Toxicity of Endogenous and Environmental Estrogens: What Is the Role of Elemental Interactions?

Stancel, George M.; Boettger‐Tong, Holly; Chiappetta, Constance; Hyder, Salman M.; Kirkland, John L.; Murthy, Lata; Loose-Mitchell, David S.

doi:10.2307/3432504

Cited by 11 publications

(12 citation statements)

References 14 publications

(18 reference statements)

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“…For example, data suggest variations between compounds in ER-ligand binding to EREs (31), time course of nuclear ER accumulation (36,52), patterns of gene activation (38), and other mechanistic characteristics. These and other data presented here suggest that the assumption that relative potency in in vitro screening assays is representative of relative potency for the most sensitive ERmediated in vivo effect has not been demonstrated to be accurate.…”

Section: Er Dynamics: Nuclear Accumulation and Impact Of Pharmacokinementioning

confidence: 99%

“…The long half-life of chlordecone, therefore, appears to moderate the relative potency of the compound in vivo, but may also moderate the qualitative estrogenic effect due to the potential importance of the time course of ER-ligand activity in the nucleus in determining the nature of the estrogenic response. For example, pharmacokinetics of the ER-ligand complex could affect the length of time that expression of some genes remain elevated (31).…”

Section: Er Dynamics: Nuclear Accumulation and Impact Of Pharmacokinementioning

confidence: 99%

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

Rudel

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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Section: Er Dynamics: Nuclear Accumulation and Impact Of Pharmacokinementioning

confidence: 99%

Section: Er Dynamics: Nuclear Accumulation and Impact Of Pharmacokinementioning

confidence: 99%

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

Rudel

1997

Environ Health Perspect

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“…At issue are both the degree to which low potency may limit hormonal effects (1,2) and the difficulty of assigning potencies to compounds with life stage-, cell-, and gene-specific effects (3)(4)(5)(6). Evaluating risk requires an accurate assessment of the relation between in vitro and animal tests of endocrine action and human responses.…”

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confidence: 99%

Cross-species and interassay comparisons of phytoestrogen action.

Whitten

Patisaul

2001

Environ Health Perspect

174

105

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This paper compiles animal and human data on the biologic effects and exposure levels of phytoestrogens in order to identify areas of research in which direct species comparisons can be made. In vitro and in vivo assays of phytoestrogen action and potency are reviewed and compared to actions, dose-response relationships, and estimates of exposure in human subjects. Binding studies show that the isoflavonoid phytoestrogens are high-affinity ligands for estrogen receptors (ERs), especially ER beta, but have lower potency in whole-cell assays, perhaps because of interactions with binding proteins. Many other enzymatic actions require concentrations higher than those normally seen in plasma. In vivo data show that phytoestrogens have a wide range of biologic effects at doses and plasma concentrations seen with normal human diets. Significant in vivoresponses have been observed in animal and human tests for bone, breast, ovary, pituitary, vasculature, prostate, and serum lipids. The doses reported to be biologically active in humans (0.4--10 mg/kg body weight/day) are lower than the doses generally reported to be active in rodents (10--100 mg/kg body weight/day), although some studies have reported rodent responses at lower doses. However, available estimates of bioavailability and peak plasma levels in rodents and humans are more similar. Steroidogenesis and the hypothalamic-pituitary-gonadal axis appear to be important loci of phytoestrogen actions, but these inferences must be tentative because good dose-response data are not available for many end points. The similarity of reported proliferative and antiproliferative doses illustrates the need for fuller examination of dose-response relationships and multiple end points in assessing phytoestrogen actions.

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“…If the chemicals tested test positive in this assay, then they are likely to cause proliferation in estrogen-sensitive cells in an animal's body (i.e., endometrium, breast tissue), and this proliferation could lead to cancer formation. 27 Fry and Toone found that when they injected fertilized sea bird eggs with DDT and its metabolites, the male chicks produced had varying degrees of intersexuality depending on dosage. The female chicks had partial-to-fully developed right oviducts, instead of just left function structure.…”

Section: Effect Of Environmental Estrogens On Wildlifementioning

confidence: 99%