Identification of environmental chemicals targeting miscarriage genes and pathways using the comparative toxicogenomics database.

Autor: Harris SM; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Jin Y; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Loch-Caruso R; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Padilla IY; Department of Civil Engineering and Surveying, University of Puerto Rico, Mayagüez, Puerto Rico., Meeker JD; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA., Bakulski KM; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA. Electronic address: bakulski@umich.edu.
Jazyk: angličtina
Zdroj: Environmental research [Environ Res] 2020 May; Vol. 184, pp. 109259. Date of Electronic Publication: 2020 Feb 19.
DOI: 10.1016/j.envres.2020.109259
Abstrakt: Background: Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses.
Methods: We used miscarriage (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in human, mouse, and rat. We assessed enrichment for gene ontology biological processes among the miscarriage genes. We prioritized chemicals (n = 25) found at Superfund sites or in the blood or urine pregnant women. For chemical-disease gene sets of sufficient size (n = 13 chemicals, n = 20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We cross-validated enrichment results.
Results: Miscarriage was annotated with 121 genes and overrepresented in inflammatory response (q = 0.001), collagen metabolic process (q = 1 × 10 -13 ), cell death (q = 0.02), and vasculature development (q = 0.005) pathways. The number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5607 (atrazine). In humans, all chemicals tested were highly enriched for miscarriage gene overlap (all p < 0.001; parathion PRR = 7, cadmium PRR = 6.5, lead PRR = 3.9, arsenic PRR = 3.5, atrazine PRR = 2.8). In mice, highest enrichment (p < 0.001) was observed for naphthalene (PRR = 16.1), cadmium (PRR = 12.8), arsenic (PRR = 11.6), and carbon tetrachloride (PRR = 7.7). In rats, we observed highest enrichment (p < 0.001) for cadmium (PRR = 8.7), carbon tetrachloride (PRR = 8.3), and dieldrin (PRR = 5.3). Our findings were robust to 1000 permutations each of variable gene set sizes.
Conclusion: We observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for miscarriage genes. Exposures to chemicals linked to miscarriage, and thus linked to decreased probability of live birth, may limit the inclusion of fetuses susceptible to adverse birth outcomes in epidemiology studies. Our findings have critical public health implications for successful pregnancies and the interpretation of adverse impacts of environmental chemical exposures on pregnancy.
Competing Interests: Declaration of competing interest The authors declare they have no actual or potential competing financial interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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