Cancer incidence in estrogen target organs and fertility problems are increasing in the generalpopulation. Exposure to environmental compounds with estrogenic properties is one of the suspected causes. Recent epidemiological studies have shown that etiological factors for these disorders might be operating in utero. The first objective of this proposal is to determine the direct target organs of estrogens during fetal life. The second objective is to determine whether in uteri exposure to estrogens leads to permanent changes in estrogen receptor activity in adulthood. For both objectives, novel estrogen-reporter mice will be used.
These transgenic mice carry aluciferase reporter gene coupled to an estrogen responsive promoter. The strength of this in vivo model is that the reporter gene serves as a common target gene in all organs and its expression provides information on potency as well as location of estrogen receptor activation. The principle of this model is that in the presence of estrogenic compounds, legend-activated estrogens receptors bindto the promoter and induce Tran activation of the reporter gene, luciferase, leading to luciferase protein expression. By supplying the luciferase substrate, luciferin, photons are emitted and luciferase expression can be quantified. The generated transgenic mice have proven useful for assessing estrogenic activity in various organs. With this model, it will be possible to determine the direct target organs of estrogens during fetal life. It has been found that otherwise hormone-dependent genes can become permanently expressed or repressed in adulthood after in utero exposure to hormones. This leads to a change in the so-called\"hormonal imprinting\" of the genes. To study this, estrogen receptor activity (e.g. luciferase expression) will be studied in adult estrogen-reporter mice exposed in utero to estrogen.
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