Signaling mechanisms of gene-environment interactions in female reproductive

项目摘要/摘要 女性生殖道先天畸形(FRT)发生在大约5%的女性活产中。 这些情况是先天性的，但通常直到青春期才被发现，青春期患者没有月经和 周期性的下腹部疼痛；如果不治疗，它们会导致不孕和怀孕或死亡 分娩。这些异常具有复杂的临床表现，其病因仍知之甚少。考虑到 FRT异常既有家族性也有散发性，病因复杂，累及 基因、环境因素，或者两者兼而有之。到目前为止，基因突变的多因素病因和发病机制的研究进展较多。 先天性FRT异常中的环境交互作用在很大程度上还没有被探索。我们最近确认了 MAP3K1功能丧失是小鼠先天性FRT异常的一种新的遗传状态-MAP3K1失活 与女性发育中的FRT缺陷和不孕症有关。MAP3K1编码一种蛋白激酶，一种 MAPK通路的上游调节因子，与不同的环境信号和发育 小路。我们已经证明，MAP3K1功能丧失可以加重二恶英的发育毒性， 无处不在的环境污染物。此外，二恶英也是一种生殖毒物，会导致FRT缺陷 与在MAP3K1基因缺失小鼠中观察到的类似。在目前的提案中，我们将检验支持的假设 初步证据表明，MAP3K1突变加上二恶英构成了汇聚的多因素病因 WNT抑制导致先天性FRT异常的研究。我们将使用体内遗传方法来检查 MAP3K1突变和二恶英暴露是否会增加FRT缺陷的发生率和/或严重程度 表型，二恶英受体，AH受体(AHR)，是否介导FRT毒性，以及该基因是否- 环境相互作用抑制了WNT的活动。我们将结合小鼠遗传学，分子组织病理学， 激光捕获显微切割结合全球基因表达谱描绘生物 在FRT发育中受遗传和环境侮辱影响的过程和分子途径。我们的目标是 了解基因-环境相互作用如何影响先天女性的分子细节 生殖异常，未来的长期目标是利用这一知识来预防和治疗这种流行的 严重影响妇女健康和生殖的疾病。

Project Summary/Abstract Congenital anomalies of the female reproductive tract (FRT) occur in approximately 5% of live birth in females. These conditions are congenital, but often go undetected until puberty when the patients fail to menstruate and suffer periodic lower abdominal pain; if left untreated, they lead to infertility and death during pregnancy or childbirth. The anomalies have complex clinical presentations with the etiology still poorly understood. Given that FRT anomaly has both familial and sporadic cases, the causative agents are likely to be complex, involving genes, environmental factors, or both. To date, the multifactorial etiology and the mechanisms of gene- environment interactions in congenital FRT anomalies are largely unexplored. We have recently identified Map3k1 loss-of-function as a novel genetic condition of congenital FRT anomaly - Map3k1 inactivation in mice is associated with developmental FRT defects and infertility in females. Map3k1 encodes a protein kinase, an upstream regulator of the MAPK pathways that crosstalk with diverse environmental signals and developmental pathways. We have shown that Map3k1 loss-of-function could aggravate the developmental toxicity of dioxin, a ubiquitous environmental pollutant. Moreover, dioxin is also a reproductive toxicant that induces FRT defects similar to those observed in the Map3k1-null mice. In the current proposal, we will test the hypothesis, supported by preliminary evidence, that Map3k1 mutation plus dioxin constitute the multifactorial etiology that converges on WNT inhibition to cause congenital FRT anomalies. We will use an in vivo genetic approach to examine whether Map3k1 mutation plus dioxin exposure potentiate the incidence and/or the severity of FRT defective phenotypes, whether the dioxin receptor, Ah receptor (AHR), mediates FRT toxicity, and whether the gene- environment interactions repress WNT activity. We will combine mouse genetics, molecular histopathogenesis, and laser capture microdissection coupled with global gene expression profiling to delineate the biological processes and molecular pathways affected by genetic and environmental insults in FRT development. We aim to understand the molecular details of how gene-environment interactions contribute to congenital female reproductive anomaly, with the long-term future goal of using this knowledge to prevent and treat this prevalent devastating disease affecting women’s health and reproductivity.