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Mapping Chemical-Gene Interactions for Developmental Lethality and Pregnancy Loss

Syed Hassan Bukhari1, Amrita Nagasuri1, Boris Oskotsky1

  • 1Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA.

Medrxiv : the Preprint Server for Health Sciences
|November 24, 2025
PubMed
Abstract

Insights

Environmental exposures can cause pregnancy loss by disrupting critical genes during development. The Chemical-Gene Atlas (CGA) tool helps identify these chemical-gene interactions and vulnerable developmental periods.

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.
Keywords:
Chemical-Gene InteractionsDevelopmental LethalityExposomicsPregnancy LossRecurrent Pregnancy Loss (RPL)

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