Published: June 05, 2026, 03:08 UTC
PFAS compounds are called forever chemicals for a reason. The carbon-fluorine bond that makes them so useful in nonstick pans, waterproof jackets, and firefighting foam also makes them virtually indestructible in the environment. They accumulate in groundwater, in soil, in the tissues of wildlife, and in human blood.
A new study from the University of Colorado Anschutz Medical Campus has identified, for the first time, a specific molecular pathway by which one of these compounds can disrupt fetal development. The work, published in Chemical Research in Toxicology, focuses on perfluorodecanoic acid (PFDA), a long-chain PFAS with ten carbon atoms and a biological half-life of approximately twelve years in human serum.
The mechanism involves a molecule called retinoic acid, the active form of vitamin A.
The Retinoic Acid Balancing Act
During early pregnancy, retinoic acid orchestrates a critical developmental sequence. It governs the formation of the face, the eyes, the jaw, the palate. The fetus cannot produce or eliminate retinoic acid on its own; it relies entirely on the mother’s liver to maintain the right concentration. Too little retinoic acid and development stalls. Too much, and the signaling goes awry.
The enzyme responsible for clearing excess retinoic acid is CYP26A1, a member of the cytochrome P450 family found primarily in the liver. It hydroxylates retinoic acid, marking it for breakdown and excretion. For normal craniofacial development to proceed, CYP26A1 must keep retinoic acid levels within a narrow therapeutic window.
PFDA disrupts both sides of this equation at once.
A Double Hit
The CU Anschutz team, led by senior author Jed N. Lampe and first author Michaela Hvizdak, tested thirteen commonly detected PFAS compounds against recombinant human CYP26A1. Most had modest effects. PFDA stood apart: at high concentrations it reduced CYP26A1 enzyme activity by more than 93 percent.
The mechanism is structural. PFDA has a long carbon chain with a carboxylate tip, a shape that closely resembles retinoic acid itself. The molecule slips into the same active site on CYP26A1, blocking access for its intended substrate. But unlike retinoic acid, PFDA is not metabolized. It sits there, occupying the enzyme’s catalytic pocket without being broken down, acting as a competitive inhibitor.
The half-maximal inhibitory concentration (IC50) was approximately 50 micromolar for both of the enzyme’s primary reactions — 4-hydroxylation and 4-oxidation of retinoic acid.
But PFDA does not stop at direct inhibition. The researchers also found that it suppresses the expression of CYP26A1 genes in primary human hepatocytes through a separate transcriptional pathway. The result is a double hit: less enzyme being made, and less of what remains being able to function.
What the Effects Look Like
The connection between disrupted retinoic acid signaling and craniofacial defects is well established from decades of epidemiological data and from the DuPont C8 Science Panel’s surveillance of communities exposed to PFAS-contaminated water. The defects include microphthalmia — underdeveloped eyes — cleft palate, abnormal jaw formation, and missing nasal structures. Craniofacial abnormalities account for roughly one in three congenital birth defects worldwide.
The new study provides the mechanistic explanation for these observations: PFDA blocks retinoic acid clearance, retinoic acid accumulates, and the signaling gradient that guides facial development is disrupted.
The researchers estimate a roughly 10 percent increase in risk of facial defects even at low exposure levels.
The Concentration Question
A significant caveat: the concentrations at which PFDA inhibits CYP26A1 in the lab — around 50 micromolar — are substantially higher than the levels typically found in human blood. The average person carries PFAS at concentrations in the low nanomolar to low micromolar range.
The authors acknowledge this gap but point to several factors that could narrow it. PFDA has a twelve-year half-life in humans, meaning it accumulates over a lifetime. It undergoes enterohepatic recirculation, continuously cycling between the liver and the intestines, which may concentrate it in liver tissue at levels far above what a blood test would show. For people with elevated exposure — firefighters, ski wax technicians, residents near manufacturing sites or contaminated water sources — liver concentrations could potentially reach the range where CYP26A1 inhibition becomes relevant.
The study was conducted entirely in vitro using recombinant enzymes and pooled primary human hepatocytes from ten female donors aged 16 to 40. No live animals or human subjects were tested. The molecular modeling relied on AlphaFold-predicted structures of CYP26A1, as no experimentally resolved crystal structure of this enzyme exists.
What It Means
The value of this study lies not in demonstrating that PFAS causes birth defects at current population exposure levels, but in providing the first clear molecular mechanism to explain the association. Before this work, the link between PFAS and developmental abnormalities rested on epidemiology and whole-organism screening. Now there is a testable hypothesis at the enzyme level.
This mechanistic clarity has practical implications. It identifies CYP26A1 as a potential biomarker for PFAS developmental toxicity. It establishes a framework for predicting which PFAS compounds are most likely to disrupt retinoic acid signaling based on their structure. And it provides regulators with a defined biological endpoint that could inform risk assessment.
The authors note that future work should examine how PFDA affects retinoic acid hydroxylases specific to the fetal liver, and whether the mechanism operates in whole-organism models.
“Most people are exposed to small amounts of PFAS in everyday life,” Lampe said in a statement. “But higher exposure can occur through contaminated water, living near manufacturing sites, or certain jobs like firefighting and ski waxing, which is why it is so important to understand the chemicals better.”
Reference
Hvizdak, M., Kandel, S.E., Lampe, J.N. “New Mechanistic Evidence for Perfluorodecanoic Acid (PFDA) Teratogenicity via CYP26A1-Mediated Retinoic Acid Metabolism and Signaling.” Chemical Research in Toxicology (2026). DOI: 10.1021/acs.chemrestox.5c00468