Embryonic development requires the orchestration of temporally precise genetic events that culminate in the formation of a complete organism. The molecular mechanisms responsible for ontogenesis are regulated by environmental and somatic factors in utero that activate or repress the expression of numerous genetic elements resulting in fetal programming of adult diseases. The aryl hydrocarbon receptor (AHR) is an important nuclear transcription factor both during embryogenesis and throughout maturity in multiple organisms. Building upon interesting studies establishing a direct, novel link between AHR and post-transcriptional regulation of the Wilms' tumor suppressor (WT1 ) gene, the overall goal of the project was to elucidate the role of AHR in the regulation of WT1 during nephrogenesis. The evidence shows that in utero exposure to environmentally relevant exposures of benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH) and AHR ligand, results in AHR allele-specific deficits in renal development manifested as decreased numbers of glomeruli, induction in urinary albumin, and podocytopenia. These findings were consistent with metanephric and organ culture data where PAHs caused AHR allele-specific reduction in renal cell differentiation markers, dysregulation of WT1 mRNA splice variants, and decreases in direct WT1 transcriptional targets. Observed deficits were linked to disruption of constitutive AHR signaling, as siRNA-mediated AHR degradation reproduced similar effects. Collectively, this evidence defined a novel role for the AHR in renal development and in fetal programming of PAH-induced environmental disease.
|Advisor:||Ramos, Kenneth S.|
|School:||University of Louisville|
|School Location:||United States -- Kentucky|
|Source:||DAI-B 69/01, Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Toxicology|
|Keywords:||Aryl hydrocarbon receptor, Fetal programming, Nephrogenesis, Renal disease, WT1, Wilms tumor|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be