Citation:

Hunter, S. Presentations: Adverse Outcome Pathways for Abnormal Phenotypes. Society of Toxicology and ISTD-WIP, Durham, North Carolina, March 15, 2016.

Impact/Purpose:

Birth defects affect many infants and the etiology for most are unknown. Although environmental factors are known to influence pregnancy outcome, thousands of chemicals, present in the environment, are untested for developmental toxicity potential. Application of computational predictive models for adverse developmental effects, based on adverse outcome pathways (AOPs), will aid in the identification and characterization of potential teratogens in the exposure universe. This research is the first step in the identification of molecular initiating events linked to abnormal morphological phenotypes. As key events and the key event relationships are defined, this approach can be used as the basis for building quantitative AOPs that an be used to assess risk following human exposure to environmental chemicals

Description:

Birth defects affect many infants and the etiology for most are unknown. Although environmental factors are known to influence pregnancy outcome, thousands of chemicals, present in the environment, are untested for developmental toxicity potential. Application of computational predictive models for adverse developmental effects, based on adverse outcome pathways (AOPs), will aid in the identification and characterization of potential teratogens in the exposure universe. The Mouse Genome Informatics phenotype database was used to identify genes associated with 10 high-level developmental phenotypes (including craniofacial, cardiovascular, skeletal and limb defects/abnormalities). Panther Classification System was then used to identify annotated pathways for genes in each phenotype. Additionally, a subset of 21 cardiovascular phenotypes, focused on abnormal heart development, and abnormal septa, atria, ventricle, outflow tract, atrioventricular canal and valve morphologies were selected from the 160 distinct phenotypes for abnormal cardiovascular system morphology and evaluated. This analysis revealed 393 genes that map collectively to 60 annotated biological pathways, resulting in a pathway-phenotype association matrix for conditions such as abnormal outflow tract and valvulo-septal defects. TGF-β, EGF, integrin, Wnt and Notch signaling pathways were common associations. The signaling pathways associated with selected cardiovascular phenotypes were used as an anchor to probe the ToxCast chemical library for bioactivity in these pathways. A Toxicological Priority Index (ToxPI) created for 1,061 ToxCast chemicals identified 223 compounds having activity in the selected pathways at concentration ≤ 1 µM. This approach does not selectively identify chemicals that are cardiac teratogens in vivo, but, does identify chemicals with a potential to affect the pathways associated with cardiovascular defects. As such, a systematic pathway-based analysis of specific developmental defects can be incorporated into an AOP-based phenotypic model for developmental toxicity.

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