Environmental health studies relate how exposures (e.g., chemicals) affect human health and disease; however, in most cases, the molecular and biological mechanisms connecting an exposure with a disease remain unknown. To help fill in these knowledge gaps, we sought to leverage content from the public Comparative Toxicogenomics Database (CTD) to identify potential intermediary steps. In a proof-of-concept study, we systematically compute the genes, molecular mechanisms, and biological events for the environmental health association linking air pollution toxicants with two cardiovascular diseases (myocardial infarction and hypertension) as a test case. Our approach integrates five types of curated interactions in CTD to build sets of “CGPD-tetramers”, computationally constructed information blocks relating a Chemical-Gene interaction with a Phenotype and Disease. This bioinformatics strategy generates 653 CGPD-tetramers for air pollution-associated myocardial infarction (involving 5 pollutants, 58 genes, and 117 phenotypes) and 701 CGPD-tetramers for air pollution-associated hypertension (involving 3 pollutants, 96 genes, and 142 phenotypes). Collectively, we identify 19 genes and 96 phenotypes shared between these two air pollutant-induced outcomes, and suggest important roles for oxidative stress, inflammation, immune responses, cell death, and circulatory system processes. Moreover, CGPD-tetramers can be assembled into extensive chemical-induced disease pathways involving multiple gene products and sequential biological events, and many of these computed intermediary steps are validated in the literature. Our method does not require a priori knowledge of the toxicant, interacting gene, or biological system, and can be used to analyze any environmental chemical-induced disease curated within the public CTD framework.
Authors: Allan Peter Davis, Thomas C Wiegers, Cynthia J Grondin, Robin J Johnson, Daniela Sciaky, Jolene Wiegers, Carolyn J Mattingly
; Full Source: Toxicological sciences : an official journal of the Society of Toxicology 2020 Jul 14;kfaa113. doi: 10.1093/toxsci/kfaa113.