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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017014-03
Application #
8231463
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Chadwick, Lisa
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$310,577
Indirect Cost
$87,827
Name
University of Memphis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
055688857
City
Memphis
State
TN
Country
United States
Zip Code
38152
Sutter, Carrie Hayes; Olesen, Kristin M; Bhuju, Jyoti et al. (2018) The AHR regulates metabolic reprogramming to promote SIRT1-dependent keratinocyte differentiation. J Invest Dermatol :
Slominski, Andrzej T; Kim, Tae-Kang; Janjetovic, Zorica et al. (2018) Differential and Overlapping Effects of 20,23(OH)?D3 and 1,25(OH)?D3 on Gene Expression in Human Epidermal Keratinocytes: Identification of AhR as an Alternative Receptor for 20,23(OH)?D3. Int J Mol Sci 19:
Wible, Ryan S; Ramanathan, Chidambaram; Sutter, Carrie Hayes et al. (2018) NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus. Elife 7:
Campion, Christina M; Leon Carrion, Sandra; Mamidanna, Gayatri et al. (2016) Role of EGF receptor ligands in TCDD-induced EGFR down-regulation and cellular proliferation. Chem Biol Interact 253:38-47
Muenyi, Clarisse S; Carrion, Sandra Leon; Jones, Lynn A et al. (2014) Effects of in utero exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin on epidermal permeability barrier development and function. Environ Health Perspect 122:1052-8
Leon Carrion, Sandra; Sutter, Carrie Hayes; Sutter, Thomas R (2014) Combined treatment with sodium butyrate and PD153035 enhances keratinocyte differentiation. Exp Dermatol 23:211-4
Kennedy, Lawrence H; Sutter, Carrie Hayes; Leon Carrion, Sandra et al. (2013) 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 differentiation. Toxicol Sci 132:235-49
Tran, Quynh T; Kennedy, Lawrence H; Leon Carrion, Sandra et al. (2012) EGFR regulation of epidermal barrier function. Physiol Genomics 44:455-69
Sutter, Carrie Hayes; Bodreddigari, Sridevi; Campion, Christina et al. (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation. Toxicol Sci 124:128-37