Abstract
This in silico toxicogenomic study aims to explore the relationship between phthalates and bisphenol A (BPA) co-exposure and obesity, as well as its comorbid conditions, in order to construct a possible set of genomic biomarkers. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) was used as the main data mining tool, along with GeneMania (https://genemania.org), ToppGene Suite (https://toppgene.cchmc.org) and DisGeNET (http://www.disgenet.org). Among the phthalates, bis(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) were chosen as the most frequently curated phthalates in CTD, which also share similar mechanisms of toxicity. DEHP, DBP and BPA interacted with 84, 90 and 194 obesity-related genes/proteins, involved in 67, 65 and 116 pathways, respectively. Among these, 53 genes/proteins and 42 pathways were common to all three substances. 31 genes/proteins had matching interactions for all three investigated substances, while more than half of these genes/proteins (56.49%) were in co-expression. 7 of the common genes/proteins (6 relevant to humans: CCL2, IL6, LPL, PPARG, SERPINE1, and TNF) were identified in all the investigated obesity comorbidities, while PPARG and LPL were most closely linked to obesity. These genes/proteins could serve as a target for further in vitro and in vivo studies of molecular mechanisms of DEHP, DBP and BPA mixture obesogenic properties. Analysis reported here should be applicable to any mixture of environmental chemicals and any disease present in CTD.
Highlights
It has been acknowledged that people are not exposed to a single, but to a great number of chemicals constantly
The information presented in Tab. 1 was obtained from the Gene tabs on the Comparative Toxicogenomics Database (CTD) website for each of the investigated substances across all the species included in the CTD database, since all the genes/proteins are listed in the CTD only if they are present in human genome (Meng et al, 2013)
The results of in silico study have indicated the presence of 31 obesity-related genes/proteins with matching interactions for DEHP, dibutyl phthalate (DBP) and bisphenol A (BPA), implying that these three substances might act in an additive manner on the development of this disorder
Summary
It has been acknowledged that people are not exposed to a single, but to a great number of chemicals constantly. This exposure usually occurs at low doses, by various routes, from a variety of sources (Kortenkamp, 2008). Considering that most mixtures contain multiple components, quantifying these interactions in terms of risk assessment is not an easy task. It includes mining published data and characterizing the mixture in the laboratory, and in silico hazard analysis and modeling (Hayes et al, 2019)
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