Environmental influence on reproductive tract function

不同的环境化学物质会影响各种生物的繁殖能力，这取决于接触的时间和剂量，并且被认为也会影响人类的繁殖。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。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，它在产前（出生前）服用会导致生殖道畸形，在新生儿（出生前后）服用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发育和功能。这些研究与人类生育能力有关，因为染料木素水平与我们在小鼠模型中达到的水平相似，是在食用大豆配方奶粉的婴儿中测量的，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。

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.