Gestational PFOS Exposure Induces Alveolar Developmental Defects by Affecting Immune–Epithelial Crosstalk in Offspring Rats

Perfluorooctane sulfonate (PFOS), an environmental endocrine-disrupting compound, can adversely affect offspring lung development following gestational exposures. However, the underlying cellular and molecular mechanisms have yet to be fully elucidated. In our research, dams were orally administered PFOS (0.1 mg/kg BW) from gestational days 11 to 20, and the offspring lungs were assessed at postnatal days 0, 7, 14, and 21. It was shown that gestational PFOS exposure induced bronchopulmonary dysplasia (BPD)-like pathology, characterized by simplified alveolar structure, glycogen retention, and collagen deposition. Single-cell RNA sequencing analysis of newborn rat lungs revealed that PFOS profoundly remodeled the pulmonary cellular landscape, resulting in a pronounced accumulation of transitional alveolar epithelial type II cells (AECIIs), and a shift of alveolar macrophages toward pro-inflammatory and pro-fibrotic phenotypes. Intercellular communication analysis indicated that molecules originating from monocytes and alveolar macrophages, including the FN1-CD44 axis, may be the major signals responsible for epithelial defects. Overall, these findings identify the disruption of AECII differentiation as a pivotal event in alveolar developmental defects and provide novel insights into the role of immune-epithelial crosstalk in PFOS-induced pulmonary toxicity.