Differential spatiotemporal regulation of lactoferrin and progesterone receptor genes in the mouse uterus by primary estrogen, catechol estrogen, and xenoestrogen.
Many xenobiotics are considered reproductive toxins because of their ability to interact with the nuclear estrogen receptors (ERalpha and ERbeta). However, there is evidence that these xenobiotics can regulate gene expression in the reproductive targets by mechanisms that do not involve these ERs. To examine this further, we compared the effects of estrogenic (o,p'-DDT [1-(o-chlorophenyl)-1-(p-chlorophenyl)2,2,2-trichloroethane] and Kepone, chlordecone) and nonestrogenic (p,p'-DDD [1,1-dichloro-2,2-bis(p-chlorophenyl)ethane], a metabolite of p,p'-DDT) xenobiotics with those of 17beta-estradiol (E2) and 4-hydroxyestradiol-17beta (4-OH-E2), a catechol metabolite of E2, on uterine expression of lactoferrin (LF) and progesterone receptor (PR). These genes are estrogen responsive in the mouse uterus. Normally, LF is expressed in the uterine epithelium, whereas PR is expressed in both the epithelium and stroma in response to estrogenic stimulation. Ovariectomized mice were injected with xenobiotics (7.5 mg/kg), E2 (10 microg/kg), 4-OH-E2 (10 microg/kg), or the vehicle (oil, 0.1 ml/mouse), and uterine tissues were processed for Northern blot and in situ hybridization. The pure antiestrogen ICI-182780 (ICI; 1 or 20 mg/kg) was used to interfere with estrogenic responses that were associated with the ERs. The results of Northern and in situ hybridization demonstrated increased uterine levels of PR and LF messenger RNAs (mRNAs) by all of these xenobiotics, but quantitatively the responses were much lower than those induced by E2 or 4-OH-E2. The results further showed that the E2-inducible epithelial LF mRNA accumulation was markedly abrogated by pretreatment with ICI (20 mg/kg). In contrast, this treatment retained the epithelial expression of PR mRNA, but down-regulated the stromal expression. In contrast, ICI had negligible effects on LF and PR mRNA responses to 4-OH-E2, indicating that this catechol estrogen exerted its effects primarily via a mechanism(s) other than the ERs. The heightened accumulation of LF mRNA in the epithelium in response to Kepone and o,p'-DDT was also severely compromised by pretreatment with ICI, but this antiestrogen had little effect on responses to p,p'-DDD. Similar to E2, Kepone increased the expression of PR mRNA in both uterine epithelium and stroma. However, pretreatment with ICI decreased stromal cell expression, whereas epithelial cell expression remained unaltered or increased. These responses were not noted in mice treated with o,p'-DDT or p,p'-DDD. Collectively, the results demonstrate that catechol estrogens or xenobiotics can alter uterine expression of estrogen-responsive genes by mechanisms that are not totally mediated by the classical nuclear ERs, and these alterations are cell type specific. We conclude that an interaction of a compound with the nuclear ERalpha and/or ERbeta is not an absolute requirement for producing specific estrogen-like effects in the reproductive target tissues.
Das
S K
SK
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Ralph L. Smith Research Center, Kansas City 66160-7338, USA. sdas@kumc.edu
Tan
J
J
Johnson
D C
DC
Dey
S K
SK
D000818:Animals; D002396:Catechols / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects*; D007781:Lactoferrin / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics*; D013997:Time Factors; D014599:Uterus / Q000187:drug effects / Q000502:physiology*; D015262:Xenobiotics / Q000494:pharmacology*
D002396:Catechols; D004965:Estrogen Antagonists; D004967:Estrogens; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D015262:Xenobiotics; D000077267:Fulvestrant; D004958:Estradiol; D007781:Lactoferrin; C034221:catechol