Developmental perfluorooctane sulfonate exposure and adult bone loss: Involvement of bone remodeling and inflammation.

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant with potential developmental toxicity. This study investigated the long-term consequences of prenatal PFOS exposure on adult bone health in offspring and explored potential mechanisms. Pregnant mice were orally administered PFOS (0, 0.3, or 3 mg/kg/day) from gestational day 11-18. The offspring were raised to adulthood (postnatal day 98) and analyzed. Micro-CT and histological analyses revealed significant deterioration of femoral microarchitecture, characterized by reduced bone mineral density, decreased trabecular number, and disrupted trabecular connectivity. These structural alterations were accompanied by a marked imbalance in bone remodeling, where male offspring exhibited predominant suppression of osteogenic activity along with enhanced bone marrow adiposity, while female offspring showed greater susceptibility to osteoclast activation. At the molecular level, PFOS exposure downregulated key osteogenic markers (Runx2, Sp7, Col1a1, OCN) and upregulated adipogenic (Pparγ, Cebpα, Fabp4, Plin1, Adipoq) and osteoclastogenic factors (RANKL, NFATC1, c-Fos, TRAP, Ctsk). A pronounced pro-inflammatory cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6, IL-17) and impaired gut barrier integrity were also observed, suggesting a potential gut-bone axis involvement. In conclusion, our study provides novel evidence that prenatal PFOS exposure causes persistent impairment of bone quality in adult offspring, with notable sexual dimorphism in response. This highlights the significant long-term skeletal risks of developmental exposure to environmental pollutants and underscores the need for considering sex-specific vulnerabilities in public health assessments.