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Isomer-Specific Activity of Dichlorodyphenyl-trichloroethane with Estrogen Receptor in Adult and Suckling Estrogen Reporter Mice

3rd Laboratory/Biotechnology (D.D.L., R.V., G.R., A.A.), Civic Hospital of Brescia, and Institute of Chemistry (R.V., G.B., S.B., A.A.), and Institute of Occupational Health and Industrial Hygiene (P.A.), University of Brescia, 25123 Brescia, Italy; and Department of Pharmacological Sciences (M.R., P.C., A.M.), University of Milan, 20133 Milan, Italy

Address all correspondence and requests for reprints to: Diego Di Lorenzo, Laboratory of Biotechnology, Civic Hospital of Brescia, 25123 Brescia, Italy. E-mail: dilorenz{at}master.cci.unibs.it.

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 17ß-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.

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