Target-specific action of organochlorine compounds in reproductive and nonreproductive tissues of estrogen-reporter male mice

Villa, Riccardo; Bonetti, E; Penza, M.; Iacobello, Carmelo; Bugari, Giovanna; Bailo, Marco; Parolini, Ornella; Apostoli, Pietro; Caimi, Luigi; Ciana, Paolo; Maggi, Adriana; Lorenzo, Diego Di

doi:10.1016/j.taap.2004.05.007

Cited by 19 publications

(14 citation statements)

References 60 publications

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“…Moreover, organochlorine has been shown estrogenic in MCF-7 cells by the expression of PR [29]. Using a transgenic mouse model, Villa and colleagues [30] showed that PR mRNA was significantly induced by DDT isomers in tissues positive for estrogen receptors, and that the estrogenic action of p , p' -DDE was more efficient in organs that expressed ERβ, such as the mammary gland. Organochlorines might induce the observed changes in PR expression either directly by binding ERs or indirectly by increasing sensitivity to endogenous estrogens, or affecting the amount and type of estrogen metabolites with estrogenic properties.…”

Section: Discussionmentioning

confidence: 99%

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

et al. 2006

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Introduction Breast cancer is the most frequent malignant disease in women. Exposure to estrogens throughout a woman's life is a risk factor for the development of breast cancer. Organochlorine compounds (OCCs), such as pesticides and polychlorinated biphenyls, are persistent lipophilic chemicals identified as endocrine disruptors, mainly with estrogenic effects. To test the hypothesis that the amount and quality of organochlorine residues in adipose tissue adjacent to breast carcinoma affect the biological behavior of the tumor, we studied biomarker expression in breast carcinoma and the OCC body burden in patients from an urban area adjacent to Paraná fluvial system, Argentina.

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Section: Discussionmentioning

confidence: 99%

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

et al. 2006

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“…This mouse technology provides an unprecedented opportunity to gain novel insights into nuclear receptor physiological functions and to identify novel drugs for their selective regulation (15,16). Indeed, the first prototype of reporter mouse generated, estrogen receptor responsive element-Luc model, originally proposed as a tool to identify selective estrogen receptor modulators (14), significantly facilitated the study of the pharmacological activity of estrogen receptor ligands (15,(17)(18)(19)(20). In addition, this mouse model revealed novel and unsought mechanisms controlling estrogen receptor activity (21)(22)(23).…”

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confidence: 99%

A Novel Peroxisome Proliferator-Activated Receptor Responsive Element-Luciferase Reporter Mouse Reveals Gender Specificity of Peroxisome Proliferator-Activated Receptor Activity in Liver

Ciana¹,

Biserni

Tatangelo³

et al. 2007

Molecular Endocrinology

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There is a growing interest in peroxisome proliferator-activated receptors (PPARs) as major players in the regulation of lipid and carbohydrate metabolism. Drugs targeting PPARs were in fact shown to have major relevance for the treatment of diseases associated with aging, such as arteriosclerosis and diabetes. However, a variety of toxic effects associated with PPAR ligand administration has been documented, including hepatocarcinogenesis, which may severely limit its therapeutic use. A better comprehension of the multiplicity of PPAR physiological functions is therefore mandatory for the development of novel, safer drugs. We here describe the generation of a novel transgenic mouse for the detection of the generalized activities of PPARs, the PPAR responsive element-Luc reporter mouse. In this model luciferase expression is under the control of a PPAR-inducible promoter in all target organs. By optical imaging and ex vivo analysis, we were able to demonstrate the remarkable gender specificity of the PPAR transcriptional activity in liver. In fact, in the liver of female PPAR responsive element-Luc, the PPAR reporter transgene is more than one order of magnitude less expressed, thus leading to the conclusion that the signaling in females is much less activated than in males. Diet or hormonal manipulations as demonstrated here by treatments with high-fat diet or gonad removal and hormone replacement do not influence this low activation. The extent of the gender difference in PPAR transcriptional activity and the ineffectiveness of hormone treatments or diet to significantly elevate liver PPAR activity in females led us to hypothesize that gender-specific epigenetic events occurring during development may affect PPAR signaling in the liver. This study sets the ground for understanding the differential susceptibility of the two genders to metabolic disorders; furthermore, the model generated provides a novel opportunity for the molecular characterization of PPAR activity in pathophysiological conditions.

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“…(f) The systems used for the in vitro and ex vivo analysis of NR-ICs (mainly estrogens and androgens) are generally composed of cells derived from reproductive tissues. Recent knowledge of the widespread distribution of NRs, in particular steroid receptors, in all tissues of an organism and their involvement in several diseases [2,18,30,50,55] make the available systems inadequate for assessing the effects of NR-ICs on the whole physiology. Moreover, the tissue levels of several NRs change with age (i.e.…”

Section: Need Of Model Systems For Nr-icsmentioning

confidence: 99%

“…The insertion of these constructs into the mouse genome through different available technologies may lead to ubiquitous and hormone-regulated expression of the reporter. Moreover, modern imaging technologies in conjunction with animals expressing luminescent or fluorescent markers provide the opportunity to generate a notable amount of information without the need for animal sacrifice [14,19,42,47,55].…”

Section: Reporter Animals For Hormone Actionmentioning

confidence: 99%

Alternatives to animal experimentation for hormonal compounds research

et al. 2009

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Alternatives to animal testing and the identification of reliable methods that may decrease the need for animals are currently the subject of intense investigation worldwide. Alternative testing procedures are particularly important for synthetic and natural chemicals that exert their biological actions through binding nuclear receptors, called nuclear receptors-interacting compounds (NR-ICs), for which research is increasingly emphasizing the limits of several models in the accurate estimation of the physiological consequences of exposure to these compounds. In particular, estrogen receptor interacting compounds (ER-ICs) have a great impact on human health from the therapeutic, nutritional, and toxicological point of view due to the highly permissive nature of the estrogen receptors towards a large number of natural and synthetic compounds. Similar to in vitro systems, recently generated animal models (e.g., animal models generated for the study of estrogen receptor ligands) may fulfill the 3R principles: refine, reduce, and replace. If used correctly, NR-regulated models, such as reporter mice, xenopus, or zebrafish, and models obtained by somatic gene transfer in reporter systems, combined with imaging technologies, may contribute to strongly decreasing the overall number of animals required for NR-IC testing and research. With these models, flexible and highly standardized parameters and reporter marker quantification can be obtained. Here, we highlight the need for the substitution of currently used testing models with more appropriate ones that can reproduce the features and reactivity of specific mammalian target tissue/organs. We consider the promotion of this advancement a research priority bearing scientific, economic, social, and ethical relevance.

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Target-specific action of organochlorine compounds in reproductive and nonreproductive tissues of estrogen-reporter male mice

Cited by 19 publications

References 60 publications

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

Estrogenic microenvironment generated by organochlorine residues in adipose mammary tissue modulates biomarker expression in ERα-positive breast carcinomas

A Novel Peroxisome Proliferator-Activated Receptor Responsive Element-Luciferase Reporter Mouse Reveals Gender Specificity of Peroxisome Proliferator-Activated Receptor Activity in Liver

Alternatives to animal experimentation for hormonal compounds research

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