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 a bility to interact with the nuclear estrogen receptors (ER alpha and E R beta). However, there is evidence that these xenobiotics can regulat e gene expression in the reproductive targets by mechanisms that do no t involve these ERs. To examine this further, we compared the effects of estrogenic (o,p'-DDT rophenyl)-1-(p-chlorophenyl)2,2,2-trichloroeth ane] and Kepone, chlordecone) and nonestrogenic (p,p'-DDD) [1,1-dichlo ro-2,2-bis(p-chlorophenyl)ethane], a metabolite of p,p'-DDT) xenobioti cs with those of 17 beta-estradiol (E-2) and 4-hydroxyestradiol-17 bet a (4-OH-E-2), a catechol metabolite of E-2, on uterine expression of l actoferrin (LF) and progesterone receptor (PR). These genes are estrog en responsive in the mouse uterus. Normally, LF is expressed in the ut erine epithelium, whereas PR is expressed in both the epithelium and s troma in response to estrogenic stimulation. Ovariectomized mice were injected with xenobiotics (7.5 mg/kg), E-2 (10 mu g/kg), 4-OH-E-2 (10 mu g/kg), or the vehicle (oil, 0.1 ml/mouse), and uterine tissues were processed for Northern blot and in situ hybridization. The pure antie strogen ICI-182780 (ICI; 1 or 20 mg/kg) was used to interfere with est rogenic responses that were associated with the ERs. The results of No rthern 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 E-2 or 4-OH-E-2. The results further showed that the E-2-inducible epithe lial LF mRNA accumulation was markedly abrogated by pretreatment with ICI (20 mg/kg). In contrast, this treatment retained the epithelial ex pression of PR mRNA, but down-regulated the stromal expression. In con trast, ICI had negligible effects on LF and PR mRNA responses to 4-OH- E-2, indicating that this catechol estrogen exerted its effects primar ily 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 a lso severely compromised by pretreatment with ICI, but this antiestrog en had little effect on responses to p,p'-DDD. Similar to E-2, Kepone increased the expression of PR mRNA in both uterine epithelium and str oma. However, pretreatment with ICI decreased stromal cell expression, whereas epithelial cell expression remained unaltered or increased. T hese responses were not noted in mice treated with o,p'-DDT or p,p'-DD D. Collectively, the results demonstrate that catechol estrogens or xe nobiotics 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 in teraction of a compound with the nuclear ER alpha and/or ER beta is no t an absolute requirement for producing specific estrogen-like effects in the reproductive target tissues.