title: Effects of the aryl hydrocarbon receptor agonist 3-methylcholanthrene on the 17β-estradiol regulated mRNA transcriptome of the rat uterus.
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.
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Helle
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Annekathrin M
authors.initials: AM
authors.lastname: Keiler
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Zierau
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Dörfelt
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
authors.affiliation: Institute of Pharmacy and Food Chemistry, Universität Würzburg, 97070 Würzburg, Germany.
authors.forename: Leane
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, University at Albany, NY 12144-2345, United States.
authors.forename: Sridar V
authors.initials: SV
authors.lastname: Chittur
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, University at Albany, NY 12144-2345, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Tenniswood
authors.affiliation: Cancer Research Center and Department of Biomedical Sciences, University at Albany, NY 12144-2345, United States.
authors.forename: JoEllen
authors.initials: J
authors.lastname: Welsh
authors.affiliation: Institute of Zoology, Molecular Cell Physiology and Endocrinology, Technische Universität Dresden, 01062, Dresden, Germany. Electronic address: georg.kretzschmar@tu-dresden.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Kretzschmar
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000633:toxicity; D020847:Estrogen Receptor Modulators / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008748:Methylcholanthrene / Q000633:toxicity*; D009928:Organ Specificity; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D011917:Rats, Inbred Lew; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D002274:Carcinogens, Environmental; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D004958:Estradiol; D008748:Methylcholanthrene
keywords: 17β-estradiol; Aryl hydrocarbon receptor; Polycyclic aromatic hydrocarbons; Uterotrophic assay; Uterus