Placental CYP450 gene dysregulation by maternal PFAS: a novel mechanism linking prenatal exposure to altered toddler growth

BACKGROUND: Maternal per- and polyfluoroalkyl substances (PFAS) exposure has been linked to adverse health effects on offspring, but the mechanisms remain unclear. The present study investigates the relationship between maternal PFAS exposure and the expression of placental cytochrome P450 enzymes (CYP19A1, CYP2J2, and CYP2E1), and explores the potential role of these enzymes in linking maternal PFAS exposure to offspring development. METHODS: We included 350 mother-infant pairs from the Jiashan birth cohort. Thirteen PFAS compounds were measured in maternal plasma collected at 8-16 weeks of gestation, while the expression levels of the three CYP genes were quantified in placental tissues collected at delivery. Offspring weight and length were measured at birth and at 1, 3, 6, 8, 12, and 24 months of age, and their ponderal index (PI) was computed. Multivariable linear regression was used to examine associations between plasma concentrations of individual PFAS and placental CYP gene expression. Quantile-based g-computation was used to examine the association of the PFAS mixture with placental CYP gene expression. A linear mixed model was used to examine the associations of maternal PFAS and placental CYP expression levels with repeated PI measurements from birth to 24 months. Multilevel mediation analysis was conducted to explore the potential mediating role of CYP genes. RESULTS: = -0.344, 95% CI: -0.571,-0.117, respectively). The PFAS mixture was associated with decreased the three CYP genes expression in the placenta of female fetuses, but no association was observed in male placentas. Additionally, placental CYP19A1 expression was associated with a decrease in girls' PI and an increase in boys' PI, respectively. However, no mediating role of CYP19A1 in the relationship between PFTrDA and PI in girls or between PFHxS and PI in boys was observed, as the indirect effect was not statistically significant. CONCLUSIONS: These results indicate that maternal PFAS exposure may disrupt placental CYP expression and the implications of these disruptions for offspring development warrant further investigation.