Environmental influence on reproductive tract function

不同的环境化学品会影响各种生物的生殖能力，这取决于暴露的时间和剂量，而且被认为也会影响人类的生殖。一个例子是植物雌激素金雀异黄素，当给新生的雌性小鼠服用时，它会对它们的繁殖能力产生长期影响。然而，他们不孕的根本原因尚不清楚。第二个例子是己烯雌酚，产前(出生前)给药会导致生殖道畸形，新生儿(出生前后)给药会导致生殖道功能障碍和癌症。我们正在使用新生儿染料木素和DES治疗来确定雌激素化合物如何影响女性生殖道的发育和功能，以及这些化合物如何通过植入时间影响女性生殖道内的胚胎发育。这些研究与人类生育能力有关，因为在服用大豆婴儿配方奶粉的婴儿中测量到的染料木素水平与我们的小鼠模型中达到的水平相似，而且在环境中发现了许多其他雌激素化合物，可能会影响生殖道的发育和功能。 新生使用DES治疗的雌性小鼠在生殖年龄不育，并在成年后患子宫癌。我们进行了一系列实验，以确定新生儿暴露如何改变成年子宫中可能解释这些表型的基因表达谱。我们发现，新生儿DES暴露改变了几种染色质修饰蛋白的蛋白水平，并导致特定基因座上的表观遗传标记发生永久性变化。这部作品出版了。我们现在正在进行一项研究，在全基因组的基础上检查新生儿DES暴露后子宫中的表观遗传标记是否有永久性的变化。这项工作正在进行中。 子宫内膜着床容受性的发育是由周期类固醇激素介导的信号调控的。目前尚不清楚这些信号是否对支持着床前发育的输卵管功能是必需的。我们发现，输卵管上皮细胞雌激素受体α缺乏的条件性基因敲除(CKO)小鼠受精减少，其胚胎在2-细胞期之前全部死亡，这是由于包括蛋白酶在内的分泌型天然免疫介质的持续存在。CKO输卵管中的蛋白酶活性升高会导致透明带蛋白ZP2的过早分裂，移植到CKO输卵管中的野生型胚胎除非同时转移蛋白酶抑制剂，否则无法正常发育。因此，上皮细胞雌激素受体α信号介导的输卵管先天免疫抑制是受精和植入前胚胎发育所必需的。这部作品出版了。

Different environmental chemicals can affect the reproductive capability of a variety of organisms, depending on the timing and dose of exposure, and are thought to impact human reproduction as well. One example is the phytoestrogen, genistein, which when given to neonatal female mice has long-term effects on their ability to reproduce. The underlying causes of their infertility, however, are not known. A second example is diethylstilbestrol, which causes reproductive tract malformations when given prenatally (before birth) and reproductive tract dysfunction and cancer when given neonatally (around the time of birth). We are using both neonatal genistein and DES treatments to determine how estrogenic compounds affect female reproductive tract development and function, and how these compounds influence embryo development within the female reproductive tract through the time of implantation. These studies are relevant to human fertility because genistein levels similar to those reached in our mouse model are measured in babies on soy-based infant formula, and many other estrogenic compounds are found in the environment and could affect reproductive tract development and function. Female mice treated neonatally with DES are infertile at reproductive age and develop uterine cancer as older adults. We performed a series of experiments to determine how the neonatal exposure changes gene expression profiles in the adult uterus that may explain these phenotypes. We found that neonatal DES exposure changes protein levels of several chromatin-modifying proteins and causes permanent alterations in epigenetic marks at specific gene loci. This work was published. We are now performing studies to examine on a genome-wide basis whether there are permanent alterations in epigenetic marks in the uterus after neonatal DES exposure. This work is ongoing. Development of uterine endometrial receptivity for implantation is orchestrated by cyclic steroid hormone-mediated signals. It is unknown if these signals are necessary for oviduct function in supporting preimplantation development. We have found that conditional knockout (cKO) mice lacking estrogen receptor alpha in oviduct epithelial cells have reduced fertilization and all their embryos die before the 2-cell stage due to persistence of secreted innate immune mediators, including proteases. Elevated protease activity in cKO oviducts causes premature cleavage of the zona pellucida protein, ZP2, and wild-type embryos transferred into cKO oviducts fail to develop normally unless rescued by concomitant transfer of protease inhibitors. Thus, oviductal innate immune suppression mediated by epithelial cell estrogen receptor alpha signaling is required for fertilization and preimplantation embryo development. This work was published.