Genomes and Genes
Cellular Determinants of Ah Receptor Signaling
Principal Investigator: Thomas R Sutter
Abstract: DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects, including carcinogenicity and teratogenicity, of a large class of environmental pollutants known as 'dioxinlike'compounds, named after the most potent congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies in Ahr null allele mice show that the AHR is necessary for most of the toxic effects of TCDD. However, the mechanism(s) of toxicity downstream of AHR activation remain(s) elusive. As dioxin toxicity does not require concordant exposure to xenobiotics, and dioxin is not metabolized to a reactive intermediate, additional physiologic processes must be disrupted by exposure to TCDD. In humans exposed to dioxin, the most often observed and best studied toxic response is chloracne. Chloracne is manifested in the skin as hyperkeratinization of the interfollicular squamous epithelium, hyperproliferation and hyperkeratinization of cells of the hair follicle, as well as a metaplastic response of the ductular sebaceous glands. How AHR-mediated changes in gene expression lead to toxicity is not well understood for any organ system including skin. Recently, dioxin via the AHR, was shown to enhance human keratinocyte differentiation and to elevate the expression of three genes involved in cornification, a late part of the differentiation process. Formation of the outermost layer of the skin, the stratum corneum, is essential to epidermal barrier function and provides protection against the outside environment and loss of water from the body. Of importance, epidermal growth factor (EGF) receptor (EGFR) signaling was shown to block both TCDD-AHR-mediated gene expression and cell differentiation. These results may in part explain how dioxin affects epidermal homeostasis and identify one mechanism by which EGFR signaling can repress AHR-mediated transcription in keratinocytes. We propose to test the hypothesis that in the epidermis, TCDD-activated AHR disrupts the epidermal barrier by increasing the transcription of genes involved in the formation and function of the stratum corneum, and that EGFR signaling acts to repress this effect. In this proposal, Aim 1 determines whether the TCDD-activated AHR transcriptionally regulates a prioritized set of epidermal target genes and whether these genes are regulated by the AHR and EGFR pathways by mechanisms similar to what has been described for CYP1A1, the prototypic AHR-regulated gene. Aim 2 elucidates the mechanism(s) by which EGFR signaling represses AHR ligand-dependent activation. Aim 3 extends our results in vivo, to determine whether TCDD affects the timing of formation and the function of the epidermal barrier. Collectively, these proposed studies will greatly enhance our understanding of the effects of TCDD on the skin, and will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in translational studies of human populations exposed to dioxin. PUBLIC HEALTH RELEVANCE: Our proposed studies address a major challenge to understand the causal relationships between activation of the AHR by TCDD, changes in gene expression, and the effects of TCDD on the epidermis. By elaborating the mechanisms of dioxin toxicity and the repression of the AHR by EGFR signaling these proposed studies will greatly improve our knowledge of the effects of dioxin on the skin as well as the risk characterization and public health policy decisions on dioxin exposure. The results of these studies will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in future translational studies of human populations exposed to dioxin.
Funding Period: 2010-05-01 - 2015-02-28
more information: NIH RePORT
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formationCarrie Hayes Sutter
W Harry Feinstone Center for Genomic Research, Department of Biological Sciences, University of Memphis, 201 Life Sciences Building, Memphis, TN 38152 3560, USA
Toxicol Sci 124:128-37. 2011..These results indicate that the epidermal permeability barrier is a functional target of the TCDD-activated AHR...
- EGFR regulation of epidermal barrier functionQuynh T Tran
Department of Biological Sciences, The University of Memphis, Memphis, Tennessee 38152, USA
Physiol Genomics 44:455-69. 2012..These results provide a systems-level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation, providing new insight into the role of EGFR imbalance in skin pathogenesis...
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiationLawrence H Kennedy
Department of Chemistry, University of Memphis, Memphis, TN, USA
Toxicol Sci 132:235-49. 2013..Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation...
- Combined treatment with sodium butyrate and PD153035 enhances keratinocyte differentiationSandra Leon Carrion
Department of Biological Sciences, University of Memphis, Memphis, TN, USA
Exp Dermatol 23:211-4. 2014..These results indicate that the combined use of a differentiation-promoting agent and an EGFR inhibitor may offer an additional approach to the management of hyperproliferative skin diseases. ..
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- Regulation/Role of AcylCer in Normal Epidermis and Atopic DermatitisPeter M Elias; Fiscal Year: 2013....
- Circadian Clock Disruption: A Mechanism for Dioxin-induced Metabolic SyndromeShelley A Tischkau; Fiscal Year: 2013..This proposal examines the novel hypothesis that dioxins exert their action through aryl hydrocarbon receptor-mediated uncoupling of homeostatic regulation of organismic circadian rhythms. ..
- AHR signaling in Mammalian and Non-Mammalian ModelsMark E Hahn; Fiscal Year: 2013....
- MOLECULAR MECHANISMS OF DIOXIN ACTIONAlvaro Puga; Fiscal Year: 2013....