MicroRNA Network Regulation of Developmental Bone Toxicity in a Human Embryonic Stem Cell Osteogenic Model

Toxicant exposure impaired osteogenic differentiation at their IC50, as reflected by altered expression of osteogenic markers and transcriptional remodeling. Global miRNA profiling revealed dysregulation of miRNAs enriched for bone-related biological processes, including regulators of osteogenic commitment and differentiation timing. Integrated miRNA–mRNA network analysis identified a subset of miRNAs linked to core osteogenic and lineage-associated pathways, including RUNX2-dependent transcription and BMP and Wnt signaling.

Modulation of representative miRNAs produced osteogenic outcomes consistent with those observed following toxicant exposure and, in some cases, was associated with partial restoration of differentiation in exposed cultures. Collectively, these findings indicate that chemically diverse developmental toxicants are associated with miRNA-mediated regulatory patterns during osteogenic differentiation. Identification of conserved miRNA signatures provides mechanistic insight into developmental bone toxicity and supports the use of miRNA network analysis as a human-relevant endpoint for skeletal hazard identification.