Aging of the Male Reproductive System in Mice

Vom Saal博士将使用两种研究策略来检验一种假设，即雄性小鼠（家鼠）在胎儿时期接触的性类固醇水平在影响衰老，特别是生殖系统的衰老方面发挥了重要作用。第一种方法是利用一种自然发生的现象，即宫内体位现象。由于在子宫内被随机放置在两个男性胎儿之间（这些男性的血清睾酮水平升高）或两个女性胎儿之间（这些男性的血清雌二醇水平升高），处于不同宫内位置的男性在胎儿期自然暴露于不同的内源性血液类固醇水平。男性的宫内位置将在剖宫产时确定，并将在以后的生活中进行检查。第二种方法是用雌二醇或睾酮治疗怀孕的女性，在接受治疗的母亲的所有男性胎儿的性别分化过程中，轻微增加这些类固醇的血清浓度。他将研究雄性小鼠在衰老过程中的寿命、老年肿瘤发病率、生育能力（与雌性成功交配并产生后代的能力）以及前列腺和精囊的功能（通过酶活性和结合激素的能力来评估）。在大脑和生殖系统的胎儿分化期间，由于各种原因，所有哺乳动物个体可能暴露于明显不同水平的性类固醇激素。虽然我们知道，幼龄成年动物的许多生殖特征的个体差异是由胎儿时期的性激素水平决定的，但没有人研究过雄性生殖衰老模式的寿命是否可以通过胎儿性激素水平来预测。在包括人类在内的大多数哺乳动物物种中，有少数老年雄性动物保留繁殖能力，而大多数雄性动物在老年时变得无生育能力。提出的实验应该提供重要的信息，解释为什么在单个雄性之间观察到如此巨大的生殖能力和寿命差异。

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.