title: Differential gene expression in response to methoxychlor and estradiol through ERalpha, ERbeta, and AR in reproductive tissues of female mice.
abstract: The reproductive and developmental effects of 17beta-estradiol (E2) and methoxychlor (MXC) observed in treated rodents appear to be linked to some unique but also overlapping patterns of gene expression. The MXC metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) was previously shown to have selective agonist activity through estrogen receptor alpha (ERalpha) and antagonist activity through ERbeta and androgen receptor (AR). To discover gene families regulated by HPTE and E2, and to characterize similarities and differences in patterns of gene expression induced by these selective ER ligands, we analyzed tissues from mice treated for 3 days with a combined treatment of E2 and HPTE (E2 + HPTE), or the antiandrogen flutamide (FLU). RNA from uteri and ovaries was analyzed with cDNA microarrays and real-time RT-PCR. Results indicate that HPTE and E2 acted similarly to regulate most gene families in the uterus, which expresses predominantly ERalpha. However, in both the uterus and the ovary, there were a few genes that displayed differential patterns of gene regulation by E2 or HPTE treatment, presumably through ERbeta, AR, or other unidentified pathways. In the uterus, progesterone receptor, ERalpha, AR, insulin-like growth factor 1, insulin-like growth factor binding protein 5, and clusterin mRNAs were significantly reduced with both E2 or HPTE treatments, whereas cathepsin B was induced. Conversely, in the ovary, induction of cathepsin B by E2 was reversed after cotreatment with HPTE, and ERbeta expression was induced similarly by HPTE and FLU but not by E2. In addition, E2 uniquely regulated glutathione peroxidase 3, glutathione S-transferase, and cytochrome P450 17alpha-hydroxylase, with no effect of HPTE or FLU treatments. This analysis demonstrated several gene families that appear to be regulated in a ligand-specific pattern, which may explain the unique but overlapping reproductive tissue pathologies following exposure to E2 and MXC.
authors.affiliation: Department of Endocrine, Reproductive and Developmental Toxicology, CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Waters
authors.forename: S
authors.initials: S
authors.lastname: Safe
authors.forename: K W
authors.initials: KW
authors.lastname: Gaido
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D004338:Drug Combinations; D004958:Estradiol / Q000633:toxicity*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D005485:Flutamide / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D005836:Genitalia, Female / Q000187:drug effects* / Q000378:metabolism; D008731:Methoxychlor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D017931:DNA Primers; D004338:Drug Combinations; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D004958:Estradiol; D005485:Flutamide; C404910:2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane; D008731:Methoxychlor