Isomer-specific activity of dichlorodyphenyltrichloroethane with estrogen receptor in adult and suckling estrogen reporter mice.
We investigated the tissue-specific effects of dichlorodyphenyltrichloroethane (DDT) isomers in adult and suckling newborn mice, using a novel mouse line engineered to express a reporter of estrogen receptor transcriptional activity (ERE-tkLUC mouse). The DDT isomers p,p'-DDT [1,1,1-trichloro2,2-bis(p-chlorophenyl) ethane] and o,p'-DDT [1,1,1-trichloro-2(p-chlorophenyl)-2-(o-chlorophenyl) ethane] were specifically selected as a weak and a strong estrogen, respectively. In adult male mice, p,p'-DDT induced luciferase activity in liver, brain, thymus, and prostate but not in heart and lung. The effect of p,p'-DDT was dose-dependent, maximal at 16 h after sc treatment, and completely blocked by the estrogen receptor antagonist ICI-182,780. In all the organs analyzed, except the liver, administration of o,p'-DDT showed a pattern of luciferase induction superimposable to that of its isomer p,p'-DDT. In liver, o,p'-DDT significantly decreased basal luciferase activity and blocked the reporter induction by 17beta-estradiol. These data lead us to hypothesize that a modulation of ER activity may be involved in the toxic effects of DDT demonstrated by epidemiological and experimental studies. Luciferase activity was also studied in 4-d-old mice lactating from a mother injected with either p,p'-DDT or o,p'-DDT. Both isomers induced a 2-fold increase in the newborn brain. An opposite effect was observed in liver, where p,p'-DDT increased and o,p'-DDT decreased luciferase, thus indicating that these compounds modulate ER activity in adult and newborn tissues by use of a similar mechanism. The ERE-tkLUC mouse proves to be a suitable tool to functionally assess the tissue specificity of estrogenic/antiestrogenic compounds in adult (as well as in suckling) mice.
Di Lorenzo
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3rd Laboratory/Biotechnology, Civic Hospital of Brescia, University of Brescia, 25123 Brescia, Italy. dilorenz@master.cci.unibs.it
Villa
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Biasiotto
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Belloli
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Ruggeri
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Albertini
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Apostoli
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Raviscioni
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Ciana
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Maggi
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D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D001921:Brain / Q000378:metabolism; D003634:DDT / Q000737:chemistry* / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics; D020218:Response Elements; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000235:genetics
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol; D003634:DDT; C016340:o,p'-DDT; D008156:Luciferases; D013937:Thymidine Kinase