Hormonally Active Agents in the Environment (1999) / Chapter Skim
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2 Hormonally Active Agents
2 Hormonally Active Agents
Pages 27-53
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From page 27... ...
A1though naturally occurring HAAs are not discussed extensively in the chapters on biologic effects, those compounds are ubiquitous in the environment and may confound background levels of exposure to HAAs (see Chapter 3~. One of the charges to the committee was to identify, if possible, the underlying mechanisms of action of HAA-related effects, and so this chapter also considers the mechanism of action of estrogenic compounds as a model of others wherein a ligand binds to a receptor and the resulting ligand receptor complex alters the transcription of mRNA, and ultimately cytoplasmic translation and protein synthesis.
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From page 28... ...
is located in the cell nucleus and is a member of the superfamily of steroid and thyroid hormone receptors that act as ligandinduced nuclear transcription factors (Evans 1988~. Steroid-thyroid hormone receptors contain several common structural domains that are conserved between the various members of this superfamily (Gronemeyer 1991; Truss and Beato 1993; Beato et al.
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From page 29... ...
For example, antiestrogenic versus estrogenic activities can occur because of the interactions of the ER with different ligands (Jordan and Murphy 1990~. As is detailed in later chapters, many organic compounds have some estrogenic or antiestrogenic activity that can lead to a variety of biologic effects (see Chapters 5-10~.
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In this regard, is it possible that estrogenic compounds with low receptor-binding affinities may still be biologically potent if they circulate for long periods within the body. Accurately measuring rapidly dissociating estrogens is difficult when they
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Other estrogenic and antiestrogenic compounds could be studied to determine whether the structural characteristics of the bound ER are different when bound to estrogen .
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1997~. ERa and ERp bind estrogenic steroid hormones, naturally occurring estrogenic compounds, and synthetic estrogens, including many of those presented in Tables 2-1 and 2-2 (Kuiper et al.
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33 .> .= ¢ o be s°Cq 3 Cq o o .~ VO o o .= _.
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34 .~ Cal ¢ Em C)
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37 .^ ·^ ·^ o cat ~ ~o o Cd ~ · ¢ ~ ~Cd Cd C)
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. HydroxyPCB congeners were later shown to bind to the ER and induce estrogenic responses in the female rodent uterus (Korach et al.1988~.
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1996~. Natural Estrogenic Compounds Several structural classes of naturally occurring compounds in plants as well as fungal metabolites exhibit estrogenic activity in various bioassays (Figure 2-3, Table 2-2~.
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Flavonoid-derived compounds, such as coumestrol and equal; ligands, such as enterolactone and nordihydroguaiaretic acid (NDGA) , which are present in food; and the fungal metabolites zearalenone, zearalenol, and zearalanol, also exhibit estrogenic activity.
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From page 41... ...
1997~. Bioassays for Estrogenic Compounds Several assay systems have been developed to measure the potential estrogenic activity of xenoestrogens and naturally occurring estrogenic compounds: Cell proliferation, ER binding, induction of estradiol-responsive genes or gene products, and transient or stably transfected cell-bioassay systems are summarized below.
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From page 42... ...
Although each of these genes or gene products is induced by estrogenic compounds, the induction response could be specific to the target organ or cell, or gene products could be induced by other classes of HAAs. For example, prolactin synthesis might be induced by epidermal growth factor, thyrotropin-releasing factor, and phorbol esters (Ramsdell and Tashjian 1985~.
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Ruh and co-workers (1995) report that the weakly estrogenic bioflavonoid naringenin inhibited estradiol-induced uterine hypertrophy, peroxidase activity, PR concentrations, and [3Hithymidine uptake in immature female rats and luciferase activity in MCF7 cells transiently transfected with the estrogenresponsive pS2-Luc plasmid.
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From page 45... ...
. The estrogenic activity of the hydroxy-PCB congeners was further investigated by two estrogen-responsive in vitro bioassays: In one, HeLa cells were stably transfected with a Gal4: human ER chimera and a 17merregulated luciferase reporter gene, and in the other, MCF7 cells were transiently transfected with a plasmid that contained an estradiol-responsive vitellogenin A2 promoter and a chloramphenicol acetyl transferase (CAT)
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report that women exposed to TCDD as a result of an industrial accident in Seveso, Italy, exhibited a decreased incidence of mammary and endometrial cancer, suggesting that comparable antiestrogenic responses were observed in cellular and animal models and humans. There also is evidence that other Ah-receptor agonists, such as polynuclear aro
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1996~. The ER can also modulate gene expression by interacting with other DNA-bound transcription factors, and estrogen-mediated transcriptional activation can be observed through ER-AP1 and ER- Spl interactions in which ER does not bind promoter DNA (Paech et al.
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These sequences of 15-20 base pairs can convey estrogen responsiveness to reporter genes when ligated upstream of an appropriate promoter sequence. They have all the characteristics of enhancer sequences that are common regulatory elements in genes.
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The nature of these interactions has not been studied to any extent, but it is crucial for explaining how estrogenic compounds function. There are published reports of the ER interacting with transcription factors associated with polymerase II, the RNA-transcribing enzyme known to synthesize mRNAs (Ing et al.
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· The indirect positive hypothesis proposes that estrogens induce the synthesis of growth factors that, in turn, cause proliferation of estrogen-sensitive cells via stroma-epithelium paracrine (Dickson et al.
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The normal function of the embryonic receptors is, as yet, not fully understood, but studies involving administration of estrogen agonists and antagonists during development suggest a role for estrogen receptors in the development of the brain, reproductive organs, and other tissues, such as bone (vom Saal et al. 1992; Greco et al.
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SUMMARY AND CONCLUSIONS The estrogen receptor and other steroid or steroidlike hormone receptors can bind with a range of compounds and as such are potential vehicles for HAAs to act upon and influence normal cellular pathways. Steroid hormone receptors control fundamental gene-regulatory mechanisms, and interaction of HAAs with these receptors may disrupt these processes.
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From page 53... ...
The multiple mechanisms of ER-mediated responses include interaction of the ER with specific DNA sequences, such as estrogen-responsive elements, interaction with other transcription factors, crosstalk with other signaling pathways, and cell-membrane-mediated responses. Estrogen and HAAs appear to induce estrogen-responsive cell proliferation and related responses through common pathways.
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