PFDA, a PFAS “forever chemical,” can cause craniofacial birth defects by disrupting retinoic acid regulation during fetal development, revealing the first clear molecular mechanism behind the link.

Researchers have long linked perfluoroalkyl and polyfluoroalkyl substances (PFAS), often called “forever chemicals,” to serious birth defects.

However, scientists have struggled to explain exactly how these pollutants affect fetal development. A new study now offers the first detailed molecular explanation, revealing how a PFAS compound known as perfluorodecanoic acid (PFDA) can cause craniofacial abnormalities before birth.

The findings were published in ACS Chemical Research in Toxicology.

“Most people are exposed to small amounts of PFAS in everyday life, but higher exposure can occur through contaminated water, living near manufacturing sites, or certain jobs like firefighting and ski waxing, which is why it’s so important to understand the chemicals better,” said the paper’s senior author, Jed Lampe, PhD, associate professor at University of Colorado Anschutz Skaggs School of Pharmacy and Pharmaceutical Sciences.

“We wanted to understand which PFAS compounds are truly harmful during fetal development, especially for people with higher exposure, and how they cause damage.”

PFDA Identified as the Most Toxic PFAS

Around 15,000 PFAS compounds are used in consumer and industrial products, but growing evidence suggests only a portion of them present major health concerns. To identify the most harmful compounds, Lampe and colleagues Michaela Hvizdak and Sylvie Kandel examined 13 commonly detected PFAS. Their results showed that PFDA was the most toxic to craniofacial development in a fetus.

The researchers found evidence linking PFDA to significant facial abnormalities seen in both people and laboratory animals. Some estimates suggest the compound may increase the risk of these defects by about 10%, even at very low exposure levels.

“This finding moves us beyond association by providing a clear explanation for how PFDA can interfere with fetal development. It’s a critical step toward understanding a vast and complex class of environmental chemicals,” said Lampe.

How PFDA Disrupts Retinoic Acid Signaling

The team discovered that PFDA interferes with retinoic acid, a molecule that plays a vital role in forming the face and head during early pregnancy. Retinoic acid controls the activity of hundreds of genes, and maintaining the correct amount is essential. Because a fetus cannot produce or safely remove excess retinoic acid, it depends entirely on the mother to keep levels balanced.

Researchers found that PFDA blocks CYP26A1, an enzyme responsible for breaking down excess retinoic acid. When the enzyme is inhibited, retinoic acid can accumulate to harmful levels and disrupt normal facial development. PFDA also reduces the activity of genes that produce CYP26A1 through a separate biological mechanism, creating what researchers describe as a “double hit” to a system that is critical for early development.

“As a result, severe craniofacial abnormalities can develop, including underdeveloped eyes and abnormal jaw formation, which were the most common effects of PFDA exposure during fetal development,” said Lampe.

Toward Better PFAS Risk Screening and Prevention

By uncovering the biological mechanism behind these developmental abnormalities, the researchers hope to help scientists create targeted laboratory tests and computer screening tools that can rapidly assess the risks posed by different PFAS compounds. Such tools could help regulators and manufacturers identify the most hazardous chemicals, distinguish them from safer alternatives, and support the development of less toxic products.

The team also believes the findings could lead to practical strategies for people with elevated PFAS exposure, including firefighters and ski wax technicians. Future research may explore ways to reduce exposure and determine whether lowering PFDA levels during pregnancy could help protect fetal development.