Sex-specific effects of in utero exposure to per- and polyfluoroalkyl substances on placental development

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that may impact placental function, and potentially gestational age acceleration (GAA), a deviation from reported and predicted gestational age. GAA potentially represents differences in cell maturation in response to a challenging environment. Objective: This study aimed to characterize the effects of individual and mixtures of PFAS on GAA, cell composition, birth length, and birthweight. Methods: Pregnant peoples were recruited from around Little Rock, Arkansas, United States between 2011 and 2014. We utilized placental DNA methylation profiles of 153 healthy pregnancies to calculate GAA and estimate the proportions of six placental cell types. PFAS were quantified in homogenized placental tissue using high-performance liquid chromatography-tandem mass spectrometry. Five PFAS were detected in over 70% of samples. We studied these five PFAS individually using multiple linear regression and as a mixture using quantile g-computation, while adjusting for confounders. The dependent variables in our models included GAA, cell proportions, birthweight, and birth length. Results: We did not observe associations between PFAS and any of our outcomes in our primary models. While GAA in male placentas were not significantly affected by PFAS, the PFAS mixture associated with decreased syncytiotrophoblast proportion (Ψ = −0.018, 95% CI [-0.032, −0.004]). PFAS mixture did not alter cell proportions in female placentas but was associated with increased GAA (Ψ = 0.269, 95% CI [0.026, 0.513]). Similarly, for females, greater GAA was associated with PFOA (β = 0.141, 95% CI [−0.016,0.040]) and PFOS (β = 0.205, 95% CI [-0.020,0.0416]). Discussion: We illustrate that PFAS may influence placental development in a sex specific manner. Suggested by decrease in syncytotrophoblast, male placenta may experience a more stunted development due to PFAS exposure. Alternatively, female placentas exhibited increased GAA, a plausible marker of elevated developmental maturation in the face of environmental adversity.