Methoxychlor stimulates estrogen-responsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor (non-ER) alpha and non-ER beta mechanism.
This study examined the effects of the xenoestrogen methoxychlor (Mxc) on messenger RNA (mRNA) concentrations of two estrogen-responsive uterine genes, lactoferrin (LF) and glucose-6-phosphate dehydrogenase (G6PD). Ovariectomized wild-type (WT) and estrogen receptor (ER) alpha-knockout (ER alphaKO) mice were treated with Mxc or estradiol-17beta (E2) to determine whether Mxc acts via pathways that involve ER alpha. In WT mice, both E2 and Mxc stimulated increases in uterine LF and G6PD mRNA concentrations in a dose-dependent manner. Competitive pretreatment with the pure antiestrogen ICI 182,780 dramatically reduced E2-stimulated increases in mRNA concentrations but had no effect on Mxc-induced effects. Competitive pretreatment with E2 had only a partially inhibitory effect on Mxc-induced responses. In the ER alphaKO mouse, E2 had little effect on uterine LF or G6PD mRNA concentrations, whereas Mxc stimulated marked increases in both LF and G6PD mRNAs. The Mxc-induced increases in LF and G6PD mRNAs in the ER alphaKO mouse were not suppressed by competitive pretreatment with either E2 or ICI 182,780. Fold increases in mRNA concentrations for both genes induced by Mxc were similar for WT and ER alphaKO mice. The results surprisingly indicate that a xenoestrogen, Mxc, can increase LF and G6PD mRNA concentrations by a mechanism that is not mediated through ER alpha or ER beta, and acts through another pathway.
Ghosh
D
D
Department of Biochemistry and Child Health, University of Missouri, Columbia 65211, USA.
Taylor
J A
JA
Green
J A
JA
Lubahn
D B
DB
D000818:Animals; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D007700:Kinetics; D007781:Lactoferrin / Q000235:genetics*; D008731:Methoxychlor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D005954:Glucosephosphate Dehydrogenase; D007781:Lactoferrin; D008731:Methoxychlor