Exposure to airborne fine particulate matter disrupts human embryonic stem cell osteogenic differentiation

Developmental bone toxicity encompasses impairments in skeletal growth and remodeling during embryonic and fetal development that can result in long-term skeletal abnormalities. Airborne fine particulate matter (FPM; ≤2.5 µm) is a size-defined fraction of particulate air pollution that occurs across diverse environments, with particularly elevated concentrations in many urban regions. While FPM exposure has been linked to bone loss and osteoporosis in adults, its effects on early skeletal development remain poorly understood. Here, we employed a human embryonic stem cell (hESC)-based osteogenic differentiation model to examine how exposure to FPM is associated with alterations in bone formation. Integrating functional, molecular, and transcriptomic analyses, we compared ambient FPM collected in Irvine, CA, with a standard reference material (SRM 1648a; urban dust). Fine PM exposure was associated with concentration-dependent reductions in alkaline phosphatase activity and calcium deposition, consistent with altered osteogenic differentiation. Transcriptomic and molecular toxicology profiling revealed enrichment of apoptotic, metabolic, and xenobiotic-response pathways alongside suppression of osteogenic gene networks. Among the differentially expressed genes, SERPINA3 emerged as a consistently upregulated gene associated to FPM exposure during osteogenic differentiation. Together, these findings provide evidence that FPM exposure could disrupt osteogenic differentiation in a human-relevant in vitro model and support the inclusion of bone-related endpoints in particle toxicology and developmental hazard-identification frameworks.