Submitted April 17, 2002
Returned for revision May 28, 2002
Accepted November 1, 2002
Toxicology
Differential Effects of Natural and Environmental
Estrogens on Endothelin Synthesis in Bovine Oviduct Cells
Karin C. Reinhart 1,
Raghvendra K. Dubey 2,
Barbara Cometti 2,
Paul J. Keller 2,
Marinella Rosselli 2*
1 University Hospital, Zurich, Switzerland
2 University Hospital - Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: mari{at}fhk.usz.ch.
Abstract
Endothelin-1 (ET-1), a vasoconstrictor and mitogenic
peptide which plays an important role within the
endocrine/reproductive system, is synthesized by oviduct
cells and regulates tubal contractility. Because
17
-estradiol (estradiol) regulates oviduct function
by influencing the synthesis of autocrine/paracrine
factors, it is feasible that 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
influence the reproductive system. Using cultures of
bovine oviduct cells (epithelial cells: fibroblast, 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. Quantitative
enzyme-linked immunoassay for ET-1 in the culture medium
revealed that 17-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, and in the following
order of potency: Xenoestrogens (0.1µmol/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 , moreover, 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 induce deleterious
effects on the reproductive system by adversely
influencing the biology and physiology of the oviduct.
Key words:
Environment •
Toxicology •
Estradiol receptor •
Growth factors •
Oviduct
