Progress 10/01/06 to 09/30/11
Outputs
OUTPUTS: Outputs in 2011 have included (1) a seminar to the Department of Biological Sciences, Jackson State University, Jackson, MS (5/10/11), (2) an invited workshop presentation "Arsenic Perturbation of Signaling Pathways in Human Keratinocytes" at the 22nd World Congress of Dermatology, Seoul, Korea (5/26/11), (3) a poster "Localization of the novel hair shaft protein VSIG8 in the hair follicle, nail unit, and oral cavity" by Rice RH, Phillips MA, Sundberg JP at Society of Investigative Dermatology Annual Meeting, Phoenix, AZ (5/5/11), (4) invited seminars "Arsenic Perturbation of Signaling Pathways in Human Keratinocytes" and "Analysis of the Corneocyte Cross-Linked Proteome" at the Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing (5/30/11), (5) invited lecture "Proteomic analysis of hair evidence", California Association of Criminalists Fall Meeting, Sacramento, CA 10/26/11, (6) lecturer (40 lecture hours plus exam) in short course "Biological Effects of Toxic Agents", University of Argentina, Salta (8/23-8/27/11), (7) invited presentation at a Toxicology Career Panel (11/29/2011) at the University of California, Berkeley to give undergraduate and graduate students career advice. PARTICIPANTS: Individuals participating in this work include scientists from the University of CA (Davis and San Francisco, CA), Lawrence Livermore National Lab, The Jackson Laboratory (Bar Harbor, ME) and universities in Germany (Muenster, Heidelberg, Koeln) and Spain (Madrid). TARGET AUDIENCES: Target audiences include (1) the medical/veterinary scientific community to understand the molecular basis of disease and (2) the regulatory scientific community to alert them to risks to the skin from toxic agents. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The proteomic findings have provided a noninvasive approach to disease diagnosis and exposure assessment using protein biomarkers. The cell culture work has permitted analysis of biotransformation of exogenous compounds in the skin and thus potential deleterious effects. The lecture material in Argentina has helped prepare the next generation of environmental scientists in that country.
Publications
- Rice RH, Phillips MA, Sundberg JP (2011) Localization of the novel hair shaft protein VSIG8 in the hair follicle, nail unit, and oral cavity. J Invest Dermatol 131:1936-1938
- Aufenvenne K, Rice RH, Hausser I, Oji V, Hennies HC, Del Rio M, Traupe H, Larcher F (2012) Long-term faithful recapitulation of transglutaminase 1-deficient lamellar ichthyosis in a skin-humanized mouse model and insights from proteomic studies. J Invest Dermatol, in press
- Schebb NH, Buchholz BA, Hammock BD, Rice RH (2012) Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts. Biochem Molec Toxicol, in press
- Rice RH, Mauro T (2012) Toxic responses of the skin. In: Casarett and Doull's Toxicology (C. D. Klaassen, ed.), 8th edition, McGraw-Hill, New York, in press
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Progress 01/01/10 to 12/31/10
Outputs
OUTPUTS: Outputs during 2010 have included (1) a seminar to the Department of Biological Sciences, Jackson State University, Jackson, MS (5/4/10), (2) an invited keynote address at the 4th International Conference on Applied Hair Science, Princeton, NJ (10/6/10), (3) an address at the Frontiers in Ichthyosis Research Scientific Meeting, Orlando, FL (6/24/10), (4) a research presentation at the Society for Investigative Dermatology National Meeting, Atlanta, GA (5/6/10), (5) 15 hr of lecture on principles of toxicology in the Program in Environmental Chemistry, Queretaro Autonomous University, Mexico (11/8-12/10 and (6) 40 hrs of lecture in a short course on biological effects of toxic agents at the University of Salta, Argentina (6/7-11/10). PARTICIPANTS: Individuals participating in this work include scientists from the University of CA (Davis, CA) and the Inner Mongolia Center for Endemic Disease Control and Research, Huhhot, Inner Mongolia, China. The work provided training for at least 3 graduate students, one postdoc and two junior scientists. TARGET AUDIENCES: Target audiences include (1) the medical/veterinary scientific community to understand the molecular basis of disease and (2) the regulatory scientific community to alert them to risks from inorganic pollutants such as arsenic in drinking water. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The findings on arsenic provided a foundation for understanding how arsenic acts inside cells to cause cancer of the skin and possibly other organs. The proteomic findings have provided a noninvasive approach to disease diagnosis and exposure assessment using protein biomarkers. The lecture material in Mexico and Argentina has helped prepare the next generation of environmental scientists in those countries.
Publications
- Reznikova TV, Phillips MA, Patterson TJ, Rice RH (2010) Opposing actions of insulin and arsenite converge on PKCδ to alter keratinocyte proliferative potential and differentiation. Molec Carcinogenesis 49:398-409 Sinitsyna NN, Reznikova TV, Qin Q, Song H, Phillips MA, Rice RH (2010) Arsenite suppression of involucrin transcription through AP1 promoter sites in cultured human keratinocytes. Toxicol Appl Pharmacol 243:275-282 Rice RH, Xia Y, Alvarado RJ, Phinney BS (2010) Proteomic analysis of human nail plate. J Proteome Res 9:6752-6758
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Progress 01/01/09 to 12/31/09
Outputs
OUTPUTS: Outputs during 2009 have included (1) seminars to the Program in Environmental Toxicology, University of California, Riverside (April 8, 2009) and the Pharmacology/Toxicology Graduate Seminar Series, University of Arizona (12/9/09), (2) a presentation at the Society for Investigative Dermatology annual meeting, Montreal, Canada (May 8, 2009), and (3) 15 hours of lecture in the Program in Environmental Chemistry, Queretaro Autonomous University, Mexico (11/23-11/27/09). PARTICIPANTS: Individuals participating in this work are scientists from the University of CA (Davis, CA), Columbia University (NY, NY) and The Jackson Laboratory (Bar Harbor, ME). The work provided opportunities for training at least five graduate students, one postdoc and two junior scientists. TARGET AUDIENCES: Target audiences include (1) the medical/veterinary scientific community to understand the molecular basis of disease and (2) the regulatory scientific community to alert them to risks from inorganics such as arsenic and copper in the air and water. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The findings on hair proteomics provide a basis for diagnosis of inferior hair quality and certain genetic diseases using noninvasive sampling. The findings on inorganic effects in cells provide a foundation for examining the mechanisms of toxic effects in culture, including the influence of dietary components.
Publications
- Berglund SR, Santana AR, Li D, Rice RH, Rocke DM, Goldberg Z (2009) Proteomic analysis of low dose arsenic and ionizing radiation exposure on keratinocytes. Proteomics 9:1925-38.
- Shimomura Y, Wajid M, Zlotogorskic A, Mohabira A, Lee YJ, Rice RH, Christiano AM (2009) Founder mutations in the lipase H (LIPH) gene in families with autosomal recessive woolly hair/hypotrichosis. J Invest Dermatol 129:1927-1934.
- Rice RH, Rocke DM, Tsai H-S, Lee YJ, Silva KA, Sundberg JP (2009) Distinguishing mouse strains by proteomic analysis of pelage hair. J Invest Dermatol 129:2120-2125.
- Rice RH, Vidrio EA, Kumfer BM, Qin Q, Willits NH, Kennedy IM, Anastasio C (2009) Generation of oxidant response to copper and iron nanoparticles and salts: Stimulation by ascorbate. Chem-Biol Interact 181:359-365
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Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: Results from the project have been disseminated in seminars at the University of Queretaro (Mexico) 4/7/08, Rene Descartes University (Paris, France) 5/15/08, L'OREAL Advanced Research Division (Paris, France) 5/16/08, and UC San Francisco 6/18/08; a platform talk at the 2nd International Conference on Arsenic in the Environment 5/23/08; 3 lectures at Novosibirsk State University (Russia) October 1-3, 2008; and a scientific poster at a Superfund Annual Meeting (Asilomar, CA) December 8, 2008. PARTICIPANTS: Two long time members of the laboratory, Marjorie A. Phillips and Qin Qin, participated in much of the research conducted during the past year. Other participating individuals included colleagues from the UC Davis campus. The project provided training and professional development for a graduate student (Tatiana Reznikova) who completed her PhD degree in the lab. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
During 2008, two research areas produced important findings. First, we established the hair proteome for the mouse and the human. Studies with a mouse strain with defective hair revealed a paucity of a specific hair protein (trichohyalin) that likely resulted in an unusual distribution of cells in the medulla. Studies with human hair from a wooly (uncombable) syndrome did not reveal any protein abnormalities, supporting identification of a defective lipase gene as the basic defect. Second, examination of cultured epidermal cell responses to arsenic revealed a preservation of proliferative potential. This effect appeared to result from suppression of two signaling pathways that attenuate growth and stimulate differentiation. First, Notch1 activation was substantially prevented, a phenomenon that leads to preservation of stem cell character in mouse epidermis. Second, expression of protein kinase C delta was suppressed, an enzyme that ordinarily stimulates apoptosis. These findings help rationalize how arsenic promotes neoplasia of the epidermis.
Publications
- Lu R, Lee G-C, Shultz M, Dardick C, Jung K, Phetsom J, Jia Y, Rice RH, Goldberg Z, Schnable PS, Ronald P, Rocke DM (2008) Assessing probe-specific dye and slide biases in two-color microarray data. BMC Bioinformatics 9:314
- Reznikova TV, Phillips MA, Rice RH (2009) Arsenite suppresses Notch1 signaling in human keratinocytes. J Invest Dermatol 129:155-161
- Nishi K, Inoue H, Schnier JB, Rice RH (2009) Cyclin D1 downregulation is important for permanent cell cycle exit and initiation of differentiation induced by anchorage-deprivation in human keratinocytes. J Cell Biochem 106:63-72
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Progress 01/01/07 to 12/31/07
Outputs
Hair, nail and epidermal callus have protein components that are extractable and identifiable, but up to 20% of the protein is cross-linked and thus not amenable to standard protein chemical purification. Advances in mass spectrometry coupled with database searching now permit identification of individual proteins in complex structures. This approach was applied first to hair to demonstrate the feasibility of identifying many proteins despite the substantial isopeptide bonding these samples display. Among the 343 identified proteins, 70 were detected in high relative abundance, including keratin intermediate filament proteins, largely extractable with denaturants. Over 300 proteins were found in the insoluble complex formed by transglutaminase cross-linking. The intracellular distribution of these proteins is wide, from cytoplasm to nucleus, mitochondria, ribosome, and plasma membrane. The results help rationalize ultrastructural features visible in mature hair.
Evidence of posttranslational modification (methylation, dimethylation, ubiquitination) of hair proteins was also obtained. Further application of this technology to cross-linked envelopes from epidermis and nail plate revealed that prominent constituents in each were junctional and other membrane-associated proteins and keratins. The findings indicate that maturing corneocytes become stabilized by enzymatically cross-linking a wide variety of proteins to complement the disulfide bonding in the cytoskeleton. The cross-linked proteins from nail plate overlapped with those in hair shaft and epidermal envelopes. Among the cross-linked proteins identified from samples of epidermis and cultured keratinocytes, previously reported components were identified as well as many new components, some of which appear novel. The lack of aberrant skin phenotype arising from ablation of genes encoding some known epidermal envelope constituents can be rationalized by redundant function among them. The
compositions of envelopes derived from cultured cells and the skin share prominent components, but many differed. The cross-linked proteome provides a sensitive criterion by which to judge how closely the physiological state in culture approaches that in vivo. Since epidermal scale, nail plate and hair shaft provide discrete non-invasive samples of the cellular proteome, this analytical approach likely will have diagnostic applications. Mouse pelage fur has now been analyzed, complementing data previously obtained for human hair and extending the list of known components. Environmental influences on epidermal cells that affect their differentiation, and hence their envelope forming ability, have also been studied. For example, growing the cells in low oxygen atmospheres (2-5% compared to ambient 21% oxygen) has revealed a striking dependence of differentiation marker expression and spontaneous envelope formation on oxygen level. In addition, exposure to salts of AsIII or SbIII
suppresses differentiation marker expression and envelope formation. The possibility that protein composition of envelopes can serve as a biomarker for certain environmental conditions is being explored.
Impacts
First, the results will provide a large set of potential markers for the differentiation of avian and mammalian epidermis and appendages. They will enhance future studies of appendage and skin development and differentiation. For example, applications to developmental mutants would be possible. Second, they will provide markers for studying skin and appendage disease. Animal models for ichthyosis exist, but their characterization would be greatly facilitated by availability of protein markers for proper epidermal function. Third, the results will provide a better foundation for studying the evolution of terrestrial epidermis from aquatic organisms. Ultimately, when the genomes of suitable species become available, analyses similar to those proposed here will permit further tracing of the evolution of the epidermis of terrestrial tetrapods.
Publications
- Patterson, T.J., and Rice, R.H. (2007). Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. Toxicol Appl Pharmacol 221:119-128.
- Lee, Y.J., Rice, R.H., and Lee, Y.M. (2006). Proteome analysis of human hair shaft: From protein identification to posttranslational modification. Molec Cell Proteomics 5:789-800.
- Rea, M.A., Zhou, L., Qin, Q., Barrandon, Y., Easley, K., Gungner, S., Phillips, M.A., Holland, W.S., Gumerlock, P.H., Rocke, D.M., and Rice, R.H. (2006). Spontaneous immortalization of human epidermal cells with naturally elevated telomerase. J Invest Dermatol 126:2507-2515.
- Ngo, M.A., Sinitsyna, N.N., Qin, Q., and Rice, R.H. (2007). Oxygen-dependent differentiation of human keratinocytes. J Invest Dermatol 127:354-361.
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Progress 01/01/06 to 12/31/06
Outputs
First, we have shown that rat and human cells differ markedly in their sensitivities to several model mutagenic/carcinogenic agents present in our food and air. Hence these cells may be useful in (1) modeling the response of other epithelial cells and (2) determining the risks to other animals, including farm animals and humans, from exposure to such compounds. Second, we have shown that human and rodent cells differ markedly in their ability to retain xenobiotic biotransforming ability in culture. We have found that an adaptation to culture of the rodent (but not human) cells is the expression of a supressor of cytochrome P450 induction, which could have an important role in vivo in influencing tumor development. Third, we have shown that telomerase activity becomes progressively deregulated during neoplasia, a process that is evident in the behavior of keratinocytes derived from tissue samples from rare individuals. This finding may permit diagnosis in population
surveys of an unusual propensity to develop cancer. Fourth, we have developed a method to analyze hair samples for structural defects. This method has revealed deficiencies in the outermost (cuticle) cells from rare skin disease syndromes in humans and mice and may be of clinical diagnostic utility.
Impacts
The results demonstrate that epidermal cells are highly active in metabolizing variety of toxic agents and exhibit consequent toxicity and mutagenicity. Since the biotransforming P450 isozymes in epidermal cells are expressed in most epithelia, it is now possible to model the other epithelia using keratinocytes. This is important because many epithelia (e.g., pulmonary, renal, liver) are not able to be studied conveniently in culture under conditions that preserve their normal function. The rat cells have a striking propensity, unlike those from human, to become insensitive by spontaneous silencing of their P450 expression. Moreover, the tissue specificity of toxic responses in the rat is dramatic. Thus, rat epidermal cells are very sensitive to polycyclic aromatic hydrocarbons, whereas esophageal cells are almost totally insensitive. Another striking difference is seen in the rat cell sensitivity to the heterocyclic amine food mutagen Trp-P-2, whereas the human cells
appear insensitive. Finally, our results demonstrate that epidermal cells are quite active in biotransforming agents that become toxic through metabolism. Epidermal cells express two cytochrome P450 isozymes (CYP1A1 and 1B1) expressed in most other epithelial cell types, which express other isozymes in addition. Thus, epidermal cells provide a convenient and simplified model for the latter epithelia that can actually be studied in serial culture (most others of interest cannot), thereby allowing us to resolve complicated combinations of isozymes into simpler components that are more easily understood.
Publications
- Walsh AA, Tullis K, Rice RH, Denison MW (1996) Identification of a novel cis-acting negative regulatory element affecting expression of the CYP1A1 gene in rat epidermal cells. J Biol Chem 271:22746-22753
- Rice RH, Wong VJ, Price VH, Hohl D, Pinkerton KE (1996) Cuticle cell defects in lamellar ichthyosis hair and anomalous hair shaft syndromes visualized after detergent extraction. Anatomical Rec 246:433-440
- Rice RH, Mehrpouyan M, Qin Q, Phillips MA, Lee YM (1996) Identification of phosphorylation sites in keratinocyte transglutaminase. Biochem J 320:547-550
- Jones G, Byford V, Makin HLJ, Kremer R, Rice RH, deGraffenried LA, Knutson JC, Bishop CW (1996) Anti-proliferative activity and target cell catabolism of the vitamin D analog, 1,24(S)-(OH)2D2 in normal and immortalized human epidermal cells. Biochem Pharmacol 52:133-140
- Phillips MA, Rice RH, Djian P, Green H (1997) The involucrin gene of the tree shrew: Recent repeat additions and the relocation of cysteine codons. Gene 187:29-34
- Kachinskas DJ, Qin Q, Phillips MA, Rice RH (1997) Arsenate suppression of human keratinocyte programming. Mutation Res 386:253-261
- Rea MA, Phillips MA, deGraffenried LA, Qin Q, Rice RH (1998) Modulation of human epidermal cell response to 2,3,7,8-tetrachlorodibenzo-p-dioxin by epidermal growth factor. Carcinogenesis 19:479-483
- Rice RH, Wong VJ, Pinkerton KE, Sundberg JP (1999) Cross-linked features of mouse pelage hair resistant to detergent extraction. Anatomical Rec 254:231-237
- Rice RH, Wong VJ, Williams ML, Price VH, Hohl D, Sundberg JP, Pinkerton KE (1999) Hair shaft defects visualized after detergent extraction. Experimental Dermatol 8:308-310
- Phillips MA, Qin Q, Rice RH (2000) Identification of an involucrin promoter transcriptional response element with activity restricted to keratinocytes. Biochem J 348:45-53
- Chun HS, Kuzmicky PA, Rucoba L, Kado NY, Rice RH (2000) Cytotoxicity and keratinocyte microsome mediated mutagenic activation of carcinogens in cultured epidermal cells. Toxicol Lett 115:165-172
- Krig SR, Rice RH (2000) TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes. Toxicol Sci 56:357-364
- Jessen BA, Phillips MA, Hovnanian A, Rice RH (2000) Role of the Sp1 response element in transcription of the human transglutaminase 1 gene. J Invest Dermatol 115:113-117
- Chun HS, Kuzmicky PA, Kado NY, Rice RH (2000) Toxicity of Trp-P-2 to cultured human and rat keratinocytes. Chem-Biol Interact 127:237-253
- Jessen BA, Qin Q, Rice RH (2000) Functional AP1 and CRE response elements in the human keratinocyte transglutaminase promoter mediating Whn suppression. GENE 254:77-85
- Rea MA, Rice RH (2000) Effect of TCDD on telomerase activity of spontaneously immortalized keratinocytes. Organohalogen Compounds, in press
- Monk SA, Denison MS, Rice RH (2000) Progressive silencing of CYP1A1 induction in rat keratinocytes. Organohalogen Compounds, in press
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Progress 01/01/05 to 12/31/05
Outputs
Pursuant to previous work on aberrations of hair structure in certain ichthyoses, examination of the proteome of normal human hair has now permitted identification of some 350 proteins. Using cultured keratinocytes, experiments have now shown that the differentiation state is strongly dependent upon the oxygen tension in the atmosphere and upon inclusion of insulin in the medium. These variables also affect the growth state of the cells. Low oxygen and absence of insulin lead to slower growth and less differentiation but to better preservation of growth ability after confluence. Low oxygen tension also suppresses toxic effects of arsenic on the cells, while at ambient oxygen levels arsenic antagonizes the suppressive effect of insulin on preservation of growth potential.
Impacts
Identification of proteins in normal human hair will permit better utilization of this resource for studying effects of diseases in humans and ultimately in farm animals. Characterizing the action of insulin on growth and differentiation promises to elucidate key signaling features in cell function that are perturbed in disease. Similarly, elucidating oxygen action promises to help understand and possibly prevent the targeting of epidermis by certain toxic agents.
Publications
- Lee C., Lee Y.M. and Rice R.H. 2005. Human epidermal cell protein responses to arsenite treatment in culture. Chem. Biol. Interact. 155:43-54.
- Rice R.H., Crumrine D., Uchida Y., Gruber R. and Elias P.M. 2005. Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity. Dermatol. Res. 297:27-133.
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Progress 01/01/04 to 12/31/04
Outputs
Present studies to elucidate the mechanism of arsenic action have shown that cultured human epidermal cells respond to arsenic exposure with dramatic changes in amounts of numerous proteins, confirming that exposure causes global effects. Among the widespread effects is the preservation of growth properties attributed to stem cells, possibly contributing to excessive growth. A diagnostic test for a disfiguring skin disease (lamellar ichthyosis) has now been applied to a case of a closely related skin condition. Examination of epidermal scale and nail showed similar features, implicating the same basic defect in the two diseases. Regulation of expression of the enzyme responsible for this defect was studied in transgenic mice and found to depend heavily upon a specific region of the gene promoter.
Impacts
Understanding the molecular basis for arsenic action may help find ways to prevent its carcinogenic effect and to characterize better the risk that exposure entails. Expanding usage of the simple test proposed for diagnosis of lamellar ichthyosis likely will permit more rapid and accurate classification of this category of skin disease and ultimately lead to improved treatments.
Publications
- Patterson TP, Ngo M, Aronov PA, Reznikova TV, Green PG, Rice RH (2003) Biological activity of inorganic arsenic and antimony reflects oxidation state in cultured keratinocytes. Chem Res Toxicol 16:1624-1631
- Phillips MA, Jessen BA, Lu Y, Qin Q, Stevens ME, Rice RH (2004) A distal region of the human TGM1 promoter is required for expression in transgenic mice and cultured keratinocytes. BioMed Central Dermatology 4(1):2
- Pustylnyak VO, Zakharova LY, Michailovna ON, Rice RH, Gulyaeva LF, Lyakhovich VV (2004) In vivo effects of protein kinase and phosphatase inhibitors on CYP2B induction in rat liver. Toxicology, in press
- Patterson TJ, Reznikova TV, Phillips MA, Rice RH (2004) Arsenic preserves germinative state in cultured human epidermal cells. Toxicology and Applied Pharmacology, in press
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Progress 01/01/03 to 12/31/03
Outputs
Present studies of cultured human epidermal cells have shown that the regulation of many genes changes with exposure to sodium arsenite or arsenate. Changes are observed even at the former drinking water standard but not at the new standard, supporting the reduction proposed by the USEPA. Further work has rationalized the relative potencies of arsenite and arsenate and showed that for both arsenic and antimony the potency reflects their oxidation states. Work with patients with a disfiguring skin disease (ichthyosis) has permitted development of a simple test for a certain category of this disease without invasive sampling. Finally, a novel type of negative regulation of an important enzyme of biotransformation has been uncovered that may be important for interpreting rodent models of human malignancy.
Impacts
Regulation of arsenic has been controversial in the absence of a suitable animal model and the lack of understanding of its mechanism of carcinogenicity. Present work supports the view arsenic acts by inducing reactive oxygen species and demonstrates a novel approach to measuring no effect levels by DNA microarray. The simple test developed for a type of ichthyosis may save patients, especially children, from the inconvenience and pain of invasive biopsy.
Publications
- Rea M.A., Gregg J.P., Qin Q., Phillips M.A., Rice R.H. 2003. Global alteration of gene expression in human keratinocytes by inorganic arsenic. Carcinogenesis 24:747-756
- Rice R.H., Crumrine D., Hohl D., Munro C.S., Elias P.M. 2003. Cross-linked envelopes in nail plate in lamellar ichthyosis. Brit J Dermatol 149:1050-1054
- Monk S.A., Denison M.S., Rice R.H. 2003. Reversible stepwise negative regulation of CYP1A1 in cultured rat epidermal cells. Arch Biochem Biophys 419:158-169
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Progress 01/01/02 to 12/31/02
Outputs
Progress in three directions has been made. First, the permeability barrier of the skin in individuals with lamellar ichthyosis is revealed to be abnormal because the layer of lipid coating mature epidermal cells is discontinuous. This defect results from the lack of a cross-linked protein envelope ordinarily surrounding each cell on which the lipid layer is deposited. Second, experiments have shown that the environmental contaminant TCDD (dioxin) interrupts the action of vitamin A in human keratinocytes, but only for some genes and not others. This action is indirect without interfering with the action of retinoid receptors. Third, The changes in gene expression in human epidermal cells we have examined as a result of TCDD exposure. The poorly understood mechanism by which this agent causes chronic toxicity, including chloracne in humans and skin tumor promotion in animals, may be elucidated from studying these changes.
Impacts
Impact TCDD residues in hazardous waste often drive the clean up process. To provide a more rational basis for clean up, and likely reduce its cost, understanding the mechanism of TCDD action should permit more accurate estimation of low dose effects. Understanding the permeability barrier defect in ichthyosis should permit better estimation of the environmental risks these individuals face.
Publications
- Elias PM, Schmuth M, Uchida Y, Rice RH, Behne M, Crumrine D, Feingold KR, Holleran WM, Pharm D (2002) Basis for permeability barrier abnormality in lamellar ichthyosis. Exp Dermatol 11:248-256.
- Krig SR, Chandraratna RAS, Chang MMJ, Wu R, Rice RH (2002) Gene-specific TCDD suppression of RAR and RXR-mediated induction of tissue transglutaminase. Toxicol Sci 68:102-108.
- Rea MR, Gregg JP, Rice RH (2002) Expression profiling of TCDD-treated human epidermal cells in culture. Organohalogen Compounds 55:469-472.
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Progress 01/01/01 to 12/31/01
Outputs
Most significant results: First, we have demonstrated that suspension culture stimulates the expression of cytochrome P450 in rat epidermal cells. This could reflect the generation of an endogenous ligand for the Ah receptor, a long sought factor. Second, we have shown that arsenic suppresses the differentiation program in human epidermal cells at concentrations equivalent to the drinking water standard. This supports efforts to lower this exposure standard. Third, we have shown that telomerase activity can be modulated by environmental agents in a line of spontaneously immortalized human epidermal cells. This appears to permit the extended lifetime and ultimate immortalization of the cells. Fourth, we have shown that an important transcription factor can redistribute in maturing epidermal cells. This may be a factor in coordinating certain genes whose expression changes during the differentiation program.
Impacts
Epidermal cells provide a convenient and sensitive model for assessing the mechanism by which toxic agents perturb cell function. The findings can guide our decision making process for setting exposure standards, as in the case of arsenic. They can also reveal a relationship between physiological and toxic responses, as in the case of dioxin (TCDD), and help understand the origins of neoplasia.
Publications
- Mazina OM, Phillips MA, Williams T, Vines CA, Cherr GN, Rice RH (2001). Redistribution of transcription factor in differentiating cultured human epidermal cells. J Invest Dermatol 117:864-870
- Rea MA, Rice RH (2001) Telomerase deregulation in immortalized human epidermal cells: Modulation by cellular microenvironment. Int J Cancer 94:669-673
- Jessen BA, Qin Q, Phillips MA, Phillips DL, Rice RH (2001) Keratinocyte differentiation marker suppression by arsenic: Mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate. Toxicol Appl Pharmacol 174:302-311
- Monk, SA, Denison MS, Rice RH (2001). Transient expression of CYP1A1 in rat epithelial cells cultured in suspension. Arch Biochem Biophys 393:154-162
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