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Updated: May 13, 2025
In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Computational simulations aided prioritization of genomic targets for congenital heart disease (CHD) against
Adarsh Kumar Shukla1, Prachi Kukshal1
1Department of Genomics Research, Sri Sathya Sai Sanjeeveni Research Foundation, Palwal, Haryana 121102, India.
Abstract:
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.
Insights
Environmental toxicants can cause developmental toxicity, potentially leading to congenital heart disease by interfering with key heart genes. Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) shows strong binding to critical cardiac proteins, suggesting a molecular mechanism for this risk.
Area of Science:
- Environmental Toxicology
- Cardiovascular Genetics
- Computational Biology
Background:
- Congenital heart disease (CHD) development is influenced by environmental factors, but the underlying molecular mechanisms involving toxicants and cardiac genes are poorly understood.
- Developmental toxicity (DT) studies are crucial for identifying environmental contributors to CHD.
- Understanding gene-toxicant interactions is essential for preventing birth defects.
Purpose of the Study:
- To identify key cardiac genes and associated environmental toxicants implicated in congenital heart disease (CHD) using in-silico methods.
- To elucidate the molecular interactions between prioritized toxicants and cardiac-specific genes.
- To investigate the potential mechanisms by which environmental exposure may lead to developmental toxicity and CHD.
Main Methods:
- Protein-protein interaction (PPI) network analysis was constructed to identify key proteins involved in CHD.
- In-silico techniques including network analysis, molecular docking, and molecular dynamics simulations were employed.
- Comparative Toxicogenomics Database (CTD) was used to validate maternal toxicants associated with developmental toxicity.
Main Results:
- A PPI network identified crucial CHD-related proteins, including GATA4, GATA6, NKX2-5, TBX5, and others.
- Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) exhibited significant binding affinities to cardiac proteins TBX20, TLL1, NKX2-5, HAND2, ZIC3, and ACTC1.
- BPDE demonstrated strong bonding with specific residues in TBX20 and TLL1 and was found to inhibit hERG II channels, suggesting potential cardiotoxic effects.
Conclusions:
- Environmental toxicants during early pregnancy may inhibit the expression of critical heart developmental genes, contributing to CHD.
- BPDE is identified as a significant toxicant with strong binding to key cardiac proteins, highlighting a potential molecular mechanism for developmental toxicity.
- Further in-vitro and in-vivo validation is necessary to confirm the findings and fully understand the toxicological impact on cardiac development.
