| Exposure to androgens during the prenatal period is essential for masculinization of the male reproductive phenotype in mammals. Male fetuses exposed to antiandrogens are permanently demasculinized in their morphology, physiology, and behavior. Female fetuses are also exposed to endogenous androgens. In some litter-bearing species, proximity of females to males in utero can partially masculinize female offspring. Furthermore, previous studies show prenatal exposure to exogenous androgens permanently masculinizes females. Discovery of androgen agonists and antagonists in the environment has placed increased emphasis on describing the effects of androgens and antiandrogens on reproductive differentiation in both males and females. The objectives of this thesis were to (1) identify the natural sources of androgens in the fetal rat, (2) investigate the predictability of early developmental “biomarkers” for androgen and anti androgen-induced reproductive alterations in the adult, and (3) examine the cumulative effects of prenatal exposure to a mixture of antiandrogens in the male rat.; Two experiments were conducted to describe the sources of variability in prenatal androgen concentrations in the rat. First, testosterone concentrations were quantified in several fetal compartments during the prenatal period. The source of androgens in the male rat fetus is the testis. Females have a significant concentration of testosterone which appears to originate from the placenta. In the Sprague-Dawley rat, males do not significantly contribute to the testosterone found in fetal females. In the second experiment, measurement of the androgen-sensitive anogenital distance (AGD) in relation to fetal positioning in utero, showed no effect of proximity of female fetuses to males fetuses on this endpoint.; In the second set of experiments, females were exposed to testosterone propionate prenatally. Offspring were assessed for reproductive alterations and the predictability of androgen-sensitive endpoints for predicting altered adult phenotype. These early markers of androgen exposure, neonatal anogenital distance and infant areola numbers, were reliable indicators of androgenized conditions in the adult female.; To examine the effect of a combination of antiandrogens on reproductive differentiation in the male rat, two reported antiandrogens, linuron and butyl benzyl phthalate, were administered individually and in combination to pregnant females. Exposure to a combination of antiandrogens resulted in greater effects than either of the chemicals administered alone. Further, anogenital distance and infant areola number were reliable indicators of the adult effects of prenatal antiandrogen exposure in males.; These findings demonstrate that permanent reproductive alterations occur due to manipulations of the fetal androgen environment in both males and females. Further, the identification of easily measured early developmental “biomarkers” for these changes is useful for the detection of environmental chemicals that interact or interfere with prenatal androgens. |
