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Differential Effects of Natural and Environmental Estrogens on Endothelin Synthesis in Bovine Oviduct Cells¹

^a Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital, 8091 Zurich, Switzerland ^b Department of Medicine, Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224

Endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide that plays an important role within the endocrine/reproductive system, is synthesized by oviduct cells and regulates tubal contractility. Because 17ß-estradiol (estradiol) regulates oviduct function by influencing the synthesis of autocrine/paracrine factors, estradiol may also regulate ET-1 synthesis. Furthermore, environmental estrogens (EEs; phytoestrogens and xenoestrogens), which structurally resemble estradiol and possess estrogenic activity, may mimic the effects of estradiol on ET-1 synthesis and may influence the reproductive system. Using cultures of bovine oviduct cells (epithelial cells:fibroblasts, 1:1), we investigated and compared the modulatory effects of estradiol, phytoestrogens, and xenoestrogens on ET-1 synthesis and determined whether these effects were estrogen receptor (ER) mediated. A quantitative ELISA for ET-1 in the culture medium revealed that 17ß-estradiol inhibits ET-1 synthesis in a concentration-dependent manner (4–400 nmol/L). In contrast to estradiol, ET-1 synthesis was induced in cell cultures treated with xenoestrogens in the following order of potency (0.1 µmol/L): 4-hydroxy-trichlorobiphenyl > 4-hydroxy-dichlorobiphenyl > trichlorobiphenyl. The stimulatory effects of xenoestrogens on ET-1 production were mimicked by the phytoestrogens biochanin-A and genistein but not by formononetin, equol, and daidzein. The oviduct cells expressed both ERs ( and ß), but the modulatory effects of estradiol, but not EEs, on ET-1 synthesis were blocked by ICI-182 780 (1 µM), a pure ER antagonist. Our results provide evidence that estradiol inhibits ET-1 synthesis in oviduct cells via an ER-dependent mechanism, whereas, EEs induce ET-1 synthesis via an ER-independent mechanism. The contrasting effects of EEs on ET-1 synthesis suggests that EEs may act as endocrine modulators/disruptors and may have deleterious effects on the reproductive system by adversely influencing the biology and physiology of the oviduct.

¹ This work was supported by the Swiss National Science Foundation (grants 32-55738.98 and 32-64040.00).

² Correspondence. FAX: 41 1 255 44 39; marinella.rosselli{at}fhk.usz.ch