Dr. Vom Saal will use two research strategies to examine the hypothesis that the levels of sex steroids to which male mice (Mus musculus domesticus) are exposed during fetal life play a major role in influencing aging, particularly of the reproductive system. The first approach involves using a naturally-occurring phenomenon, the intrauterine position phenomenon. Males occupying different intrauterine positions are naturally exposed to different endogenous blood steroid levels during fetal life due to being randomly positioned in utero between 2 male fetuses (these males have elevated serum levels of testosterone) or between 2 female fetuses (these males have elevated serum levels of estradiol). The intrauterine position of males will be identified at cesarean delivery, and they will be raised for examination during later life. The second approach will involve treating pregnant females with either estradiol or testosterone to slightly increase serum concentrations of these steroids during sexual differentiation in all male fetuses of treated mothers. He will examine lifespan, the incidence of tumors in old age, fertility (the capacity to successfully mate with females and sire young), and functioning of the prostate and seminal vesicles (as assessed by enzyme activity and capacity to bind hormones) during aging in male mice. During the fetal period of differentiation of the brain and reproductive system, individuals in all mammalian species may be exposed to markedly different levels of sex steroid hormones due to a variety of reasons. While it is known that individual differences in many characteristics relating to reproduction in young-adult animals are determined by levels of sex hormones during fetal life, no one has examined whether lifespan of the pattern of reproductive aging in males might be predicted by fetal sex hormone levels. In most mammalian species, including man, there are a few aged males who retain the capacity to reproduce, while the majority of males become reproductively inactive in old age. The proposed experiments should provide important information concerning why such dramatic differences in reproductive capacity and lifespan are observed between individual males.
