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。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。我们已经发表的工作表明，新生儿DES暴露在出生后第5天完成治疗时，会导致改变基因的增强子区域的表观遗传标记在基因组范围内发生变化。我们现在正在进行全基因组研究，以检查在新生儿DES暴露后，子宫中是否存在开放染色质位置的变化或额外的表观遗传标记，如DNA甲基化。我们还在检查这些标记是否在幼年(16日龄)小鼠和成人身上持续存在；这项工作正在进行中。我们还发表了详细描述在新生儿DES暴露后在子宫中发育的异常子宫内膜细胞的分子表型的工作，这些细胞在成人的癌症病变中被发现。我们正在使用基因敲除小鼠模型来测试特定的分子是否是癌症发展的驱动因素。我们发表的工作表明，转录因子SIX1调节发育中雌激素类化学物质暴露后异常的子宫内膜上皮细胞分化和癌症潜伏期。最后，我们发表的工作表明，由于发育转录因子在金雀异黄素暴露期间异常表达，出生时暴露于金雀异黄素的小鼠改变了子宫图案、子宫内膜腺发育和着床失败。

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. 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 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 are now performing 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; this work is ongoing. We have also published work describing in detail the molecular phenotype of the abnormal endometrial cells that develop in the uterus following neonatal DES exposure and are found in the cancer lesions in adults. We are using knockout mouse models to test whether specific molecules are drivers of cancer development. We published work showing that the transcription factor SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer latency following developmental estrogenic chemical exposure. Finally, we published work showing that mice exposed neonatally to genistein have altered uterine patterning, endometrial gland development and implantation failure due to abnormal expression of developmental transcription factors during genistein exposure.