Divergent epigenetic and transcriptional responses to bisphenol A and thalidomide in human pluripotent stem cells

Evaluating epigenetic toxicity during early development is important for understanding how chemical exposure may influence developmental trajectories. We compared the effects of bisphenol A (BPA) and thalidomide (TMD) on differentiation, gene expression, and enhancer-associated epigenetic states in human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). TMD produced more fold-change-defined responsive genes than BPA and a larger set of genes shared across conditions, together with locus-specific H3K27ac changes near LEFTY2 , MT1X , and MT1H . These responses were associated with altered expression of lineage-related genes during subsequent differentiation. In contrast, BPA produced fewer responsive genes, with limited initial H3K27ac changes but altered lineage-associated gene expression during embryoid body differentiation. Notably, both chemicals were associated with changes in lineage markers, including HAND1 , FOXA2 , and SOX1 , although the patterns differed between the two cell lines and across developmental stages. These findings suggest that BPA and TMD elicit divergent epigenetic and transcriptional responses in human pluripotent stem cells and highlight the value of comparative pluripotent stem cell models and epigenomic analyses for understanding chemical effects during early developmental stages. They further raise the possibility that even subtle differences in cellular state at the time of exposure may influence subsequent responses to chemical perturbation.