Mapping Chemical-Gene Interactions for Developmental Lethality and Pregnancy Loss

Area of Science:

• Reproductive toxicology
• Developmental biology
• Environmental health

Background:

• Pregnancy loss impacts 10-15% of pregnancies, influenced by genetic and environmental factors.
• Existing resources lack organization for chemical-gene interactions by gestational timing, maternal-fetal compartment, or lethality context.

Purpose of the Study:

• To bridge the gap in understanding chemical-gene interactions related to pregnancy loss.
• To develop a resource organizing chemical-gene evidence by developmental context.

Main Methods:

• Merged Intolerome genes and Comparative Toxicogenomics Database data.
• Created a network of 928 lethality-associated genes and ~4,000 chemicals.
• Developed the Chemical-Gene Atlas (CGA) application with four filters for hypothesis generation and clinical translation.

Main Results:

• Identified five clinically important genes (F5, F2, AURKB, PADI6, FOXD1) associated with recurrent pregnancy loss (RPL).
• Demonstrated differential exposomic patterns of Bisphenol A (BPA) and Benzo[a]pyrene (B[a]P) affecting these genes.
• Showcased disruption of gene expression, methylation, coagulation pathways, and placental function.

Conclusions:

• Genes with loss-of-function intolerance, particularly in metabolic and cardiovascular systems, are susceptible to environmental disruption.
• Environmental exposures impact critical developmental windows like implantation, placental development, and early organogenesis.
• The CGA platform offers a scalable model for investigating chemical-gene interactions causing developmental lethality.