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。 用植物雌激素金雀异黄素治疗的新生雌性小鼠由于输卵管胚胎发育不足和植入缺陷而不育。在过去的一年里，我们进行了一系列的实验来描述输卵管的异常。我们发现已知的调节女性生殖道功能的炎性反应因子的形态和基因表达模式发生了显著变化。我们还发现，异常的输卵管环境会导致胚泡发育的异常，这可能是由于输卵管黏膜对妊娠的免疫反应改变的结果；然而，这些异常并不排除胚胎移植后成功的足月发育。这些研究发表在《生殖生物学》上。我们还发现，新生金雀异黄素暴露在雌性小鼠幼崽身上会导致尿道下裂，这是外生殖器中的一种尿道口异常；这一发现发表在《分子生殖与发展》杂志上。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。我们正在完成对女性生殖道的形态和基因表达的评估。该项目将生成正常猕猴输卵管和子宫发育的基因表达谱，并提供对比对照组和双酚A处理组时基因表达谱和组织学是否存在差异的证据。

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 the phytoestrogen genistein are infertile because of deficiencies in embryo development in the oviduct and defects in implantation. During the past year we performed a series of experiments to characterize the abnormalities in the oviduct. We found significant alterations in morphology and permanently altered patterns of gene expression of inflammatory response factors known to modulate female reproductive tract function. We also found that the abnormal oviduct environment causes abnormalities in blastocyst development that are likely a consequence of alterations in the oviduct mucosal immune response to pregnancy; however, these abnormalities do not preclude successful term development after embryo transfer. These studies were published in Biology of Reproduction. We also found that neonatal genistein exposure to female mouse pups causes hypospadias, an abnormality of the urethral opening in the external genitalia; this finding was published in Molecular Reproduction & Development. 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 are finalizing our evaluation of the morphology and gene expression in the female reproductive tract. This project will generate a gene expression profile of developing normal Rhesus monkey oviduct and uterus, and also provide evidence regarding whether there are differences in the gene expression profiles and histology when comparing control and BPA-treated groups.