Environmental influence on reproductive tract function

不同的环境化学品可以影响各种生物的生殖能力，这取决于暴露的时间和剂量，并且被认为也会影响人类生殖。一个例子是植物雌激素，染料木黄酮，当给予新生雌性小鼠时，对它们的繁殖能力有长期影响。第二个例子是己烯雌酚（DES），它在产前（出生前）给药时会导致生殖道畸形，在产后（出生前后）给药时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黄酮和DES治疗，以确定雌激素化合物如何影响女性生殖道发育和功能。这些研究与人类生育力有关，因为在婴儿中测量的染料木黄酮水平与我们的小鼠模型中达到的水平相似，这些婴儿食用大豆婴儿配方奶粉，并且在环境中发现了许多其他雌激素化合物，可能会影响生殖道发育和功能。 用染料木黄酮或DES治疗的雌性小鼠在生殖年龄时不育，并在老年时发展为子宫癌。我们已经发表的工作表明，新生儿DES暴露导致在出生后第5天完成治疗时改变基因的增强子区域的表观遗传标记的全基因组变化。我们现在已经进行了研究，以检查在全基因组的基础上是否有开放的染色质位点或额外的表观遗传标记，如DNA甲基化后，在新生儿DES暴露在子宫中的改变。我们还在研究这些标记是否在幼年（16天）小鼠和成年小鼠中持续存在。我们已经发现，有持久的变化，在幼年和成年小鼠新生儿DES暴露后的表观遗传标记，并有特定的转录因子介导的这些变化。这项工作将提交出版不久。我们还使用单细胞RNA测序和空间测序来确定新生儿雌激素化学品暴露对子宫细胞分化的长期影响。这些研究已经确定了导致癌症发展的异常分化模式，特别是子宫上皮细胞。这项工作已提交出版。

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. A second example is diethylstilbestrol (DES), 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. 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 either genistein or DES are infertile at reproductive age and develop uterine cancer as older adults. We already published work showing that neonatal DES exposure causes genome-wide changes in epigenetic marks at enhancer regions of altered genes at the completion of treatment on postnatal day 5. We have now performed studies to examine on a genome-wide basis whether there are alterations in open chromatin sites or additional epigenetic marks such as DNA methylation in the uterus after neonatal DES exposure. We are also examining whether these marks persist in juvenile (16 day old) mice and adults. We have found that there are persistent alterations in epigenetic marks in both juvenile and adults mice following neonatal DES exposure and that there are specific transcription factors that mediate some of these changes. This work will be submitted for publication shortly. We are also using single cell RNA sequencing and spatial sequencing to determine the long-term effects of neonatal estrogenic chemical exposure on uterine cellular differentiation. These studies have identified abnormal patterns of differentiation, particularly in uterine epithelial cells, that lead to cancer development. This work has been submitted for publication.