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

Abstract

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.

Characterization of the ERβ – /–mouse heart

“…Analysis by Affymetrix of the effects of estrogen in the mouse heart showed very few estrogen-regulated RNAs (6), and in two separate lines of ERE-reporter mice (7,8), estradiol did not induce reporter genes in the heart. The question is still whether there are functional estrogen receptors in the myocardium.…”

Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice

“…Organs showing a high fold induction of luciferase after estrogen exposure include bone, adrenal, liver, prostate, kidney, colon and lung. Some of these organs were also found to be relatively responsive in pMAR mice, although the fold induction was lower than in INS7 mice (Ciana et al 2001, Di Lorenzo et al 2002, while adrenal and colon tissue was not described. In ERIN mice, high inducibility was found in the kidney and slight induction in the adrenal gland, but no induction was found in lung, while bone, prostate and colon were not examined (Nagel et al 2001).…”

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…In prostate cancer, c-Met, rather than EGFR or ErbB, has been the tyrosine kinase receptor implicated in metastasis (Humphrey et al, 1995;Pisters et al, 1995;Nishimura et al, 1998;Knudsen et al, 2002;van Leenders et al, 2002;Nakashiro et al, 2003;Knudsen and Edlund, 2004). The role of EGFR/Erb2 in prostate cancer, unlike breast cancer, remains controversial (Maygarden et al, 1992;De Miguel et al, 1999;Skacel et al, 2001;Di Lorenzo et al, 2002). Thus, CD82 may regulate different receptors in different cell or tumor types.…”