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

雌二醇是最强大的雌激素，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，如雄性和雌性的尿液和汗液中。作为一种小亲脂分子，雌二醇可以通过鼻腔或皮肤接触进入血液。在用老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住在一起的个体之间转移，从雄性的排泄物传递到雌性的大脑和生殖器官。因此，它作为一种信息素，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能像其他小分子一样，在鼻腔接触后直接进入大脑。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通过有许多雌激素受体的子宫。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形式。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个体之间转移。在没有雄性的情况下住在一起的雌性显示出暂停的发情周期；我们将测试这是由于雌二醇和黄体酮共享的假设。我们还将测试一个假设，即女性的黄体酮水平在面对含有雌二醇的新男性尿液时提供了抵抗她可能失去妊娠的能力。在另一系列的实验中，我们将研究由于压力源、新男性和雌激素刺激暴露导致的早期妊娠失败所涉及的子宫机制。我们假设受精卵不能在子宫内植入是因为雌激素与黄体酮的比例升高，由于来自新雄性排泄物的雌二醇，来自雌性在压力下自身腺体的雌二醇，或者来自环境雌激素。这些刺激反过来又被假设破坏了e-钙粘蛋白，一种将受精卵与子宫壁结合的粘附分子，以及子宫的闭合，也使它们保持在适当的位置。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.