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Research Topics
Health and Human Services Department of Defense Veterans Affairs Health and Human Services Gulf War Information Department of Defense Gulf War Information Veterans Affairs Gulf War Information Home Home Advanced Search Glossary FAQs Site Map Contact Us
 Research Topics    |    Major Focus Areas
Research Topics
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Project Summary

Title: The Aromatic Hydrocarbon Receptor (AhR) as a Biomarker of Susceptibility
Synopsis: The primary goal of the project was to investigate the potential role of a particular protein in mediating the adverse biologic effects caused by exposure to hydrocarbons from oil well fires.
Overall Project Objective: To test the hypothesis that the aromatic hydrocarbon receptor(AhR) is a molecular biomarker for polycyclic aromatic hydrocarbon (PAH) susceptibility. Veterans of the Persian Gulf war were potentially exposed to relatively high doses of PAHs in smoke emanating from Kuwaiti oil well fires. The high incidence of physical complaints by Gulf War veterans may reflect previously documented PAH toxicities including suppression of the immune system and neurologic dysfunction.
Status/Results to Date: The primary goal of the project supported by the DVA and administered through the Boston Environmental Hazards Center was to investigate the potential role of a protein receptor, the aryl hydrocarbon receptor (AhR), in mediating the adverse biologic effects caused by exposure to hydrocarbons such as those found in plumes from oil well fires and diesel engine exhaust. We have demonstrated both in defined cell culture and animal model systems that activation of this receptor results in suppression of the immune system, aberrant cell growth, and induction of cancer. Furthermore, we have demonstrated for the first time that the AhR plays a critical role in normal and abnormal cell growth in the absence of environmental ligands. Using molecular biology as a tool we have characterized the intracellular mechanisms through which the AhR effects these activities and have engineered AhR transgenic mice with which to project the human risk of exposure to AhR activators. We have evaluated the AhR gene in over 50 Persian Gulf war veterans and demonstrated that it is virtually identical in each individual, suggesting that a considerable risk is shared by all individuals exposed to environmental AhR activators. The results of these studies are presented in 16 full length manuscripts published in and/or submitted to the highest tier scientific journals and in 21 abstracts presented at international scientific meetings (see below). Most recently, we have demonstrated how the AhR can be targeted for treatment of breast cancer, prostrate cancer, and leukemia. In summary, enormous progress has been made. The past achievements and future directions of this body of work were submitted to the DVA for competitive renewal under guidelines set forth and made public by the DVA. The application was peer reviewed and, following an intensive site-visit, received an extremely favorable review. However, a programmatic change annulled the scientific review. As a consequence, all studies, including those targeting the AhR for cancer treatment, will stop and a number of projects will remain unfinished.
Project:VA-4E
Agency:Department Of Veterans' Affairs
Location:VAMC Boston
P.I. Name:David Sherr, Ph. D.
Research Type:Mechanistic
Research Focus:Environmental Toxicology
Focus Category:Genetic Studies
Status:Complete
Study Start Date:October 01,1994
Estimated Completion Date:December 31,1999
Specific Aims: 1. Confirm that AhR expression levels correlate with PAH bioactivity. 2. Optimize the use of single strand conformational polymorphism (SSCP) analysis to detect AhRgene polymorphism and mutations in mice. 3. Apply results to human studies. Results obtained in the fulfillment of aims 1 and 2 will define the conditions for employing AhR levels and gene polymorphism as molecular biomarkers of PAH susceptibility.
Methodology: For the first aim, initial experiments require molecular genetic manipulation to produce strains of mice expressing various levels of the AhR. AhR gene constructs have been made and tested both in vitro and in vivo. Analysis of the effects of ectopic AhR expression require cellular biology techniques including flow cytometry, cell culture and analysis of the immunologic competency of lymphocytes in vivo and in vitro. For human studies, we have optimized the use of single strand conformational polymorphism (SSCP) analyses. DNA is extracted from peripheral blood lymphocytes from Persian Gulf War veterans who complete Projects 1 and 4. Double stranded DNAs from these samples are separated by heating followed by rapid cooling on ice. The three-dimensional conformation reassumed by each strand is determined by its nucleic acid sequence. Single nucleotide changes can be detected when the reannealed DNAs are electrophoresed on 6% acrylamide gels. Samples showing variant banding patterns are cloned and sequenced to compare putative AhR alleles.
Most Recent Publications:

Yamaguchi K, Near RI, Matulka R, Schneider A, Toselli PA, Trombino AF, Sherr D. Activation of the aryl hydrocarbon receptor/transcription factor and bone marrow stromal cell-dependent preB cell apoptosis. J Immunol, 1;158(5):2165-73, Mar 1997. Abstract

Matulka R, Yamaguchi K, Shneider A, Near RI, Trombino AF, Sherr D. Ah receptor expression in bone marrow stromal cells influences DMBA-induced pro-B cell apoptosis. Society of Toxicology Meeting, Anaheim, CA, Apr 1996. Meeting

Near RI, Matulka R, Shneider A, Mann K, Sherr D. Apoptosis signals mediated via the aromatic hydrocarbon receptor (AhR) have different efficacy with different stromal lines and toxins. Society of Toxicology Meeting, Anaheim, CA, Apr 1997. Meeting

Trombino AF, Jenkins TA, Matulka R, Near RI, Sherr D. Aryl hydrocarbon receptor ligands modulate MCF-10F breast epithelial cell growth. The Toxicologist, Submitted, 2000. Article

Shneider A, Sherr D. Benzo(a)pyrene induces NF-kB in mouse hepatoma cells. Society of Toxicology Meeting, Anaheim, CA, Apr 1997. Meeting

Matulka R, Mann K, Sherr D. DMBA (7,12-dimethlbenzathracene) induces pre-B cell death via a soluble stromal cell factor. The Toxicologist, 42:190, 1998. Article

Mann K, Yamaguchi K, Trombino AF, Near RI, Sherr D. DMBA-induced apoptosis of B lymphocytes from murine bone marrow cultures. Society of Toxicology Meeting, Anaheim, CA, Apr 1996. Meeting

Mann K, Lawrence BP, Trombino AF, Kerkvliet N, Sherr D. DMBA-induced pre-B cell apoptosis is both stromal and AhR-dependent, but not P-450IA mediated. Society of Toxicology Meeting, Anaheim, CA, Apr 1997. Meeting

Vaziri C, Schneider A, Sherr D, Faller D. Expression of the aryl hydrocarbon receptor is regulated by serum and mitogenic growth factors in murine 3T3 fibroblasts. J Bio Chem, 18;271(42):25971-7, Oct 1996. Abstract

Trombino AF, Near RI, Matulka R, Yang S, Hafer LJ, Toselli PA, Kim DW, Sovak M, Rogers A, Sonenshein G, Sherr D. Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigensis. Breast Cancer Res Treat, 63(2):117-31, Sep 2000. Abstract

Yamaguchi K, Shneider A, Ju S-T, Sherr D. Fluoranthene mediated apoptosis in murine T cell hybridomas is Ah receptor independent. Society of Toxicology Meeting, Anaheim, CA, Apr 1996. Meeting

Yamaguchi K, Near RI, Shneider A, Cui H, Ju S-T, Sherr D. Fluoranthene mediated apoptosis in murine T cell hybridomas is aryl hydrocarbon receptor independent. Toxicology and Applied Pharmacology, 139:144, 1996. Article

Yamaguchi K, Near RI, Shneider A, Cui H, Ju S-T, Sherr D. Fluoranthene-induced apoptosis in murine T cell hybridomas is independent of the aromatic hydrocarbon receptor. Toxicology and Applied Pharmacology, 139(1):144-52, Jul 1996. Abstract

Cui H, Ju S-T, Sherr D. Functional expression of Fas (CD95) protein in autoimmune lpr mice. Cell Immunol, 25;174(1):35-41, Nov 1996. Abstract

Quadri SA, Qadri AX, Sherr D. Galangin, a naturally occurring bioflavonoid, is an aryl hydrocarbon receptor/transcription factor inhibitor. N/A, Submitted for Publication, 1999. Article

Yamaguchi K, Matulka R, Shneider A, Toselli PA, Trombino AF, Yang S, Hafer LJ, Mann K, Tao XJ, Tilly JL, Near RI, Sherr D. Induction of PreB cell apoptosis by 7,12-dimethylbenz[a]anthracene in long-term primary murine bone marrow cultures. Toxicology and Applied Pharmacology, 147(2): 190-203, Dec 1997. Abstract

Maecker B, Shen CF, Vonderheide RH, von Bergwelt-Baildon M, Bedor M, Schnipper D, Nadler L, Sherr D, Schultz JL. Induction of tumor-specific CTL responses with a peptide derived from cytochrome P450 1B1, a widely expressed tumor associated protein. Blood, 1999. Article

Wu M, Lee H, Bellas RB, Schauer SL, Arsura M, Katz D, Fitzgerald MJ, Sherr D, Rothstein TL, Sonenshein G. Inhibition of NF-kappa B/Rel induces apoptosis of murine B cells. EMBO, 2;15(17):4682-90, Sep 1996. Abstract

Wu M, Arsura M, Bellas RB, Fitzgerald MJ, Lee H, Schauer SL, Sherr D, Sonenshein G. Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells. Molec Cell Biol, 16(9):5015-25, Sep 1996. Abstract

Quadri SA, Qadri AX, Sherr D. Inhibition of polyaromatic hydrocarbon-induced apoptosis in murine pre-B cells by a dietary flavonoid, galangin. The Toxicologist, 42, 189, 1998. Article

Mann K, Quadri SA, Qadri AX, Shneider A, Sherr D. Involvement of NF-KB-and c-myc in DMBA-induced pre-B lymphocyte apoptosis. The Toxicologist, 42:189, 1998. Article

Trombino AF, Yang S, Hafer LJ, Qadri AX, Rogers A, Sherr D. Modulation of aromatic hydrocarbon receptor expression in 7, 12-dimethylbenz[a]anthracene-induced rat mammary tumors. Society of Toxicology Meeting, Anaheim, CA, Apr 1997. Meeting

Schlezinger J, Sherr D. NF-KB activation in bone marrow stromal cells is required for polycyclic aromatic hydrocarbon-induced pre-B lymphocyte apoptosis. N/A, In Preparation, 2000. Manuscripts

Trombino AF, Matulka R, Yang Y, Hafer LJ, Rogers A, Sherr D. Nuclear expression of the aryl hydrocarbon receptor (AhR) in 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors and human breast cancer cell lines. The Toxicologist, 42:316, 1998. Article

Trombino AF, Yamaguchi K, Sherr D, Near RI. PAH-induced apoptosis in bone marrow B cells requires supporting stromal cells containing the Ah receptor. Society of Toxicology Meeting, Anaheim, CA, Apr 1996. Meeting

Mann K, Doerre C, Sherr D, Quadri SA. Polycyclic aromatic hycrocarbon-induced pre-B cell apoptosis is mediated by down-regulation of NF-kappa B. N/A, Submitted for publication, 1999. Article

Near RI, Matulka R, Mann K, Shneider A, Gogate SU, Trombino AF, Sherr D. Regulation of preB cell apoptosis by aryl hydrocarbon receptor/transcription factor-expressing stromal/adherent cells. Society for Experimental Biology and Medicine, 221:242-252, 1999. Abstract

Mann K, Matulka R, Trombino AF, Near RI, Sherr D. Requirement of stromal cells in PAH-induced apoptosis of pre-B cells. American Association of Immuniologist, Fase B. J., Atlanta, GA, 1996. Meeting

Perez GI, Wang S, Sherr D, Tilly JL. Role of apoptosis and the aryl hydrocarbon receptor (AhR) in toxicity of polycylic aromatic hydrocarbons (PAHs) in murine antral follicles. Cell Death and Reproductive Physiology, Chicago, IL, Apr 1996. Article

Quadri SA, Qadri AX, Sherr D. Signal transduction in PAH-induced pre-B cell apoptosis. The Toxicologist, In Press, 1999. Article

Maecker B, Vonderheide RH, von Bergwelt-Baildon M, Bedor M, Shen CF, Schultz JL, Sherr D. The AhR and CYP1B1 as targets for peptide/tumor-specific cancer immunothearpy. The Toxicologist, Submitted, 2000. Article

Vaziri C, Sherr D, Shrteider A, Faller D. The aryl hydrocarbon receptor is a serum-inducible gene in murine 3T3 fibroblasts. Society of Toxicology Meeting, Anaheim, CA, Apr 1996. Meeting

Quadri SA, Kim DW, Gazourian L, Sonenshein G, Sherr D. The aryl hydrocarbon receptor/transcription factor (AhR) and the Rel A nuclear factor kB subunit cooperate to transactivate the c-myc promoter. The Toxicologist, Submitted, 2000. Article

Kim DW, Gazourian L, Quadri SA, Sherr D, Sonenshein G. The aryl hydrocarbon receptor/transcription factor (AhR) and the Rel A nuclear factor-kappa B subunit cooperate to transactivate the c-myc promoter. N/A, Submitted for Publication, 1999. Article

Schlezinger J, Sherr D. The aryl hydrocarbon receptor/transcription factor as a regulator of cell growth. N/A, In Preparation, 2000. Manuscripts

Mann K, Hahn M, Trombino AF, Lawrence BP, Kerkvliet N, Sherr D. The role of DMBA metabolites in preB cell apoptosis. The Toxicologist, In Press, 1999. Article

Mann K, Matulka R, Hahn M, Trombino AF, Lawrence BP, Kerkvliet N, Sherr D. The role of polycyclic aromatic hydrocarbon metabolism in dimethylbenz[a]anthracene-induced pre-B lymphocyte apoptosis. Toxicology and Applied Pharmacology, 15;161(1):10-22, Nov 1999. Abstract