Per- and polyfluoroalkyl substances (PFAS) differentially inhibit placental trophoblast migration and invasion in vitro

By John T Szilagyi, Anastasia N Freedman, Stewart L Kepper, Arjun M Keshava, Jackie T Bangma, and Rebecca C Fry
Toxicol. Sci.
April 1, 2020
DOI: 10.1093/toxsci/kfaa043

Per- and polyfluoroalkyl substances (PFAS) are used as industrial surfactants and chemical coatings for household goods such as Teflon. Despite regulatory efforts to phase out legacy PFAS, they remain detectable in drinking water throughout the United States. This is due to the stability of legacy PFAS and the continued use of replacement compounds. In humans, PFAS have been detected in placenta and cord blood and are associated with low birthweight and preeclampsia risk. Preeclampsia is a leading cause of maternal mortality and is driven by insufficient endometrial trophoblast invasion, resulting in poor placental blood flow. PFAS alter invasion of other cell types, but their impact on trophoblasts is not understood. We therefore assessed the effects of PFAS on trophoblast migration, invasion, and gene expression in vitro. Trophoblast migration and invasion was assessed using a modified scratch assay in the absence or presence of Matrigel, respectively. Treatment with perfluorooctanoic sulfate (PFOS), perfluorooctanoic acid (PFOA), and GenX (1000 ng/mL) each decreased trophoblast migration over 24 h. However, only GenX (1000 ng/mL) significantly inhibited trophoblast invasion. Treatment with PFOS, PFOA, and GenX also decreased trophoblast expression of chemokines (e.g. CCL2), chemokine receptors (e.g. CCR4), and inflammatory enzymes (e.g. ALOX15) involved in migration. Inhibition of chemokine receptors with pertussis toxin (10 ng/mL), a G-protein inhibitor, inhibited trophoblast migration similar to the PFAS. Taken together, PFAS decrease trophoblast migration, invasion, and inflammatory signaling. By understanding the mechanisms involved, it may be possible to identify the biological and exposure factors that contribute to preeclampsia.

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