Differential Activation of a Mouse Estrogen Receptor β Isoform (mER β 2) with Endocrine-Disrupting Chemicals (EDCs)

Abstract

Background:Endocrine-disrupting chemicals (EDCs) are suspected of altering estrogenic signaling through estrogen receptor (ER) α or β (mERβ1 in mice). Several EDC effects have been reported in animal studies and extrapolated to human studies. Unlike humans, rodents express a novel isoform of ERβ (mERβ2) with a modified ligand-binding domain sequence. EDC activity through this isoform remains uncharacterized.Objectives:We identified the expression pattern of mERβ2 in mouse tissues and assessed the estrogenic activity of EDCs through mERβ2.Methods:mERβ2 mRNA expression was measured in mouse tissues. HepG2 cells were used to assess the transactivation activity of mERβ isoforms with EDCs and ER co-activators. 293A cells transiently transfected with mER isoforms were used to detect EDC-mediated changes in endogenous ER target gene expression.Results:Expression of mERβ2 mRNA was detected in mouse reproductive tissues (ovary, testis, and prostate) and lung and colon tissues from both female and male mice. Five (E2, DES, DPN, BPAF, Coum, 1-BP) of 16 compounds tested by reporter assay had estrogenic activity through mERβ2. mERβ2 had a compound-specific negative effect on ERβ/ligand-mediated activity and ER target genes when co-expressed with mERβ1. mERβ2 recruited coactivators SRC2 or SRC3 in the presence of EDCs, but showed less recruitment than mERβ1.Conclusion:mERβ2 showed weaker estrogenic activity than mERβ1 in our in vitro system, and can dampen mERβ1 activity. In vivo models of EDC activity and ER-mediated toxicity should consider the role of mERβ2, as rodent tissue responses involving mERβ2 may not be reproduced in human biology.Citation:Donoghue LJ, Neufeld TI, Li Y, Arao Y, Coons LA, Korach KS. 2017. Differential activation of a mouse estrogen receptor β isoform (mERβ2) with endocrine-disrupting chemicals (EDCs). Environ Health Perspect 125:634–642; http://dx.doi.org/10.1289/EHP396

The promiscuous estrogen receptor: Evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

“…Unfortunately, various industrial chemicals containing phenolic groups can disrupt physiological responses to the ER in healthy people, and thus act as endocrine disruptors (Figure 4) [8][9][10][11][12]. Figure 4.…”

“…Many synthetic chemicals in the environment contain a phenolic group corresponding to the A ring on E2 and often contain a D ring with some similarity to the D ring on E2, which together promotes binding to the ER, disrupting normal estrogen physiology (Figure 4) [10,11,40]. For example, the phenolic hydroxyls on bisphenol A (BPA) contact Arg-394 and Glu-353 and His-524 in human ERα (Figure 8) [14,41].…”

The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

“…Unfortunately, various industrial chemicals containing phenolic groups can disrupt physiological responses to the ER in healthy people, and thus act as endocrine disruptors ( Figure 4) [8][9][10][11][12].…”

Species and Tissue Differences in β-Estradiol 17-Glucuronidation

“…Numerous studies have evaluated the in vivo effects of E2 using experimental animal models such as rats and mice, and many researchers have attempted to extrapolate the animal data to humans. [9][10][11] Since species differences in the kinetics of serotonin 12) and propofol glucuronidation 13) have been reported between human and rodents, it would be expedient to clarify whether similar differences occur in E17G formation.…”