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Estradiol and Bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells.

ABSTRACT: Hormonal alterations during development have lifelong effects on the prostate gland. Endogenous estrogens, including 17beta-estradiol (E(2)), and synthetic estrogenic endocrine disruptors, such as bisphenol A (BPA), have similar effects on prostate development. Increasing exposure to estrogens within the low-dose, physiologic range results in permanent increases in the size and androgen responsiveness of the prostate, whereas exposure within the high-dose, pharmacologic range has the opposite effects.We tested the hypothesis that the low-dose effects of estrogens on the developing prostate are associated with increased expression of androgen receptor (Ar) and estrogen receptor 1 (alpha) (Esr1) genes in mesenchyme cells.Ar and Esr1 mRNA levels were quantified in primary cultures of fetal mouse prostate mesenchyme cells treated with E(2) and BPA.Ar and Esr1 mRNA expression increased in response to E(2), with thresholds of 0.001 and 0.037 nM, respectively; and in response to BPA, with a threshold of 1 nM for both mRNAs. We did not observe the expected inhibition of Ar mRNA expression by pharmacologic levels of E(2) relative to unexposed cells.The observed induction of gene expression occurred at concentrations within the range of free E(2) previously shown to permanently increase prostate size, thus supporting the involvement of direct effects of estrogens on gene expression in prostate mesenchyme. The effects of BPA occurred within the range of concentrations currently measured in human serum, demonstrating the vulnerability of developing tissues to xenoestrogens.

SUBMITTER: Richter CA

PROVIDER: S-EPMC1892114 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Estradiol and Bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells.

Richter Catherine A CA Taylor Julia A JA Ruhlen Rachel L RL Welshons Wade V WV Vom Saal Frederick S FS

Environmental health perspectives 20070227 6

<h4>Background</h4>Hormonal alterations during development have lifelong effects on the prostate gland. Endogenous estrogens, including 17beta-estradiol (E(2)), and synthetic estrogenic endocrine disruptors, such as bisphenol A (BPA), have similar effects on prostate development. Increasing exposure to estrogens within the low-dose, physiologic range results in permanent increases in the size and androgen responsiveness of the prostate, whereas exposure within the high-dose, pharmacologic range ...[more]

PMID: 17589598

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Project description:Estradiol-17beta (E(2)beta) and its metabolites, which are sequentially synthesized by cytochrome P450s and catechol-O-methyltransferase to form 2 and 4-hydroxyestradiol (OHE(2)) and 2- and 4-methoxestradiol (ME(2)), are elevated during pregnancy. We investigated whether cytochrome P450s and catechol-O-methyltransferase are expressed in uterine artery endothelial cells (UAECs) and whether E(2)beta and its metabolites modulate cell proliferation via ER-alpha and/or ER-beta and play roles in physiological uterine angiogenesis during pregnancy. Cultured ovine UAECs from pregnant and nonpregnant ewes were treated with 0.1 to 100.0 nmol/L of E(2)beta, 2-OHE(2), 4-OHE(2), 2-ME(2), and 4-ME(2). ER-alpha or ER-beta specificity was tested using ICI 182 780, ER-alpha-specific 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinyleth oxy)phenol]-1H-pyrazole dihydrochloride, ER-beta-specific 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo [1,5-a]pyrim idin-3-yl]phenol antagonists and their respective agonists ER-alpha-specific 4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol and ER-beta-specific 2,3-bis(4-Hydroxyphenyl)-propionitrile. Angiogenesis was evaluated using 5-bromodeoxyuridine proliferation assay. Using confocal microscopy and Western analyses to determine enzyme location and levels, we observed CYP1A1, CYP1A2, CYP1B1, CYP3A4, and catechol-O-methyltransferase expression in UAECs; however, expressions were similar between nonpregnant UAECs and pregnant UAECs. E(2)beta, 2-OHE(2), 4-OHE(2), and 4-ME(2) treatments concentration-dependently stimulated proliferation in pregnant UAECs but not in nonpregnant UAECs; 2-ME(2) did not stimulate proliferation in either cell type. Proliferative responses of pregnant UAECs to E(2)beta were solely mediated by ER-beta, whereas responses to E(2)beta metabolites were neither ER-alpha nor ER-beta mediated. We demonstrate an important vascular role for E(2)beta, its cytochrome P450- and catechol-O-methyltransferase-derived metabolites, and ER-beta in uterine angiogenesis regulation during pregnancy that may be dysfunctional in preeclampsia and other cardiovascular disorders.

Dataset Information

Estradiol and Bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells.

Publications

Estradiol and Bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells.

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