Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats

Markaverich, Barry M.; Webb, Brett T.; Densmore, Charles L.; Gregory, Rebecca R.

doi:10.2307/3432433

“…In (34,35). In more recent experiments, it increased uterine wet and dry weights but did not cause depletion of cytosolic ER, accumulation of nuclear ER, or uterine hyperplasia and DNA synthesis, all characteristic estrogen responses (36). Lack of uterine DNA synthesis was observed in these experiments even after multiple injections of coumestrol, indicating that coumestrol was not like estriol or other short-acting or weak endogenous estrogens, which have been shown to mimic more potent estrogens following chronic dosing.…”

Section: Introductionmentioning

confidence: 77%

Predicting health effects of exposures to compounds with estrogenic activity: methodological issues.

Rudel

¹

1997

Environ Health Perspect

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Many substances are active in in vitro tests for estrogenic activity, but data from multigenerational and other toxicity studies are not available for many of those substances. Controversy has arisen, therefore, concerning the likelihood of adverse health effects. Based on a toxic equivalence factor risk assessment approach, some researchers have concluded that exposure to environmental estrogens is not associated with estrogen receptor (ER)-mediated health effects. Their rationale cites the low potency of these compounds in in vitro assays relative to estradiol, and the widespread exposure to pharmaceutical, endogenous, and dietary estrogens. This reasoning relies on two assumptions: that the relative estrogenic potency in in vitro assays is predictive of the relative potency for the most sensitive in vivo estrogenic effect; and that all estrogens act via the same mechanism to produce the most sensitive in vivo estrogenic effect. Experimental data reviewed here suggest that these assumptions may be inappropriate because diversity in both mechanism and effect exists for estrogenic compounds. Examples include variations in ER-ligand binding to estrogen response elements, time course of nuclear ER accumulation, patterns of gene activation, and other mechanistic characteristics that are not reflected in many in vitro assays, but may have significance for ER-mediated in vivo effects. In light of these data, this report identifies emerging methodological issues in risk assessment for estrogenic compounds: the need to address differences in in vivo end points of concern and the associated mechanisms; pharmacokinetics; the crucial role of timing and duration of exposure; interactions; and non-ER-mediated activities of estrogenic compounds. Environ Health Perspect 1 05(Suppl 3): 655-663 (1997)

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“…Increases in uterine weight have been reported for CM (Hunter et al 1999;Markaverich et al 1995;Tinwell et al 2000), MXC (Eroshenko and Cooke 1990;Laws et al 2000;Mehmood et al 2000), and BPA (Ashby and Tinwell 1998;Laws et al 2000;Papaconstantinou et al 2000). Increases in uterine epithelial cell height have been shown for CM (Medlock et al 1995;O'Connor et al 2000), for MXC (Eroshenko and Cooke 1990;Newbold et al 2001;Rourke et al 1991), and for BPA (Markey et al 2001;Papaconstantinou et al 2000;Steinmetz et al 1998).…”

mentioning

confidence: 89%

Increases in mouse uterine heat shock protein levels are a sensitive and specific response to uterotrophic agents.

Papaconstantinou

¹

,

Fisher

²

,

Umbreit

³

et al. 2002

Environ Health Perspect

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There is increasing consensus that the uterotrophic estrogenicity assay should be coupled with other morphometric or molecular end points that might enhance its sensitivity. We have previously shown that bisphenol A (BPA), similarly to 17ss-estradiol (E2), increases levels of uterine heat shock proteins (hsps), mainly hsp90alpha and glucose-regulated protein (grp) 94. In this study we investigated whether increases in uterine hsp levels are a specific response of estrogens or estrogen mimics. We therefore examined the ability of a) E2, diethylstilbestrol (DES), and tamoxifen (TAM); b) the xenoestrogens coumestrol (CM), methoxychlor (MXC), BPA, and dibutyl phthalate (DBP); c) the progestin medroxyprogesterone (MED); d) the glucocorticoid dexamethasone (DEX); and e) phytol (PHY), a precursor to a retinoid X and peroxisome proliferator-activating receptor agonist, to increase uterine weights and alter uterine morphology and hsp levels. We showed that DES, TAM, CM, MXC, and BPA significantly increased uterine weights and uterine hsp90alpha and grp94 levels. Even though the doses of CM, MXC, and BPA used were much higher than the E2 dose, those treatments resulted in lower increases in uterine weight. On the other hand, increases in grp94 levels were equal to those induced by E2 treatment. Treatments with MED, DEX, DBP, or PHY did not significantly alter uterine weight or morphology and had no significant effects on uterine hsp levels. The results of this study suggest that only the estrogens increase uterine hsp90alpha and grp94 levels, and that this hsp effect is a more sensitive uterotrophic response than uterine weight increase.

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“…Nuclear ER levels return to approximately control levels about 10 hr after treatment with estradiol (46). Cytosolic ER levels decrease as nuclear ER levels increase and ultimately increase above control levels (36,46 estrogen is apparent from their study. The weak estrogen dimethylstilbestrol (DMS) and its dimethylether DMS-(OMe)2, which does not bind ER, were tested in the assay.…”

Section: Er Dynamics: Nuclear Accumulation and Impact Of Pharmacokinementioning

confidence: 99%

“…Although these factors are important to consider in predicting the health effects of exposure to compounds with estrogenic activity, the conclusion that environmental estrogens will not be associated with adverse health effects relies on several assumptions that must be carefully examined (27 (34,35). In more recent experiments, it increased uterine wet and dry weights but did not cause depletion of cytosolic ER, accumulation of nuclear ER, or uterine hyperplasia and DNA synthesis, all characteristic estrogen responses (36). Lack of uterine DNA synthesis was observed in these experiments even after multiple injections of coumestrol, indicating that coumestrol was not like estriol or other short-acting or weak endogenous estrogens, which have been shown to mimic more potent estrogens following chronic dosing.…”

Section: Introductionmentioning

confidence: 99%

Predicting Health Effects of Exposures to Compounds with Estrogenic Activity: Methodological Issues

Rudel¹

1997

Environmental Health Perspectives

View full text Add to dashboard Cite

Many substances are active in in vitro tests for estrogenic activity, but data from multigenerational and other toxicity studies are not available for many of those substances. Controversy has arisen, therefore, concerning the likelihood of adverse health effects. Based on a toxic equivalence factor risk assessment approach, some researchers have concluded that exposure to environmental estrogens is not associated with estrogen receptor (ER)-mediated health effects. Their rationale cites the low potency of these compounds in in vitro assays relative to estradiol, and the widespread exposure to pharmaceutical, endogenous, and dietary estrogens. This reasoning relies on two assumptions: that the relative estrogenic potency in in vitro assays is predictive of the relative potency for the most sensitive in vivo estrogenic effect; and that all estrogens act via the same mechanism to produce the most sensitive in vivo estrogenic effect. Experimental data reviewed here suggest that these assumptions may be inappropriate because diversity in both mechanism and effect exists for estrogenic compounds. Examples include variations in ER-ligand binding to estrogen response elements, time course of nuclear ER accumulation, patterns of gene activation, and other mechanistic characteristics that are not reflected in many in vitro assays, but may have significance for ER-mediated in vivo effects. In light of these data, this report identifies emerging methodological issues in risk assessment for estrogenic compounds: the need to address differences in in vivo end points of concern and the associated mechanisms; pharmacokinetics; the crucial role of timing and duration of exposure; interactions; and non-ER-mediated activities of estrogenic compounds. Environ Health Perspect 1 05(Suppl 3): 655-663 (1997)

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Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats

Cited by 32 publications

References 47 publications

Predicting health effects of exposures to compounds with estrogenic activity: methodological issues.

Predicting health effects of exposures to compounds with estrogenic activity: methodological issues.

Increases in mouse uterine heat shock protein levels are a sensitive and specific response to uterotrophic agents.

Predicting Health Effects of Exposures to Compounds with Estrogenic Activity: Methodological Issues

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