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

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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.