Dataset Information

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

ACCESS DATA

Publications

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

Donoghue Lauren J LJ Neufeld Thomas I TI Li Yin Y Arao Yukitomo Y Coons Laurel A LA Korach Kenneth S KS

Environmental health perspectives 20160916 4

<h4>Background</h4>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.<h4>Objectives</h4>We identified the expression pattern of mERβ2 in mouse tissues ...[more]

PMID: 27634370

Similar Datasets

Project description:BackgroundThe effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations.ObjectivesWe hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care.MethodsAdult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations.ResultsGerm cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved.DiscussionRats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets