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ESTROGEN SYNTHESIS IN FETAL SHEEP BRAIN: EFFECT OF MATERNAL TREATMENT WITH AN AROMATASE INHIBITOR.
Roselli, Charles1, Resko, John1, Stellflug, John2, Stormshak, Fredrick3, 1 2 3
ABSTRACT- In many mammalian species, including sheep, exposure during prenatal development to androgens that can be converted to estrogens by cytochrome P450 aromatase permanently masculinizes adult sexual behaviors and patterns of gonadotropin secretion. Because it has never been demonstrated that the fetal sheep brain can aromatize androgen to estrogen, we measured the distribution of aromatase activity (AA) in the sheep brain during the critical period for sexual differentiation. We also determined whether administration of the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), could cross the placenta and act in fetal brain. Seven pregnant ewes were utilized. On day 50 of gestation, three of the ewes were given ATD implants (six 4 gm Silastic packets implanted subcutaneously) and the other four received sham surgeries. Two weeks later (day 64 of gestation), the implants were removed and the fetuses were surgically delivered. Blood was collected from jugular vein of the dam as well as from the umbilical artery and vein. Sera were subsequently analyzed for steroids. Brains were removed from the fetuses, dissected and snap frozen. AA was measured in duplicate samples of homogenates using the 3H2O assay. High concentrations of AA were present in the hypothalamus and amygdala (0.8-1.4 pmol/h/mg protein). Low concentrations were measured in the other areas studied (0.02-0.1 pmol/h/mg protein). The Michalis-Menten constant (Km) for aromatase in the fetal sheep brain was 3-4 nM. No significant sex differences in AA were observed in the fetal brain. ATD treatment produced 80% inhibition of AA in most brain areas, but did not significantly alter serum profiles of the major sex steroids. These data demonstrate that high levels of AA are found in the fetal sheep brain during the critical period for sexual differentiation. They also demonstrate that AA can be inhibited in the fetal lamb brain by treating the mother with ATD, without affecting early fetal development. Supported by NIH grant R01 RR14270.
KEY WORDS: aromatase, sheep, sexual differentiation, brain
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