Differential Activation of a Mouse Estrogen Receptor β Isoform (mERβ2) with Endocrine-Disrupting Chemicals (EDCs)

Background: Endocrine-disrupting chemicals (EDCs) are suspected of altering estrogenic signaling through estrogen receptor (ER) alpha or beta (mER beta 1 in mice). Several EDC effects have been reported in animal studies and extrapolated to human studies. Unlike humans, rodents express a novel isoform of ER beta (mER beta 2) with a modified ligand-binding domain sequence. EDC activity through this isoform remains uncharacterized. Objectives: We identified the expression pattern of mER beta 2 in mouse tissues and assessed the estrogenic activity of EDCs through mER beta 2. Methods: mER beta 2 mRNA expression was measured in mouse tissues. HepG2 cells were used to assess the transactivation activity of mER beta 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 mER beta 2 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 mER beta 2. mER beta 2 had a compound-specific negative effect on ER beta/ligand-mediated activity and ER target genes when co-expressed with mER beta 1. mER beta 2 recruited coactivators SRC2 or SRC3 in the presence of EDCs, but showed less recruitment than mER beta 1. Conclusion: mER beta 2 showed weaker estrogenic activity than mER beta 1 in our in vitro system, and can dampen mER beta 1 activity. In vivo models of EDC activity and ER-mediated toxicity should consider the role of mER beta 2, as rodent tissue responses involving mER beta 2 may not be reproduced in human biology.