Reproductive impacts of excreted and environmental estrogens, including steroid transfer between individuals

雌二醇是最强的雌激素，也可以说是最强的类固醇激素。它存在于许多哺乳动物的排泄物中，如尿液和汗液，无论是雄性还是雌性。作为一种亲脂的小分子，雌二醇会在鼻腔或皮肤接触后进入血液。在小鼠追踪放射性标记雌二醇的实验中，该实验室已经证明，雌二醇可以在一起居住的个体之间转移，从男性的排泄物传递到女性的大脑和生殖器官。因此，它起着信息素的作用，影响青春期的时间或怀孕的成功或失败。我们计划研究雌激素是否可以像其他一些小分子一样，在鼻腔暴露后直接进入大脑。由于雌二醇在男性附睾液和精液中含量丰富，我们还将检查它是否能直接传递到子宫，那里有许多雌激素受体。我们将使用几种技术来确定转移的雌二醇在多大程度上保持生物活性。我们还将研究它与黄体酮的相互作用，黄体酮也可以在同居的个体之间转移。在没有雄性的情况下，雌性动物表现出暂停的发情周期；我们将检验这一假设，即这是由于共享雌激素和黄体酮造成的。我们还将测试这一假设，即在面对富含雌二醇的新男性尿液时，女性的孕酮水平提供了对潜在妊娠损失的抵抗力。在另一系列实验中，我们将研究因应激源、新男性和暴露于雌激素刺激而导致早期妊娠失败的子宫机制。我们假设，受精卵无法植入子宫是因为雌激素与孕酮的比率上升，这是由于新雄性的排泄物中的雌二醇，压力期间雌性自身的腺体中的雌二醇，或者是环境中的雌激素。这些刺激反过来被假设为扰乱e-钙粘素，一种将受精卵绑定到子宫壁的黏附分子，以及将它们固定在适当位置的子宫的关闭。总的来说，这些项目应该促进对性类固醇如何充当信息素以及环境刺激如何模仿这些信息素的理解。

Estradiol is the most powerful estrogen and arguably the most powerful steroid hormone. It is found in excretions such as urine and perspiration of many mammals, both in males and females. As a small lipophilic molecule, estradiol can pass into the bloodstream after nasal or dermal exposure. In experiments with mice tracing radiolabelled estradiol, this laboratory has shown that estradiol can transfer between individuals that are housed together, being passed from excretions of males to the brain and reproductive organs of females. It thereby acts as a pheromone, influencing the timing of puberty or the success or failure of pregnancy. We plan to examine whether estradiol can, like some other small molecules, pass directly to the brain after nasal exposure. As estradiol is abundant in the male epididymis and seminal fluid, we will also examine whether it can pass directly to the uterus where there are many estrogen receptors. We will use several techniques to determine the extent to which transferred estradiol remains in bioactive form. We will also examine its interactions with progesterone, which can also transfer between cohabiting individuals. Females housed together without males show suspended estrous cycling; we will test the hypothesis that this is due to sharing of estradiol and progesterone. We will also test the hypothesis that a female's progesterone levels provide resistance to her potential loss of pregnancy in the face of estradiol-laden novel-male urine. In another series of experiments, we will examine the uterine mechanisms that are involved in early pregnancy failure due to stressors, novel males, and exposure to estrogenic stimuli. We hypothesize that fertilized ova fail to implant in the uterus because of rises in the ratio of estrogens to progesterone, due to estradiol from novel males' excretions, from the females' own glands during stress, or from environmental estrogens. These stimuli in turn are hypothesized to disrupt e-cadherin, an adhesion molecule that binds the fertilized ova to the uterine wall, and the closure of the uterus that also holds them in place. Collectively these projects should advance understanding of how sex steroids act as pheromones and how environmental stimuli can mimic these pheromones.**