Reproductive and general metabolic effects of phytoestrogens in mammals

Kaldas, Rami S.; Hughes, Claude L.

doi:10.1016/0890-6238(89)90042-7

Cited by 83 publications

(22 citation statements)

References 25 publications

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“…The mixed agonistic-antagonistic effects of these chemical groups on estrogen-mediated processes in mammals and mammalian cells are well established (41)(42)(43). Many flavanoids have now been shown to competitively bind to ER␣ (15,44) and induce reporter gene activity in transiently transfected MCF-7 cells and yeast containing E2-responsive reporter constructs (45,46).…”

Section: Assaysmentioning

confidence: 99%

Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) α and ERβ

Routledge¹,

White²,

Parker³

et al. 2000

Journal of Biological Chemistry

321

172

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It has been proposed that tissue-specific estrogenic and/or antiestrogenic actions of certain xenoestrogens may be associated with alterations in the tertiary structure of estrogen receptor (ER) ␣ and/or ER␤ following ligand binding; changes which are sensed by cellular factors (coactivators) required for normal gene expression. However, it is still unclear whether xenoestrogens affect the normal behavior of ER␣ and/or ER␤ subsequent to receptor binding. In view of the wide range of structural forms now recognized to mimic the actions of the natural estrogens, we have assessed the ability of ER␣ and ER␤ to recruit TIF2 and SRC-1a in the presence of 17␤-estradiol, genistein, diethylstilbestrol, 4-tert-octylphenol, 2,3,4,5-tetrachlorobiphenyl-ol, and bisphenol A. We show that ligand-dependent differences exist in the ability of ER␣ and ER␤ to bind coactivator proteins in vitro, despite the similarity in binding affinity of the various ligands for both ER subtypes. The enhanced ability of ER␤ (over ER␣) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ER␤ to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2. We conclude that ligand-dependent differences in the ability of ER␣ and ER␤ to recruit coactivator proteins may contribute to the complex tissue-dependent agonistic/antagonistic responses observed with certain xenoestrogens.One of the greatest challenges in understanding the mechanisms of estrogen action has been to determine how different estrogen receptor (ER) 1 ligands (steroidal estrogens, antiestrogens, xenoestrogens) produce such diverse biological effects. The recent discovery of a second subtype of the estrogen receptor, named estrogen receptor-␤ (ER␤) to distinguish it from the classical ER (now renamed ER␣), adds another level of complexity to the mechanism of estrogen action and has opened new possibilities by which estrogens might exert tissue-and cell-specific effects (1). Indeed, it has been shown that ⌭R␣ and ER␤ differ in terms of their ability to activate gene expression from either the consensus estrogen response element (ERE) from the VTG gene or the divergent ERE from the luteinizing hormone ␤ gene in transiently transfected Cos-1 cells (2). Moreover, ⌭R␣ and ER␤ activate and inhibit, respectively, transcription from an AP1 enhancer site when complexed to 17␤-estradiol (E2), whereas ER␤ was a transcriptional activator on AP1 sites when complexed to antiestrogens (3). Studies in rodents have revealed that the distribution and relative levels of ⌭R␣ and ER␤ expression differ among tissues. For example, ⌭R␣ is predominantly expressed in the pituitary, uterus, ovary (oviduct and germinal epithelium), mammary gland, testis, epididymis, and kidney, whereas ER␤ is the predominant form in regions of the hypothalamus, ovary (granulosa cells), prostate gland, lung, and bladder (4 -8). The coexpression of ⌭R␣ and ER␤ in certain tissues and cells, and the ability of ⌭R␣ and ER␤ to form heterodimers and bind...

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Section: Assaysmentioning

confidence: 99%

Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) α and ERβ

Routledge¹,

White²,

Parker³

et al. 2000

Journal of Biological Chemistry

321

172

View full text Add to dashboard Cite

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“…Diethylstilbestrol (DES), a synthetic non-steroidal estrogen, exhibits a high estrogenic activity by binding to the ERs, and is thus a useful model compound for evaluating the potential toxicity of a wide range of chemicals that affect or mimic estrogen activity [7]. Previous studies have shown that fetal and/or neonatal treatment of rodents with DES induces adverse changes similar to those that occur after administration of estradiol-17β [1,10,34], dichlorodiphenyl trichloroethane (DDT) and methoxychlor (an estrogenic pesticide currently used as a substitute for DDT) [14,38]. It is suggested that many of the adverse changes to the testis and reproductive tract induced by exposure to estrogens result from a combination of high estrogen and low andro-gen activity [39].…”

mentioning

confidence: 99%

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Warita

Sugawara

Yue

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. For the purpose of investigation of working mechanisms in endocrine disruptors, we evaluated the dose-related effects of fetal and/or neonatal exposure to an estrogenic compound on the male reproductive organs in adult mice, particularly with respect to gene expression of steroidogenic acute regulatory protein (StAR). The pregnant ICR mice were given subcutaneous injections of 10 µg/day/ animal of diethylstilbestrol (DES) to subject the fetal mice to in utero exposure (IUE). Subsequently, the newborn male mice were subjected to neonatal exposure (NE) by treatment with vehicle or 0.1-10 µg/day/animal of DES. Fertility rates of each group were as follows: control, 100%; IUE only, 60%; IUE+NE 0.1 µg, 25%; IUE+NE 1 µg, 0%; IUE+NE 10 µg, 0%. In general histology, germ cell layers in the seminiferous tubules were thinned in the group of IUE+NE 10 µg. Hypoplasia of the Leydig cells, in which the staining intensity of eosin was diminished, was also observed in the groups of IUE+NE 0.1-10 µg. The androgen receptor (AR) and estrogen receptor alpha (ERα) immunoexpression in the Leydig cells of IUE+NE 1-10 µg was slightly lower than that in the controls. Longterm dysfunction of the hypothalamo-pituitary-testicular axis, including sustained hypoproduction of gonadotropin and testosterone, and altered expressions of steroid hormone receptors and StAR genes were observed. The hypothalamo-pituitary control of gonadotropin secretion may be affected by the smaller doses of estrogenic agents than the reproductive organs. Furthermore, the fertility rate in the male mice exposed to this estrogenic agent was closely correlated with the testosterone levels, and even more so with the rate-limiting factor of steroidogenesis, StAR. This finding suggests that endocrine disruptors have an important pronounced effect on StAR gene expression. KEY WORDS: diethylstilbestrol (DES), endocrine disruptors, fertility rate, fetal and/or neonatal exposure, steroidogenic acute regulatory protein (StAR).

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“…The in vitro effect of genistein is biphasic; low concentrations stimulate cell growth and estrogen-dependent gene expression, whereas higher concentrations inhibit cell growth [Wang et al, 1996]. Estrogen antagonistic effects of genistein may be mediated through the induction of sex hormone binding globulin (SHBG) [Mousavi and Adlercreutz, 1993], inhibition of aromatase [Campbell and Kurzer, 1993] and 17␤-hydroxysteroid oxidoreductase activities [Makela et al, 1994[Makela et al, , 1995, and impairment of the CNS or pituitary response to gonadotropins [Faber and Hughes, 1991;Kaldas and Hughes, 1989; reviewed in Adlercreutz and Mazur, 1997].…”

Section: Phytoestrogens: Isoflavonesmentioning

confidence: 98%

Clinical development of estrogen modulators for breast cancer chemoprevention in premenopausal vs. postmenopausal women

Lawrence¹,

Malpas²,

Sigman³

et al. 2000

J. Cell. Biochem.

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Tamoxifen has proven to be beneficial in the chemoprevention of breast cancer in women at increased risk for the disease. Other compounds that mediate the estrogen pathway remain to be tested for clinical efficacy. The mechanism of action, efficacy, and dose response of the estrogen modulators is determined by the hormonal milieu of the host which should be considered in the early clinical trials for dose range finding studies and surrogate endpoint biomarker (SEB) evaluation. This review presents the hormonal effects to consider in the clinical testing of an agent in premenopausal vs. postmenopausal cohorts. Recommended SEBs that may be evaluated in Phase I/II clinical trials of estrogen modulators for breast cancer chemoprevention are presented. J. Cell. Biochem. Suppl. 34:103-114, 2000. 2000 Wiley-Liss, Inc.Key words: selective estrogen receptor modulators; SERMs; aromatase inhibitors; isoflavones; ovarian-pituitary axis; bone turnover; lipid metabolism; endometrium Hormonal approaches to breast cancer have been successful in both the treatment and prevention of the disease. Studies in breast cancer epidemiology and laboratory in vitro and in vivo investigations have suggested a role for estrogen in the initiation, promotion and spread of breast cancer. In the treatment setting, estrogen modification with oophorectomy or tamoxifen has had a significant impact on the survival of women diagnosed with breast cancer [Early Breast Cancer Trialists Group, 1992]. The chemopreventive properties of tamoxifen were first demonstrated by the reduction of second primaries in a meta-analysis of breast cancer survivors who had taken the drug for five years [Fisher et al., 1989;Rutqvist et al., 1991]. Based on this analysis, tamoxifen became the lead compounds in breast cancer chemoprevention studies. A large breast cancer prevention trial recently completed in the United States showed a 49% risk reduction for invasive breast cancer among subjects who took tamoxifen; the benefit was seen in both pre-and postmenopausal age groups [Fisher et al., 1998]. These results are encouraging, and other compounds that affect estrogen are currently under evaluation to determine whether they might have clinical advantages over tamoxifen. Clinical testing of estrogen modulators has shown that the hormonal milieu is a critical determinant of their mechanism of action, efficacy, and dose response. This review will present some of the estrogen-mediated effects to be considered in testing estrogen modulators for cancer prevention in premenopausal and postmenopausal women.The clinical effects of estrogen have been extensively studied in postmenopausal women. In this population, decreased estrogen is associated with risk for osteoporosis, cardiovascular disease, and vasomotor symptoms. Emerging evidence suggests that neuropsychiatric function may also be impacted [Grady et al., 1992;Henderson et al., 1994]. In contrast, the effect of estrogen modulation in premenopausal women is largely unknown, although the impact in this younger coh...

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Reproductive and general metabolic effects of phytoestrogens in mammals

Cited by 83 publications

References 25 publications

Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) α and ERβ

Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) α and ERβ

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

Clinical development of estrogen modulators for breast cancer chemoprevention in premenopausal vs. postmenopausal women

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