Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Tissue-specific regulation of estrogen receptor in CD1 mice

DeVito, Michael J.; Thomas, Thresia; Martin, Eugene; Umbreit, Thomas H.; Gallo, Michael A.

doi:10.1016/0041-008x(92)90126-d

Cited by 105 publications

(41 citation statements)

References 33 publications

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“…A number of possible mechanisms, nevertheless, have been suggested for the anti-estrogenic actions of TCDD, which include stimulation of estrogen metabolism [14,15], a possible direct antiestrogenic action [13,16,17], and also possible alterations of the binding interaction between the estrogen receptor and its response element [18,19]. Since TCDD is an extremely potent agonist for the aryl hydrocarbon receptor (AhR), which mediates the induction of a number of drug-metabolizing enzymes in liver as well as in extrahepatic tissues [20], it has been widely considered that chronic TCDD administration may alter the multiple pathways of endogenous estrogen metabolism in certain ways that may contribute to an altered hormonal activity and also tumor incidence in various estrogen target organs.…”

Section: Introductionmentioning

confidence: 99%

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every two weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 μg/kg b.w. once every two weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD, a potent Ah receptor agonist, may have an obesity-inducing effect in animals fed a HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals a HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2-and 4-hydroxylation of 17β-estradiol in animals fed a control diet, but surprisingly not in animals fed a HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of 1 This study was supported, in part, by a grant from the American Cancer Society (RSG-02-143-01-CNE to BTZ) and also by grants from the NIH (CA92391, CA97109 and ES05022). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD. NIH Public Access

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Section: Introductionmentioning

confidence: 99%

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Zhu

Gallo

Burger

et al. 2008

Toxicology and Applied Pharmacology

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“…PCB77, a dioxinlike coplanar biphenyl, was discovered to produce antiestrogenic responses (27). In this case, the antiestrogenicity may be mediated by induction of estrogen metabolizing enzymes (28), through downregulation of estrogen receptors (29), or decreased affinity of the ligand:receptor complex for the DNA estrogen response element (30), rather than competitive inhibition at the estrogen receptor. This nonortho-substituted PCB was modeled in the non-coplanar conformation which possibly accounts for the relatively "active" predicted value.…”

Section: Discussionmentioning

confidence: 99%

Using Three-Dimensional Quantitative Structure-Activity Relationships to Examine Estrogen Receptor Binding Affinities of Polychlorinated Hydroxybiphenyls

Waller¹,

Minor²,

McKinney³

1995

Environmental Health Perspectives

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Certain phenyl-substituted hyd ns of environmental concen have the potential to disrupt the endocrine system of animals, apparently in association with their estrogenic properties. Competition with natural estrogens for the estrogen receptor isaa possible mechanism by which such effects could occur. We used comp molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) (11).In addition to the PCB family of chemicals, other phenyl-substituted hydrocarbons such as the biphenyl ethanes and ethylenes related to diethylstilbestrol (DES) (12) and triphenylethanes (13), including tamoxifen and nafoxidine, have been shown to be ligands of the estrogen receptor. A common substructure of many of these chemicals is a phenolic ring system, with an obvious relationship to the phenolic A ring in estradiol (Fig. 1). However, it is not clear if in all cases the hydroxyl group has unique properties as a substituent or if any similar-sized (isosteric) group, such as chlorine, could replace it. Such a substructure serves as a unique way to align the molecules for comparing the overall structures of otherwise structurally diverse chemicals. In this way it may be possible to determine their estradiol equivalency (14) in a manner analogous to determining the dioxin equivalency (15) of structurally related chlorinated aromatic hydrocarbons of environmental health concern. We used comparative molecular field analysis (CoMFA) (16), a three-dimensional quantiative structure-activity relationship (QSAR) paradigm, to examine the unique physicochemical properties of polychlorinated hydroxybiphenyls (Table 1) underlying their estrogen receptor binding affinities and thus their potential estradiol equivalency. MethodsThe SYBYL molecular modeling software package (version 6.0, Tripos Associates, Inc., St. Louis, Missouri) was used to do all molecular modeling. The coordinates for estradiol and DES were retrieved from the Cambridge Structural Database. The remaining molecules were constructed in SYBYL using the sketch option. All molecules were minimized using the standard Tripos force field (17) to an energy change convergence criterion of 0.001 kcal/mol. The SYBYL geometries were used as starting coordinates for full-geometry optimization using MOPAC 5.0 (Quantum Chemistry Program Exchange, Indiana University, Bloomington, Indiana) with the AMI (18) model Hamiltonian.For each biphenyl molecule (including DES), using the MOPAC/AMI optimized structure as a starting point, the conformational space about the twist bond(s) connecting the two ring systems was explored. This bond was systematically searched at 50 increments. The lowest energy conformer obtained from the search was then subjected to full MOPAC/AM1 optimization. This structure was then aligned relative to estradiol by root-mean-squares (RMS) fit of the hydroxyphenyl ring (A) carbons and the corresponding carbons of the para-substituted ring of the molecule to be fitted. Due to structural symmetry of the biphenyls, several alignments w...

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“…Moreover, this toxicant alters the action of estrogen in reproductive organs in a manner that is both age dependent and target-organ specific (44,45). Importantly, dioxin also adversely affects leukocyte production of cytokines known to participate in the regulation of uterine physiology (10,(46)(47)(48).…”

Section: Immune Alterations In Endometriosismentioning

confidence: 99%

Immunoresponsiveness in Endometriosis: Implications of Estrogenic Toxicants

Rier¹,

Dc²,

Bowman³

et al. 1995

Environmental Health Perspectives

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Endometriosis is a reproductive disease characterized by the growth of endometrial cells at sites outside the uterus. This disease is a serious disorder associated with chronic pain and infertility, which may be present in 6 million women in this country. Traditional medical therapy has consisted of hormonal regimens that limit the action of endogenous estrogen. The etiology of endometriosis is unknown, but studies suggest that soluble factors known as cytokines play a role in disease pathogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is an environmental toxicant that alters the action of estrogen in reproductive organs and adversely affects immunocompetence. The incidence of endometriosis was determined in rhesus monkeys that were chronically exposed to dioxin for a period of approximately 4 years. Ten years after termination of dioxin treatment, the presence and severity of endometriosis was assessed by surgical laparoscopy. The incidence of endometriosis correlated with dioxin exposure and disease severity was dependent upon the dose administered. Moderate to severe endometriosis was not found in control animals but was documented in three of seven animals exposed to 5 ppt dioxin (43%) and in five of seven animals exposed to 25 ppt dioxin (71 %). The frequency of spontaneous disease in the control group was 33%, similar to an overall prevalence of 30% in 304 rhesus monkeys with no history of dioxin exposure. This study indicates that endometriosis may be associated with dioxin exposure in the rhesus. In view of overwhelming evidence that cytokines participate in the mediation of reproductive-endocrine phenomena and regulation of endometrial growth, future assessment of the effects of environmental toxicants on reproductive health may depend upon our understanding of the bidirectional cytokine network between the immune and endocrine systems. -Environ Health Perspect 103(Suppl 7): 151-156 (1995)

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Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Tissue-specific regulation of estrogen receptor in CD1 mice

Cited by 105 publications

References 33 publications

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Using Three-Dimensional Quantitative Structure-Activity Relationships to Examine Estrogen Receptor Binding Affinities of Polychlorinated Hydroxybiphenyls

Immunoresponsiveness in Endometriosis: Implications of Estrogenic Toxicants

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