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

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

SUBMITTER: Donoghue LJ 

PROVIDER: S-EPMC5381991 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature