetic and environmental interactions. Phthalates, a common class of endocrine-disrupting chemicals, have been implicated in adverse reproductive outcomes, yet their role in pregnancy loss remains unclear. In this study, we adopted a multidisciplinary approach integrating epidemiological analysis, bioinformatics, and animal experiments to investigate the association between phthalate exposure and pregnancy loss. Analysis of 1445 women from NHANES data showed that higher mono(carboxynonyl) phthalate (MCNP) concentrations were associated with increased odds of pregnancy loss (OR3rd=1.43, 95% CI: 1.10-1.86; P-trend = 0.007) and recurrent pregnancy loss (OR3rd=1.50, 95% CI: 1.08-2.10; P-trend = 0.008). In mixture modeling, overall phthalate exposure was linked to greater likelihood of pregnancy loss, with MCNP contributing substantially. Exploratory mediation analysis indicated that bilirubin, interpreted as a potential intermediary biomarker, accounted for a modest proportion of the statistical association. Integration of toxicological databases with placental transcriptomic data from recurrent pregnancy loss cases highlighted oxidative stress and inflammation-related pathways. In a mouse model, maternal oral exposure to DiDP, a parent compound associated with MCNP formation, was associated with increased fetal resorption and altered placental structure and signaling responses, including changes in PI3K-Akt-mTOR-related markers. Collectively, our findings suggest that phthalate exposure, particularly higher MCNP levels, is associated with pregnancy loss and that systemic metabolic and placental responses may contribute to this association. These results underscore the importance of reducing phthalate exposure among women of reproductive age.