Gestational Exposure to Low-Dose PFOA During Organogenesis Induces Embryofetal Developmental Alterations in Rats

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in human biological matrices, including placenta and umbilical cord blood, indicating early-life exposure. Perfluorooctanoic acid (PFOA), one of the most prevalent PFAS, has been associated with endocrine disruption and adverse reproductive outcomes. However, most toxicological studies rely on high-dose exposure models that do not reflect real-world conditions, limiting translational relevance. This study evaluated the effects of gestational exposure to environmentally relevant doses of PFOA during organogenesis on maternal toxicity and embryofetal development in Wistar rats. Pregnant females were orally exposed from gestational day (GD) 6 to 15 to control, 10, 100, or 1000µg/kg/day PFOA. On GD20, maternal and fetal parameters were assessed. PFOA exposure induced subtle maternal effects, including reduced gestational weight gain at the highest dose and biochemical alterations such as decreased total protein and uric acid levels, alongside increased calcium concentrations. Despite limited maternal toxicity, significant developmental alterations were observed. Notably, fetal growth patterns were altered, with a shift from AGA toward LGA at the intermediate dose in both sexes, suggesting a potential non-monotonic dose-response pattern. Structural analyses revealed congenital cardiomegaly and skeletal abnormalities, including supernumerary ribs, incomplete ossification, and sternal agenesis. These findings demonstrate that gestational exposure to environmentally relevant PFOA doses during organogenesis induces developmental toxicity even in the absence of overt maternal toxicity. Although these results are consistent with the concept that early developmental windows are highly sensitive to environmental contaminants, postnatal and long-term evaluations are required to determine whether these embryofetal changes persist or translate into later-life functional outcomes.