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

雌激素是最强大的雌激素，可以说是最强大的类固醇激素。它存在于许多哺乳动物的排泄物中，如男性和女性的尿液和汗液。作为一种小的亲脂性分子，雌二醇可以通过鼻腔或皮肤接触后进入血液。在用小鼠追踪放射性标记雌二醇的实验中，该实验室表明雌二醇可以在一起饲养的个体之间转移，从雄性的排泄物转移到雌性的大脑和生殖器官。因此，它作为信息素，影响青春期的时间或怀孕的成功或失败。我们计划研究雌二醇是否可以像其他一些小分子一样，在鼻暴露后直接进入大脑。由于雌二醇在男性附睾和精液中含量丰富，我们还将检查它是否可以直接进入子宫，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保持生物活性形式的程度。我们还将研究它与孕酮的相互作用，孕酮也可以在同居个体之间转移。没有男性一起圈养的女性表现出暂停发情周期，我们将检验这是由于共享雌二醇和孕酮的假设。我们还将测试一个假设，即女性的孕酮水平提供阻力，她潜在的损失怀孕在面对雌二醇负载新男性尿。在另一系列的实验中，我们将研究子宫机制，参与早孕失败，由于压力，新的男性，暴露于雌激素刺激。我们推测，受精卵未能植入子宫，因为雌激素与孕酮的比例上升，由于雌二醇从新的男性的排泄物，从女性自己的腺体在压力下，或从环境雌激素。这些刺激反过来被假设为破坏e-钙粘蛋白，一种将受精卵结合到子宫壁的粘附分子，以及将它们保持在适当位置的子宫闭合。总的来说，这些项目应该促进对性类固醇如何作为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.