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，以及这些化合物如何在植入期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, 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.