Guest Speaker - 

Jed Lampe, PhD, from the University of Colorado

Discussion - 

Evidence for PFAS teratogenicity through inhibition of retinoic acid metabolism and signaling in the developing fetus

Abstract - 

PFAS, or per- and polyfluoroalkyl substances, are ubiquitous environmental contaminants that are associated with a variety of diseases in humans. Early data from worker exposure at the DuPont plant in Parkersburg, West Virginia pointed to a significant increase in craniofacial abnormalities and stillbirths in women who were exposed to significant amounts of PFAS in the production of Teflon. These effects are mirrored in laboratory animals, where in utero PFAS exposure causes craniofacial and limb morphological defects. PFAS structurally resemble several of the endogenous fatty acid ligands of cytochrome P450 (CYP) enzymes that are crucial for neonatal development, including the morphogen all-trans-retinoic acid (atRA -Vitamin A). atRA regulates over 500 target genes during embryogenesis, including those related to craniofacial development. Excess exposure of atRA in utero can lead to craniofacial and limb abnormalities, such as those observed after maternal exposure to PFAS. During pregnancy, circulating atRA concentrations are tightly maintained at the low nanomolar level, primarily through metabolism by CYP26A1, while CYP3A7 is responsible for metabolism in the developing fetus. We hypothesize that inhibition of CYP26A1 and CYP3A7 atRA metabolism leads to excessive atRA buildup and the resulting crainofacial abnormalities observed in both animals and humans. We performed an in vitro screening of 13 prominent PFAS to measure their potential to inhibit CYP26A1 and CYP3A7 metabolism of atRA. Of the PFAS tested, PFDA was our most potent inhibitor of CYP26A1, with an IC50 of 49.5 µM and 51.3 µM for 4-hydroxy- and 4-oxo-RA metabolite formation, respectively, whereas PFUnDA was the most potent inhibitor of CYP3A7 at 20.9 µM and 17.9 µM for 4-hydroxy- and 4-oxo-RA metabolite formation. Similarly, both PFDA and PFUnDA were demonstrated to inhibit CYP26A1 and CYP3A7 in hepatocyte model cell culture systems. PFDA additionally perturbed atRA metabolism and signaling in female hepatocytes following 48 h semi-static incubations, with a number of pathways either up or downregulated based on RNAseq analysis. Taken together, these data point to the inhibition of atRA metabolism and signaling as an important toxicological pathway for PFAS exposure in the developing fetus and neonate.

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