Stage-specific cardiotoxicity induced by bisphenol A using human pluripotent stem cell-derived 2D- and 3D-cardiomyocyte models

Bisphenol A (BPA), a widely used industrial chemical with endocrine-disrupting properties, raises developmental and cardiotoxicity concerns. We established a stage-specific cardiotoxicity platform using human pluripotent stem cell (hPSC)-derived cardiomyocytes in two-dimensional and three-dimensional (3D) cultures. BPA exposure at ⩾10 µM significantly reduced cell viability and downregulated pluripotency and cardiac lineage markers such as OCT4, NKX2-5, and cTnT in a stage-dependent manner. Electrophysiological analysis revealed that acute exposure to 10 µM BPA disrupted action potentials in hPSC-derived cardiomyocytes, inducing membrane depolarization and rhythm disturbances. Furthermore, 3D cardiac tissues treated with 10 or 50 µM BPA exhibited severe mitochondrial deformation and impaired contractile function, as observed by TEM and beating analysis. Reproducing these effects in a personalized hPSC line validated the platform's applicability for patient-specific toxicity assessment. These findings highlight the importance of integrating developmental stage-specific and 3D human-relevant models for comprehensive cardiotoxicity evaluation of environmental chemicals such as BPA.