Computational simulations aided prioritization of genomic targets for congenital heart disease (CHD) against developmental toxicity.

The determination of developmental toxicity (DT) is an emerging approach to investigate the environmental factors contributing to the development of congenital heart disease (CHD). However, the molecular interactions between these toxicants and cardiac-specific genes, along with the mechanisms, are not yet fully understood. This innovative study employed advanced in-silico techniques, such as protein-protein interaction (PPI) profiling, network analysis and molecular docking and dynamics simulations, to prioritize genomic targets and their associated toxicants. The study constructed a PPI network for CHD and identified key proteins includings GATA4, GATA6, NKX2-5, TBX5, MYH6, MYH11, TLL1, ANKRD1, CFC1, CRELD1, ZIC3, ACTC1, TBX20, TBX1, and HAND2. Fourteen maternal toxicants were reviewed and validated as potential causes of developmental toxicity using the Comparative Toxicogenomics Database (CTD). The minimum binding affinities of "Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)" against proteins TBX20, TLL1, NKX2-5, HAND2, ZIC3, and ACTC1, were -9.6, -9.5, -8.8, -8.7, -8.7, and -8.5 (kcal/mol), respectively compared to other toxicants. The residues PHE425 of TBX20 and PHE235 of TLL1 illustrated a strong bonding pattern with BPDE and demonstrated lower root mean square fluctuation (RMSF). Additionally, the compound it was found to inhibit hERG II channels, which could imply potential cardio-toxic effects. The study revealed that environmental toxicants during early pregnancy could inhibit the expression of prioritized heart developmental genes, highlighting the need for further in-vitro and in-vivo validation.