Methoxychlor stimulates estrogen-responsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor (Non-ER)α and Non-ERβ 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 alpha KO) mice were treated with Mxc or estradiol-17 beta (E-2) to determine whether Mxc acts via pathways that involve ER alpha. In WT mice, both E-2 and Mxc stimulated increases in uterine LF and GGPD mRNA concentrations in a dose-dependent manner. Competitive pretreatment with the pure antiestrogen ICI 182,780 dramatically reduced E-2-stimulated increases in mRNA concentrations but had no effect on Mxc-induced effects. Competitive pretreatment with E-2 had only a partially inhibitory effect on Mxc-induced responses. In the ER alpha KO mouse, E-2 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 alpha KO mouse were not suppressed by competitive pretreatment with either E-2 or ICI 182,780. Fold increases in mRNA concentrations for both genes induced by Mxc were similar for WT and ER alpha KO 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.