Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes

Abstract

Although biological effects of endocrine disrupting chemicals (EDCs) are often observed at unexpectedly low doses with occasional nonmonotonic dose-response characteristics, transcriptomewide profiles of sensitivities or dose-dependent behaviors of the EDC responsive genes have remained unexplored. Here, we describe expressome analysis for the comprehensive examination of dosedependent gene responses and its applications to characterize estrogen responsive genes in MCF-7 cells. Transcriptomes of MCF-7 cells exposed to varying concentrations of representative natural and xenobiotic estrogens for 48 h were determined by microarray and used for computational calculation of interpolated approximations of estimated transcriptomes for 300 doses uniformly distributed in log space for each chemical. The entire collection of these estimated transcriptomes, designated as the expressome, has provided unique opportunities to profile chemical-specific distributions of ligand sensitivities for large numbers of estrogen responsive genes, revealing that at low concentrations estrogens generally tended to suppress rather than to activate transcription. Gene ontology analysis demonstrated distinct functional enrichment between high-and low-sensitivity estrogen responsive genes, supporting the notion that a single EDC chemical can cause qualitatively distinct biological responses at different doses. Expressomal heatmap visualization of dose-dependent induction of Bisphenol A inducible genes showed a weak gene activation peak at a very low concentration range (ca. 0.1 nM) in addition to the main, strong gene activation peak at and above 100 nM. Thus, expressome analysis is a powerful approach to understanding the EDC dose-dependent dynamic changes in gene expression at the transcriptomal level, providing important information on the overall profiles of ligand sensitivities and nonmonotonic responses.

The Effects of Soy Supplementation on Gene Expression in Breast Cancer: A Randomized Placebo-Controlled Study

“…There is extensive evidence that FGFR2 drives cancer growth through its role as a potent oncogene, and increased FGFR2 expression is a marker of poor prognosis in BC (40)(41)(42). We found statistically significant overexpression of FGFR2 by microarray and qPCR in tumors of patients taking soy compared with placebo and increased expression in two paired tumor samples before and after soy supplementation.…”

Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

“…Future studies need to explore effects at lower doses, since EDCs can elicit a nonmonotonic response that significantly deviates from the usual sigmoidal curve (Vandenberg et al, 2012). In another transcriptomics study in which MCF-7 cells were exposed to varying concentrations of BPA, a weak gene activation peak at a very low concentration range (~0.1 nM) was observed in addition to the main peak of gene activation (Shioda et al, 2013). Additionally, an investigation of the combinatorial effects of bisphenols would reflect real-world exposure conditions even if estrogenic effects of chemical mixtures in vitro are predicted by the use of concentration addition models (Evans et al, 2012).…”

“…BPA is one of the best-studied endocrine disrupting chemicals (EDCs), with more than 75 out of 91 published studies showing associations between BPA exposure and human health as of May 2013 (Rochester, 2013). The primary mode of action of BPA is the activation of estrogen receptor (ER) mediated transcription (Shioda et al, 2013). Biomonitoring studies suggest that the urine from a majority of individuals in industrialized countries contain measurable BPA and metabolites (Gerona et al, 2016).…”

Endocrine Disruption by Mixtures in Topical Consumer Products

“…The non-monotonic nature of most endocrine responses [137], together with the unclear interactions of endocrine actives, still needs an answer. While collecting more data from research on individual substances, a precautionary method should be applied to finished products aimed to be used by high risk categories (babies and children, pregnant and breast-feeding women) or in the genital area, or that can strongly effect the environment (toiletries, sunscreens), to benefit both the consumers and the manufacturers.…”