Mapping Chemical-Gene Interactions for Developmental Lethality and Pregnancy Loss

Purpose: Pregnancy loss affects 10 to 15% of clinically recognized pregnancies and is driven by genetic and environmental factors. Interactions between genes and chemicals critically shape developmental outcomes, yet existing resources do not organize chemical gene evidence by gestational timing, maternal fetal compartment, or lethality context. Methods: To minimize this gap, we merged Intolerome genes and the Comparative Toxicogenomics Database databases to create a filtered network of 928 lethality associated genes and ~4,000 chemicals. We developed the Chemical Gene Atlas (CGA) application, which analyzes chemical gene interactions using four filters supporting hypothesis generation and clinical translation. Results: Using recurrent pregnancy loss (RPL) as a case study, CGA identified five clinically important genes (F5, F2, AURKB, PADI6, and FOXD1) demonstrating different exposomic patterns with Bisphenol A (BPA) and Benzo[a]pyrene (B[a]P). These exposures affect gene expression, methylation, and coagulation pathways and placental function. Our findings demonstrate that genes with loss of function intolerance, especially those expressed in metabolic and cardiovascular systems, are susceptible to environmental disruption during critical windows of development, including implantation, placental development, and early organogenesis. Conclusion: The CGA platform provides a scalable model to investigate chemical-gene interactions leading to developmental lethality. CGA is available at https://cgatlas.org/.