Effects of the aryl hydrocarbon receptor agonist 3-methylcholanthrene on the 17β-estradiol regulated mRNA transcriptome of the rat uterus. Issue 171 (July 2017)

• Record Type: Journal Article
• Authors: Helle, Janina; Keiler, Annekathrin M.; Zierau, Oliver; Dörfelt, Peggy; Vollmer, Günter; Lehmann, Leane; Chittur, Sridar V.; Tenniswood, Martin; Welsh, JoEllen; Kretzschmar, Georg
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 171(2017)
• Page Start: 133
• Page End: 143
• Publication Date: 2017-07
• Subjects: Polycyclic aromatic hydrocarbons -- 17β-estradiol -- Uterus -- Aryl hydrocarbon receptor -- Uterotrophic assay; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.03.004
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: E2 upregulates the expression of 1356 genes and downregulates the expression of 1134 genes in a standard adult rat uterotrophic assay. Regulation of PG synthesis by E2 probably leads to a downregulation of labor inducing PGF2 α. Additional treatment with 3-MC inhibits the effect of E2 on most genes, including those belonging to PG synthesis and regulation. Upregulation of ERβ, but not E2 metabolism, could be identified as a likely factor involved in the antiestrogenic effects of 3-MC. Abstract: Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion of organic compounds, abundant in exhaust fumes and cigarette smoke. They act by binding to the aryl hydrocarbon receptor (AHR) which induces expression of phase 1 and phase 2 enzymes in the liver. PAH induced AHR activation may also lead to adverse effects by modulating other pathways, for example estrogen receptor (ER) signaling in the female reproductive tract. We have investigated the effects of the PAH 3-methylcholanthrene (3-MC) on 17β-estradiol (E2) dependent signaling in the uterus of ovariectomized rats to characterize the cross talk between AHR and ER on an mRNA transcriptome wide scale. A standard three day uterotrophic assay was performed in young adult Lewis rats. Treatment induced effects were analyzed using histology, immunohistochemistry and gene expression analysis by microarray and qPCR . 3-MC shows broad E2 antagonistic effects on uterine mRNA transcription of the vast majority of E2 regulated genes, significantly altering prostaglandin biosynthesis, complement activation, coagulation pathways and other inflammatory response pathways. The regulation of ER expression in the uterus, but not the regulation of E2 metabolism in the liver, was identified as a potentially important factor in mediating this general antiestrogenic effect. The regulation of prostaglandin biosynthesis by E2 is important for inflammation-like events during pregnancy including the initiation of birth. Our results suggest that adverse effects of PAHs on prostaglandin related pathways are likely caused by the interference with E2 signaling, specifically by inhibiting the E2 mediated downregulation of PGF2α. Characterization of the generalized antagonistic effect of 3-MC on E2 dependent signaling in the rat uterus thus contributes to a better understanding of molecular mechanisms of the toxicity of PAHs in female reproductive organs.