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。我们发表的工作表明，新生儿接触DES会改变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。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。 接触大豆配方奶粉的婴儿有证据表明阴道上皮细胞具有雌激素活性。在与NIEHS的Jack Taylor团队的合作中，我们发现这些婴儿的阴道上皮细胞改变了甲基化。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 published work showing that neonatal DES exposure changes protein levels of several chromatin-modifying proteins and causes permanent alterations in epigenetic marks at specific gene loci. 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. Infants exposed to soy formula have evidence of estrogenic activity in vaginal epithelial cells. In collaboration with Jack Taylor's group at NIEHS, we found that the vaginal epithelial cells in these infants has altered methylation. This work was published.