Exposure to environmentally relevant levels of GenX affects placental and offspring development in mice

Hexafluoropropylene Oxide Dimer Acid (GenX or HFPO-DA), a fluorochemical used in industrial applications such as non-stick coatings and water-repellent textiles, has emerged as a replacement for perfluorooctanoic acid (PFOA). Its widespread use has led to detection in air, soil, and drinking water, raising concerns about potential health impacts. This study investigates the effects of exposure to environmentally relevant levels of GenX on placental and offspring development in mice. Female mice were exposed to GenX for short-term (11 days) or subchronic (100 days) durations. Both short-term and subchronic exposure resulted in alterations in body weight gain, placental weight, and placental efficiency. Dams exposed subchronically also exhibit altered fetal weight and impaired placental structure. In the labyrinth layer of placenta, subchronic exposure to GenX caused disordered vasculature, characterized by enlarged vessel lumens, discontinuous signals of maternal (MCT1) and fetal (MCT4) vascular networks, and impaired mitochondria in fetal sinus endothelial cells. The placental mRNA profile revealed imbalanced expression of factors essential for proper angiogenesis, with increased levels of Vegfa and Angpt1, and decreased levels of Tie2. Additionally, male pups of the subchronically exposed dams exhibited higher birth weight, increased weight gain and reduced anogenital distance (AGD), while premature puberty onset was observed in female pups. This study provides the first evidence that subchronic exposure to environmentally relevant levels of GenX affects placental angiogenesis, potentially contributing to altered development in offspring. These findings offer new insights into the health impacts of GenX on reproductive development and raise concerns about its safety as a PFOA alternative.