Chem Res Toxicol. 2026 Mar 30. doi: 10.1021/acs.chemrestox.5c00468. Online ahead of print.
ABSTRACT
Craniofacial abnormalities account for roughly one-third of all congenital birth defects worldwide. A growing body of evidence suggests that per– and polyfluoroalkyl substances (PFAS) are teratogenic in humans and laboratory animals, causing craniofacial morphological defects. PFAS structurally resemble the natural ligands of cytochrome P450 (CYP) enzymes involved in neonatal development, including the morphogen all-trans-retinoic acid (atRA). atRA regulates over 500 target genes during embryogenesis, including those related to craniofacial development. During pregnancy, circulating atRA concentrations are tightly maintained at the low nanomolar level. The fetus cannot synthesize atRA de novo, nor can the fetal liver reliably clear excess morphogen entering from maternal circulation to meet physiological demands. Therefore, maternal atRA homeostasis is paramount to proper fetal growth and development. In adults, members of the CYP26 family play a primary role in atRA clearance, including CYP26A1. PFAS disruption of maternal hepatic atRA metabolism via CYP26 may represent one pathological mechanism for the significant birth defects associated with prenatal exposure. We performed an in vitro screening of 13 prominent PFAS to measure their potential to inhibit CYP26A1 and CYP26B1 metabolism of atRA. Of the PFAS tested, PFDA was the most potent inhibitor of CYP26A1, with half-maximal inhibitory concentrations of 49.5 and 51.3 μM for 4-hydroxy- and 4-oxo-retinoic acid metabolite formation, respectively. No significant inhibition of CYP26B1 was observed. PFDA additionally perturbed atRA metabolism and signaling in female primary human hepatocytes following 48 h semistatic incubations. Based on our data, the atRA metabolic pathway through CYP26A1 regulation is a target for prenatal PFDA exposure, likely invoking irreversible consequences for the vulnerable fetus and neonate.
PMID:41910604 | DOI:10.1021/acs.chemrestox.5c00468