(257) Perfluorochemicals paradoxically exert immunosuppressive effects in fetal membranes: implications for preterm premature rupture of membranes

Perfluorochemicals (PFCs) are ubiquitous xenobiotics used in the manufacturing of common household products. These “forever chemicals” persist in human tissues for many years and can exert immunomodulatory effects. Select PFCs have been implicated in adverse pregnancy outcomes, with higher concentrations detected in amniotic fluid and cord blood in spontaneous preterm birth. We leveraged a human pregnancy cohort and in vitro methodology to test the hypothesis that PFCs induce inflammation in fetal membranes, thus compromising membrane integrity and risk of preterm premature rupture of membranes (PPROM).


Study Design:

Relative PFC abundance was assessed by untargeted metabolomics in amnion and chorion from cases of PPROM (n=25) and term controls (n=25) in a prospective pregnancy cohort. Data were log₂ transformed and analyzed by two-way ANOVA (p < 0.05) with calculation of false discovery rates (q < 0.1). For in vitro experiments, amnion epithelial cells (AECs) were treated with PFCs (PFOS, PFOA, PFNA, or PFHxS) for 24h with doses based on physiologic concentrations. Proinflammatory cytokine IL-8 was measured in cell culture media (n=3/condition) by ELISA. One-way ANOVAs with correction for multiple comparisons were performed.


Results:

Demographic characteristics were similar between groups (Fig. 1). Amnion and chorion from PPROM had higher abundance of PFOS versus term though the difference did not persist after correction for multiple comparisons (Fig. 1). A similar trend was seen for PFOA. Unexpectedly, PFOS, PFOA, PFNA, and PFHxS all decreased basal levels of IL-8 in AECs in a dose-dependent manner (Fig. 2, p < 0.05). 


Conclusion:

PFC accumulation in fetal membranes, an understudied reproductive tissue, may drive immune perturbations underlying PPROM. Contrary to our hypothesis, these xenobiotics exert an immunosuppressive effect in the amnion, potentially rendering fetal membranes more susceptible to other sources of physiologic stress, including microbial challenge. Mechanisms by which PFCs drive reproductive outcomes, including preterm birth, warrant future investigation. Harrison Award (KG, LA)