Dataset Information

Hepatic transcriptome analysis of male and female Eastern Mosquitofish (Gambusia holbrooki) exposed to a progestin and anti-progesterone reveals the mode of action of endocrine disruption of synthetic steroids in an aquatic organism

ABSTRACT: Major classes of hormone mimics that have been studied include environmental estrogens and androgens, but recent studies have also demonstrated the significant impacts of natural and synthetic progesterones in the environment. The objective of this study was to evaluate the molecular and physiological impacts of progestin, anti-progestin, and mixture exposures in the Eastern Mosquitofish (G. holbrooki). By comparison of gene expression profiles and modulated biological processes in the three groups, it was determined that mifepristone acts more as a progestin than as an anti-progestin, as has also been demonstrated in other species of fish. This work contributes to the overall knowledge of the impacts of this class of chemical contaminats on aquatic organisms, which are a sentinel species for pollutants as aquatic ecosystems often become a reservoir for anthropogenic contaminants.

ORGANISM(S): Gambusia holbrooki

PROVIDER: GSE55518 | GEO | 2014/09/01

SECONDARY ACCESSION(S): PRJNA239818

REPOSITORIES: GEO

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Project description:Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR-mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding. ChIP experiments show that progestin promoted the interaction of USF1 with the proximal promoter of the Cdc2 gene, and Usf1 knockdown abrogated Cdc2 progestin-dependent transcriptional regulation providing a mechanism for direct regulation of its expression. Finally, Cdc2 knockdown blocked R5020 induced UIII cell proliferation. We conclude that progestin induced proliferation of endometrial stromal cells requires ERK1-2 and AKT mediated early regulation of USF1, that induces Cdc2. To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets.

Dataset Information

Hepatic transcriptome analysis of male and female Eastern Mosquitofish (Gambusia holbrooki) exposed to a progestin and anti-progesterone reveals the mode of action of endocrine disruption of synthetic steroids in an aquatic organism

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