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1: Rocz Panstw Zakl Hig 2000;51(3):211-28 [Selected aspects of xenoestrogens'mode of action taken from a group of persistent organochlorine compounds ]. [Article in Polish] Strucinski P, Ludwicki JK, Goralczyk K, Czaja K. Zaklad Toksykologii Srodowiskowej Panstwowy Zaklad Higieny 00-791 Warszawa. Diese E-Mail-Adresse ist vor Spambots geschützt! Zur Anzeige muss JavaScript eingeschaltet sein! The presence of many chemical pollutants in the environment and their potential impact to human health creates rather justified anxiety. Many of these pollutants feature such unwelcome characteristics as: persistence in different environmental media, ability to bioaccumulate and biomagnify in individual food chains, as well as ability to undergo long-range atmospheric transport. Compounds meeting these criteria include above all a large group of persistent organochlorine compounds. Recently, debate has increased concerning endocrine disrupting activity of these compounds and especially their ability to produce biologic responses comparable to those of endogenous estrogens (e.g., 17 beta-estradiol). It has been hypothesized that these compounds, among others, may be associated with increased incidence of breast cancer and other estrogen-related cancers in women due to increased proliferation of breast epithelial cells. The organochlorine xenoestrogens may produce this effect following binding to a hormone receptor (with or without metabolic activation) or by affecting the 17 beta-estradiol pathways leading to increased formation of more potent estrogenic metabolites. Numerous studies performed since early 1990s have examined the relationship between organochlorines levels in serum or adipose tissue and breast cancer, but the results are not consistent. This may be caused by various criteria of selecting the case and control groups, different compounds analyzed or different statistical approaches. None of these studies included endocrine disruptors' exposure in early and critical stages of development--from conception up to puberty age--the results of which would manifest in far future. Nevertheless the results of measurements, especially in adipose tissue are more reliable for this purpose because they reflect the whole life exposure and may be recognized as one of many environmental risk factors of cancer development. Publication Types: Review Review, tutorial PMID: 11138478 [PubMed - indexed for MEDLINE] 1: J Pharmacol Exp Ther 2001 Feb;296(2):329-37 Assessment of the effects of metabolism on the estrogenic activity of xenoestrogens: a two-stage approach coupling human liver microsomes and a yeast estrogenicity assay. Elsby R, Maggs JL, Ashby J, Paton D, Sumpter JP, Park BK. Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom. Concern that the reproductive health of humans is being affected by exposure to xenoestrogens has led to the development of various in vitro and in vivo screening assays for the identification of suspected xenoestrogens. However, the estrogenic activity of a chemical determined in vitro may not necessarily predict its activity in vivo if the chemical is metabolized during the assay and/or in vivo. Therefore, to investigate the role of metabolism in modulating the estrogenic activity of suspected xenoestrogens, we have devised a two-stage approach coupling incubations with either human or rat hepatic microsomes with a yeast estrogenicity (transcription) assay. We have assessed the activity of the proestrogenic pesticide 99.5% methoxychlor [1,1,1-trichloro-2,2-bis-(4-methoxyphenyl)ethane, MXC] (EC(50) = 4.45 +/- 1.9 ,icroM, n = 6) and a structural analog, methoxybisphenol A [2,2-bis-(4-methoxyphenyl) propane, MBPA], in the yeast estrogenicity assay and also established that yeast (Saccharomyces cerevisiae), unlike human liver microsomes, are not able to demethylate MXC or MBPA to estrogenic metabolites. This indicates that the proestrogen MXC has weak intrinsic estrogenic activity. Using 99.5% MXC and 17beta-estradiol as paradigms, we have demonstrated how metabolism can enhance or suppress, respectively, estrogenic activity. The effect of metabolism on the activities of the weak xenoestrogens 3,17beta-bisdesoxyestradiol [1,3,5(10)-estratriene] and 6-hydroxytetralin (5,6,7,8-tetrahydro-2-naphthol) was also assessed. This two-stage approach can distinguish the estrogenic activity of a suspect chemical from the activity due to its more, or less, active metabolites and will aid in the evaluation of novel xenoestrogens and, more importantly, proestrogens. PMID: 11160614 [PubMed - indexed for MEDLINE]

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