Signaling mechanisms of gene-environment interactions in female reproductive

女性生殖基因-环境相互作用的信号机制

• 批准号: 10594545
• 负责人: YING XIA
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594545
• 关键词: Abdominal Pain; Adult; Affect; Aryl Hydrocarbon Receptor; Biological Process; Cell Culture Techniques; Cessation of life; Childbirth; Clinical; Complex; Congenital Abnormality; Congenital Disorders; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Developmental Toxicant; Dioxins; Disease; Dose; Embryo; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Exposure to; Female; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Goals; Histology; Human; Immunohistochemistry; Incidence; Infertility; Investigation; Knockout Mice; Knowledge; Laboratories; Left; Link; Live Birth; MAP Kinase Gene; MAP3K1 gene; Mediating; Menstruation; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Nature; Pathway interactions; Patients; Periodicals; Phenotype; Pregnancy; Puberty; Regulation; Reporter; Repression; Research; Risk; Severities; Sexual Development; Signal Pathway; Signal Transduction; Structure of paramesonephric duct; Testing; Tetrachlorodibenzodioxin; Toxic effect; Vagina; WNT Signaling Pathway; Women' s Health; congenital anomaly; developmental disease; developmental toxicity; experimental study; falls; gene environment interaction; genetic approach; genetic makeup; genetic risk factor; high risk; human disease; hymen; in vivo; laser capture microdissection; loss of function; mouse genetics; mouse model; mutant; novel; prenatal exposure; prevent; reproductive; reproductive tract; toxicant; transcription factor; transcriptome

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.

项目总结/摘要 女性生殖道（FRT）的先天性异常发生在大约5%的活产女性中。 这些情况是先天性的，但往往不被发现，直到青春期时，患者无法生育， 患有周期性下腹疼痛;如果不治疗，会导致不孕和怀孕期间死亡，或 分娩这些异常具有复杂的临床表现，其病因仍然知之甚少。鉴于 FRT异常有家族性和散发性病例，致病因素可能很复杂，包括 基因、环境因素或两者兼而有之。迄今为止，多因素病因学和基因- 先天性FRT异常中的环境相互作用在很大程度上未被探索。我们最近发现 Map 3 k1功能丧失是先天性FRT异常的一种新遗传条件-小鼠中Map 3 k1失活 与女性发育性FRT缺陷和不孕症有关。Map 3 k1编码一种蛋白激酶， MAPK通路的上游调节子，与不同的环境信号和发育信号发生串扰 途径。我们已经证明，Map 3 k1功能的丧失会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，可导致FRT缺陷 类似于在Map 3 k1缺失小鼠中观察到的那些。在目前的建议中，我们将测试假设，支持 初步证据表明，Map 3 k1突变加上二恶英构成了多因素病因， WNT抑制导致先天性FRT异常。我们将使用体内遗传学方法来检查 Map 3 k1基因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，是否二恶英受体，Ah受体（AHR），介导FRT毒性，以及基因- 环境相互作用抑制WNT活性。我们将结合联合收割机小鼠遗传学，分子组织发生学， 激光捕获显微切割结合全局基因表达谱来描绘生物学特征， FRT发展过程中受遗传和环境损伤影响的过程和分子途径。我们的目标 了解基因-环境相互作用如何导致先天性女性生殖缺陷的分子细节， 生殖异常，长期的未来目标是利用这些知识来预防和治疗这种流行的 影响妇女健康和生殖能力的毁灭性疾病。