Research Project 7: Estrogen Receptor-AhR Interactions in the CNS

研究项目7：中枢神经系统中雌激素受体-AhR 相互作用

• 批准号: 7529681
• 负责人: GLORIA V CALLARD
• 金额: $ 20.85万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7529681
• 关键词: Adult; Alternative Splicing; Aryl Hydrocarbon Receptor; Brain; Cell physiology; Cellular biology; Chemicals; Condition; Cyprinodontidae; Development; Dioxins; Elements; Endocrinology; Environment; Environmental Estrogen; Estrogen Receptors; Estrogens; Fundulus heteroclitus; Gene Expression; Genes; Genetic Markers; Hormonal; Laboratories; Maintenance; Measures; Mediating; Methods; Modeling; Molecular; Neuronal Plasticity; Neurotoxins; Non-Steroidal Estrogens; Normal tissue morphology; Peripheral; Receptor Signaling; Research Project Grants; Role; Signal Pathway; Signal Transduction; Standards of Weights and Measures; Tissues; Transact; Zebrafish; aging brain; environmental chemical; neurodevelopment; programs; promoter; receptor; relating to nervous system; repaired; response; superfund site; teleost fish

Steroida! and non-steroidal estrogen-like chemicals (environmental estrogens, EE) that mimic or block hormonal estrogen actions on estrogen receptors (ER), and dioxin-like chemicals that interact with arylhydrocarbon receptors (AhR), are widespread in the environment and common contaminants at Superfund sites. ER mediated signaling is known to have a critical role in neurodevelopmental programming and in the maintenance of neuroplasticity and repair in the adult and aging brain. Although ER and AhR/ARNT signaling pathways converge at multiple points in peripheral tissues, the normal role of AhR signaling in the CNS, and brain specific mechanisms and effects of ER-AhR interactions are largely unknown. Here we investigate the hypothesis that EE and dioxins are neurotoxicants, by virtue of their ability to disrupt neural estrogen signaling and estrogen responsive genes in the CNS. A corollary of this hypothesis is that irreversible chemical effects on estrogen dependent neurodevelopmentaf programming alter responses to hormonal estrogen and subsequent EE and dioxin exposures, and dysregulate estrogendependent components of neuroplasticity and self-repair in the adult and aging brain. Specific aims are to: (1) Determine separate and convergent actions of ER and AhR signaling pathways on gene expression during developmental programming, and in the adult and aging brain; (2) Determine corresponding changes in estrogen responsive neural genes and cellular processes of neurodevelopment, neuroplasticity and repair; (3) Characterize estrogen-dioxin actions and interactions on developmentally programmed alternative splicing decisions in the CNS; (4) Identify cis-elements and transacting cellular factors that mediate estrogen and dioxin actions and interactions on the neural cyp19B gene promoter.

Steroida !和非甾体雌激素样化学物质（环境雌激素，EE），模拟或阻断