Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity

The function of the uterus is regulated by female sex steroids and it is, t herefore, used as the classical target organ to detect estrogenic action. U terine response to estrogens involves the activation of a large pattern of estrogen-sensitive genes. This fact offers the opportunity to analyze the e strogenic activity of xeno- and phytoestrogens, and the mechanisms of their molecular action by a correlation of the uterotropic activity and their ab ility to modulate the expression of estrogen-sensitive genes. We have analy zed the expression of androgen receptor (AR), progesterone receptor (PR), e strogen receptor (ER), clusterin (CLU), complement C3 (C3), and GAPDH mRNA in the rat uterus following oral administration of ethinylestradiol (EE), b isphenol A (BPA), o,p'-DDT (DDT); p-tert-octylphenol (OCT) and daidzein (DA I). A significant stimulation of the uterine wet weight could be observed a fter administration of all the substances. The activity of all analyzed com pounds to stimulate uterine weight was low in comparison to EE. DDT has the highest activity to stimulate uterine weight whereas BPA and DAI turned ou t to be less potent. The analysis of gene expression revealed a very specif ic profile of molecular action in response to the different compounds which cannot be detected by judging the uterotropic response alone. A dose depen dent analysis revealed that C3 mRNA is already modulated at doses where no uterotropic response was detectable. Although DAI and BPA were very weak st imulators of uterine growth, these substances were able to alter the expres sion of AR, ER and C3 very strongly. Based on these investigations the anal yzed compounds can be subdivided into distinct classes: First, compounds wh ich exhibit a similar gene expression fingerprint as EE (e.g. OCT); second, compounds exhibiting a significant uterotropic activity, but inducing a pa ttern of gene expression different from EE (e.g. DDT); and third, compounds like BPA and especially DAI which exhibit a very low uterotropic activity, but nevertheless modulate the expression of estrogen-sensitive genes. Thes e findings strongly suggest that the fingerprint of uterine gene expression is a very sensitive tool to investigate estrogenicity of natural and synth etic compounds and offers the possibility to get information in regard to t he molecular mechanisms involved in the action of the respective compounds. (C) 2000 Elsevier Science Ltd. All rights reserved.