THE ARYL HYDROCARBON RECEPTOR AND OVARIAN DEVELOPMENT

点击翻译按钮获取中文摘要

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that, together with the AHR nuclear translocator (ARNT), binds to dioxin responsive elements (DREs) to regulate gene expression. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is an AHR ligand. TCDD is known to produce a wide variety of physiological and pathological responses, including reproductive dysfunction in vertebrates. The AHR is thought to play a role in the cell cycle, and recent evidence suggests that this may occur through an interaction with the product of the retinoblastoma tumor suppressor gene. The retinoblastoma protein binds transcription factors necessary for cell cycle progression from G1 to S phase. Two distinct regions on the AHR form independent complexes with hypophosphorylated pRB and this interaction is enhanced by AHR ligand binding. The central hypothesis of this study is that the AHR signaling pathway plays an important role in normal ovarian development, and when disrupted by environmental contaminants, oogenesis is altered. Unlike mammalian models, Fundulus express two divergent paralogs of the AHR. These AHRs differ in their tissue specific expression as well as in the putative pRB binding sites. Investigating the functional differences between these receptors in the Fundulus ovary will further define the role of Fundulus AHR1, the mammalian AHR homolog, in cellular physiology. Fundulus populations in areas contaminated with halogenated aromatic hydrocarbons develop heritable resistance to the toxic effects of dioxin. We will approach the central hypothesis that the AHR is important in ovarian development from two perspectives. To test the hypothesis that Fundulus AHR1 and Fundulus AHR2 are functionally distinct in ovarian development we will evaluate expression of the AHRs in ovarian cell types among reproductive stages by immuncytochemistry. Cell specific apoptosis and histopathology will be assessed in TCDD treated dioxin resistant and sensitive Fundulus. Interactions of AHR1 and AHR2 with pRB will be investigated by cloning and characterizing pRB in Fundulus and by the use of in vitro binding assays to assess AHR binding.