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Abstract
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous drinking water contaminants of concern due to mounting evidence implicating adverse health outcomes associated with exposure, including reduced kidney function, metabolic syndrome, thyroid disruption, and adverse pregnancy outcomes. In an 18-year longitudinal repeated measures study of adult humans (N = 210), an interquartile (IQR) increase in serum perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA) was associated with a -1.62% (95% CI= -3.02, -0.23), -1.95% (95% CI= -3.41, -0.49), and -2.47% (95% CI= -4.48, -0.45) decrease in estimated glomerular filtration rate, respectively, and an IQR increase in serum perfluorooctanesulfonate (PFOS) was associated with a 10.21% increase in serum TSH (95% CI: 2.29, 18.74). Adverse pregnancy outcomes were studied in pregnant CD-1 mice exposed to perfluorooctanoic acid (PFOA: 0, 1, or 5 mg/kg/day) or a PFOA replacement (GenX: 0, 2, or 10 mg/kg/day) from embryonic day (E) 0.5 to E11.5 or E17.5. Generally, effects induced by GenX occurred with shorter latency or at lower internal concentrations than PFOA. Exposure to GenX or PFOA resulted in increased gestational weight gain. Embryo weight was 9.4% lower relative to controls after exposure to 5 mg/kg/day PFOA. Effect sizes for several outcomes were similar for higher doses (5 mg/kg/day PFOA and 10 mg/kg/day GenX) and lower doses (1 mg/kg/day PFOA and 2 mg/kg/day GenX), including higher maternal liver weights, abnormal liver histopathology, higher placental weights and embryo-placental weight ratios, and greater incidence of placental abnormalities relative to controls. Transcriptome-wide gene expression analysis of placentas revealed significant enrichment of pathways involved in cholesterol and lipid transport (e.g. liver X receptor activation), innate immune response/inflammation (e.g. acute phase response signaling), and hemostasis (e.g. atherosclerosis signaling). Human-derived placental trophoblasts were utilized in an in vitro high-throughput toxicity (HTTS) screen to evaluate the effect of 42 unique PFAS on trophoblast viability and function, and dose-response models were applied to determine EC50 values for viability (27/42, 66%), proliferation (28/42, 68%), and mitochondrial membrane potential (19/42, 45%). Collectively, these data highlight adverse health outcomes associated with PFAS exposure, demonstrate the placenta is a susceptible target tissue, and propose potential molecular mechanisms of placental toxicity.
