Graduate Student Sookmyung Women's University Sookmyung women's university, Republic of Korea
Abstract: Congenital heart diseases (CHDs), such as ventricular septal defects (VSDs), tetralogy of Fallot (TOF), and transposition of the great arteries (TGA), are among the most common congenital anomalies, often linked to environmental and chemical exposures during early pregnancy. While epidemiological studies have identified teratogens, such as maternal hyperglycemia and certain medications as risk factors for CHDs, their direct impact on human heart development remains poorly understood due to the limitation of animal models. To address this, we utilized a human induced pluripotent stem cell (hiPSC)-derived elongating heart organoid (eHO) model, which closely mimics the early stages of heart tube formation and subsequent elongation and looping, to investigate how teratogens influence the pathogenesis of CHDs. Using high glucose as a representative teratogen, we demonstrated its detrimental effects on eHO development, including significantly smaller size and reduced heart tube elongation. Furthermore, high glucose-treated eHOs exhibited aberrant looping dynamics, with accelerated and increased curvature, indicating disrupted morphogenetic regulation. Gene expression analysis revealed notable impairment in cardiac differentiation, with reduced levels of key cardiac markers such as NKX2-5 and TNNT2. Additionally, we observed significant DNA damage, indicating disrupted cellular integrity during heart development. These findings provide the first evidence of a direct, causal link between high glucose exposure and defects in early heart morphogenesis, particularly in the timing and degree of heart tube looping, a process essential for the proper alignment of heart chambers. The eHO model offers significant potential as a robust platform for modeling the effects of teratogens on early heart development and screening preventive interventions and therapeutic strategies aimed at teratogen-induced heart defects.
