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。在过去的一年里，我们进行了一系列实验，以确定新生儿暴露如何改变成人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Cholmatin修饰蛋白的蛋白质水平，并导致特定基因座上的表观遗传标记发生永久性变化。我们正在继续研究，以确定染料木素和DES对女性生殖道功能影响的表观遗传学机制。 有证据表明，在啮齿动物中，产前暴露于环境相关剂量的双酚A(BPA)会导致卵巢和雌性生殖道发育异常。尽管啮齿动物研究提出了对人类暴露于双酚A的担忧，但关于双酚A对人类或非人类灵长类动物模型发育的影响的信息很少。Patricia Hunt博士(华盛顿州大学)加州大学戴维斯分校灵长类中心的Cathy VandeVoort博士发起了一项研究，旨在研究怀孕第二或第三个三个月期间母亲暴露于双酚A对雌性恒河猴胎儿发育的影响。用两种不同的双酚A剂量策略对猴子进行治疗，并收集了所有组织。我们已经完成了对女性生殖道的形态和基因表达的评估。该项目建立了正常猕猴输卵管和子宫发育的基因表达谱，并提供了比较对照组和双酚A处理组时基因表达谱和组织学差异的证据。这部作品已提交出版。

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. During the past year 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 chormatin-modifying proteins and causes permanent alterations in epigenetic marks at specific gene loci. We are continuing studies to determine the epigenetic mechanisms underlying the effects of both genistein and DES on female reproductive tract function. There is evidence in rodents that prenatal exposure to environmentally relevant doses of bisphenol A (BPA) causes abnormal ovarian and female reproductive tract development. Although the rodent studies have raised concerns regarding human exposure to BPA, there is minimal information regarding the effects of BPA on development in humans or non-human primate models. Dr. Patricia Hunt (Washington State Univ.) and Dr. Cathy VandeVoort (UC Davis Primate Center) initiated a study to examine the effects of maternal BPA exposure during either the 2nd or 3rd trimesters of pregnancy on development of female Rhesus monkey fetuses. The monkeys were treated using 2 different BPA dosing strategies, and all tissues have been collected. We have finished our evaluation of the morphology and gene expression in the female reproductive tract. This project generated a gene expression profile of developing normal Rhesus monkey oviduct and uterus, and also provided evidence for differences in the gene expression profiles and histology when comparing control and BPA-treated groups. This work has been submitted for publication.