Activation of brain estrogen receptors in mice lactating from mothers exposed to DDT.
The insecticide dichlorodiphenyltrichloroethane (DDT) interferes with physiological endocrine processes modulating estrogens receptor activity. Most of the data describing the DDT mechanism of action have been collected in vitro or in reproductive tissues in vivo. Here we use a new transgenic mouse model to investigate the DDT effects on estrogens receptor activation in vivo in non-reproductive tissues. In particular, we demonstrate that DDT is able to activate estrogen receptors in the brain and the liver of adult mice after acute administration, and it is active in lactating mice when accumulated in the mother's milk. Furthermore, we demonstrate that the acute administration of DDT activates estrogen receptors with a different kinetics with respect to 17beta-estradiol. Experiments with a breast cancer cell line engineered to express luciferase under the transcriptional control of activated estrogen receptors reveal that the microsomal metabolization of DDT is required for its full activity on estrogen receptors. Taken together these data lead to hypothesize that the delayed DDT time course on estrogen receptor activation in vivo might be due to a necessary step of metabolism of the compound.
Mussi
P
P
Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Ciana
P
P
Raviscioni
M
M
Villa
R
R
Regondi
S
S
Agradi
E
E
Maggi
A
A
Di Lorenzo
D
D
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects*; D002277:Carcinoma; D045744:Cell Line, Tumor; D003634:DDT / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007774:Lactation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011869:Radioligand Assay / Q000379:methods; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods
D011960:Receptors, Estrogen; D004958:Estradiol; D003634:DDT; D008156:Luciferases