AhR- and ER-Regulated Genes in Brain Development

描述（由申请人提供）：我们的长期目标是确定发育暴露于二恶英和其他普遍存在的芳烃受体（AhR）配体改变成年生殖功能的机制。我们最近发现，一个单一的发展暴露于有效的AhR配体，2，3，7，8-四氯二苯并-p-二恶英（TCDD），干扰雌激素依赖性分化的男性前腹侧室周核（AVPV）。AVPV控制女性的黄体生成素（LH）释放模式;因此，TCDD暴露的男性具有女性样AVPV结构，并且在成年期显示女性LH释放的周期模式。考虑到雌二醇（E2）来自胎儿产生的睾酮是负责性分化过程中，我们假设，TCDD干扰E2调节的一组基因在发展过程中。为了验证这一假设，我们将使用Affyssin微阵列和聚类分析来识别受E2和TCDD调控的性别特异性基因。我们将使用“冗余模型”，测试我们的假设所预测的针对同一组基因的不同动物治疗方法。我们将使用RT-QPCR、原位杂交组织化学、发育个体发生研究、剂量反应研究和启动子分析来验证我们的微阵列研究结果。我们的研究结果将是重要的识别基因的潜在影响二恶英和其他无处不在的AhR配体的生殖毒性，以及对其他神经功能的破坏围产期TCDD暴露在性别特异性的方式。这些发现对于基于机制的风险评估以及开发预防神经毒性的药物干预措施非常重要。

DESCRIPTION (provided by applicant): Our long-term objective is to determine the mechanisms by which developmental exposure to dioxins and other ubiquitous arylhydrocarbon receptor (AhR) ligands alters reproductive functions in adulthood. We recently showed that a single developmental exposure to the potent AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), interferes with estrogen-dependent sexual differentiation of the male anteroventral periventricular nucleus (AVPV). The AVPV controls the female pattern of luteinizing hormone (LH) release; therefore, TCDD-exposed males have a female-like AVPV structure and they show the female, cyclic pattern of LH release in adulthood. Considering that estradiol (E2) derived from fetal production of testosterone is responsible for the sexual differentiation process, we hypothesize that TCDD interferes with E2 regulation of a set of genes during development. To test this hypothesis, we will use Affymetrix microarrays and cluster analysis to identify sex-specific genes that are regulated by E2 and TCDD. We will use a "redundancy model", testing different animal treatments predicted by our hypothesis to target the same set of genes. We will validate our microarray findings using RT-QPCR, in situ hybridization histochemistry, developmental ontogeny studies, dose response studies and promoter analysis. Our findings will be important for identifying genes underlying effects of dioxins and other ubiquitous AhR ligands on reproductive toxicity, as well as on other neural functions disrupted by perinatal TCDD exposure in a sex-specific manner. Such findings will be important for mechanism-based risk assessment, as well as for development of pharmaceutical interventions to prevent neurotoxicity.