Research interests

Toxicology is the study of how chemicals poison biological systems. In our human toxicology work, we seek to understand how chemicals, particularly environmental pollutants turn normal cells into cancer cells. We focus on damage to DNA, since this type of damage is the most common cause of cancer and we investigate: 1) how chemicals damage DNA; 2) how cells repair that damage; and 3) how the lack of repair leads to cancer.

The DNA structure is a double-stranded helix, which is packed with proteins into structures called chromosomes to allow for cell division. Breaking both strands of DNA creates a lesion that is difficult to repair as genetic information is lost. Altering either the structure or number of chromosomes can lead to cancer. These events are part of a phenomenon called genomic instability. Cancer cells are known to exhibit genomic instability and increasing data indicate that these events may occur early in the formation of cancer.

We study genomic instability by primarily considering two events: DNA double strand breaks and chromosome abnormalities. Because our interest is in human cancer, we focus on effects in human cells though we may use other cellular models as well. Chemicals of focus include chromium, arsenic, lunar dust, depleted uranium and metal nanoparticles.

For example, hexavalent chromium (Cr(VI)) is known to cause lung cancer in humans. What is unknown is how it causes cancer. Lung cancer exhibits a type of genomic instability called chromosome instability, which is characterized by changes in both chromosome structure and number. We are the first lab to demonstrate that hexavalent chromium causes chromosome instability, DNA double strand breaks and neoplastic transformation in human lung cells. Now we are investigating how it causes these effects. We hope that by determining how hexavalent chromium causes genomic instability we might identify how to prevent chromium-induced cancers and events that are important to lung cancer progression in general that might lead to new treatment approaches or new ways to avoid lung cancer.

Our initial work determined that particulate chromate induced numerical chromosome instability. Further study showed that there is an increase in both the number of metaphases with too few chromosomes (hypodiploid) and the number of metaphases with twice the number of chromosomes (tetraploid). We next began exploring the potential cause of this effect. We started by considering the effects on centrosomes, the structures that direct cell division by controlling the mitotic spindle. Centrosome amplification (cells with greater than two centrosomes) is a hallmark of lung cancer and can induce numerical chromosome instability by unequally pulling the chromosomes into the daughter cells. We found that particulate chromate induced centrosome amplification producing cells with four to eighteen centrosomes.

We also considered whether bypass of the spindle assembly checkpoint was playing a role. The spindle assembly checkpoint is a set of cellular proteins that operate as a network to regulate and monitor assembly of the mitotic spindle, which allows growing cells to divide into two cells. This checkpoint prevents cell division until all of the chromosomes are attached to the spindles and ready to separate. Bypassing the spindle assembly checkpoint can cause aneuploidy. We found that particulate chromate does indeed cause spindle assembly checkpoint bypass. Normal cells with a properly functioning checkpoint should stop in metaphase when exposed to demecolchicine. Cells treated with particulate chromate, however, bypass the checkpoint and continue through metaphase into anaphase which is seen as premature anaphase and premature centromere division. Current investigations are aimed at understanding the molecular events that cause centrosome amplification and spindle assembly checkpoint bypass.

 

In our marine toxicology work, we seek to understand how toxic a chemical is to a marine species in an effort to understand how environmental pollutants might be endangering them. We focus on damage to DNA, since this type of damage can interfere with the ability of these species to reproduce and the ability of their offspring to survive. Thus our hypothesis is that environmental contaminants are decreasing the reproductive success of marine species.

For example, we are investigating the genetic effects of environmental contaminants on North Atlantic right whales by using their closest living relative, the bowhead whale, as a surrogate model. Our research focuses on five classes of environmental contaminants (polycyclic aromatic hydrocarbons, metals, anti-fouling agents, anticorrosives, and radionuclides) that pose a specific concern for right whales (1) and investigates the genetic effects of these chemicals on cell lines developed from bowhead reproductive and somatic tissues (testis, ovary, lung and skin). This research also investigates the genetic effects of these contaminants on cell lines developed from right whale skin, lung, and testis.

With the data obtained from these efforts, we will be able to determine: 1) which classes of contaminants damage the reproductive organs of whales; 2) the sensitivity of reproductive organs compared to somatic tissues (lung and skin); and 3) how bowhead cells compare to right whale cells. Furthermore, this proposal investigates cell lines from animals of different age classes (adult and sub-adult), different genders and multiple individuals from both species.

This work will help us to begin to understand the intra-species differences (age, sex and individuals) in the response to the genetic effects of environmental contaminants by using cell lines from each animal. And also look at the differences between reproductive and somatic tissues. In addition, we are interested in understanding the mechanisms of DNA damage repair in these species and compare with our human studies.

This study will greatly enhance our knowledge of the physiology and toxicology of the right whale. Moreover, it will create tools (cell lines) that can serve as right whale-specific models, which can be used by other investigators to better understand additional aspects of right whale genetics, physiology, immunology and biochemistry, as well as investigations into the effects of other contaminants and infectious agents.

 

 

Publications

• Xie, H., Wise, S.S., and Wise, Sr., J.P. Deficient Repair of Particulate Chromate-Induced DNA Double Strand Breaks Leads To Neoplastic Transformation. Mutation Research. 649: 230-238, 2008.
• Wise, Sr. J.P., Wise, S.S, Kraus, S. Shaffiey, F., Grau, M., Li Chen, T., Perkins, C., Thompson, W.D., Zheng, T., Zhang, Y., Romano, T., and O’Hara, T. Hexavalent Chromium Is Cytotoxic and Genotoxic to the North Atlantic Right Whale (Eubalaena glacialis) Lung and Testes Fibroblasts. Mutation Research. 650: 30–38, 2008.
• Goodale, B.C., Walter, R., Pelsue, S.R., Thompson, W.D., Wise, S.S., Winn, R.N., Mitani, H., Wise Sr., J.P. The Cytotoxicity and Genotoxicity of Hexavalent Chromium in Medaka (Oryzias latipes) Cells. Aquatic Toxicology 87: 60–67, 2008.
• Brooks, B., O’Brien, T.J., Ceryak, S., Wise, Sr., J.P., Wise, S.S., Wise, Jr., J.P., DeFabo, E. and Patierno, S.R. Excision Repair is Required for Genotoxin-Induced Mutagenesis in Mammalian Cells. Carcinogenesis 29(5): 1064–1069, 2008.
• Wise, S.S., Holmes, A.L., and Wise, Sr., J.P. Hexavalent chromium-induced DNA damage and repair mechanisms. Reviews on Environmental Health 23(1): 39-57, 2008.
• Holmes, A.L., Wise, S.S., Goertz, C.E.C., Dunn, J.L., Gulland, F.M.D., Gelatt, T., Beckmen, K.B., Burek, K., Atkinson, S., Bozza, M., Taylor, R., Zheng, T., Zhang, Y., Aboueissa , A., and Wise, Sr., J.P. Metal Tissue Levels in Steller Sea Lion (Eumetopias jubatus) Pups. Marine Pollution Bulletin 56(8) 1416-1421, 2008.
• Savery, L.C., Grlickova-Duzevik, E., Wise, S.S., Thompson, W.D., Hinz, J.M., Thompson, L.H., and Wise, Sr., J.P. Role of the Fancg Gene in Protecting Cells from Particulate Chromate-Induced Chromosome Instability. Mutation Research, 626(1-2): 120-127, 2007.
• Camrye, E., Wise, S.S., Milligan, P., Gordon, N., Goodale, B., Stackpole, M., Patzlaff, N., Aboueissa, A., and Wise, Sr., J.P. Ku80 Deficiency Does Not Affect Particulate Chromate-Induced Chromosome Damage and Cytotoxicity in Chinese Hamster Ovary Cells. Toxicological Sciences, 97(2):348-54, 2007.
• Wise, S.S., Thompson, W.D., Aboueissa, A., Mason, M.D., and Wise, Sr., J.P. Particulate Depleted Uranium Is Cytotoxic and Clastogenic to Human Lung Cells. Chemical Research in Toxicology, 20(5):815-820, 2007.
• Zhang, Y., Holford, T.R., Leaderer, B.,Boyle, B., Zhu, Y., Wang, R., Zou, K., Zhang, B., Wise, Sr., J.P., Qin, Q., Kilfoy, B., Han, J., and Zheng, T. Ultraviolet Radiation Exposure and Risk of Non-Hodgkin Lymphoma. American Journal of Epidemiology, 165(11):1255-64, 2007.
• Stackpole, M.M., Wise, S.S., Goodale, B.C. Duzevik, E.G., Munroe, R.C., Thompson, W.D., Thacker, J., Thompson, L.H., Hinz, J.M., and Wise, Sr., J.P. Homologous Recombination Protects Against Particulate Chromate-Induced Genomic Instability in Chinese Hamster Cells. Mutation Research. 625: 145-154, 2007.
• Xie, H., Holmes, A.L., Wise, S.S., Huang, S., Peng, C., and Wise, Sr., J.P. Neoplastic Transformation of Human Bronchial Cells by Lead Chromate Particles. American Journal of Respiratory Cell and Molecular Biology. 37(5): 544-552, 2007.
• Grlickova-Duzevik E., Wise, S.S., Munroe, R.C., Thompson, W.D., and Wise, J.P., Sr. XRCC1 Protects against Particulate Chromate-Induced Chromosome Damage and Cytotoxicity in Chinese Hamster Ovary Cells. Toxicological Sciences, 92(1): 96-102, 2006.
• Holmes, A.L., Wise, S.S., Sandwick, S.J., Lingle, W.L., Negron, V.C., Thompson W.D., and Wise, Sr., J.P. Chronic Exposure to Lead Chromate Causes Centrosome Abnormalities and Aneuploidy in Human Lung Cells. Cancer Research, 66(8): 4041-4048, 2006.
• Wise, Sr., J.P., Goertz, C.E.C., Wise, S.S., Morin, A.T., Dunn, J.L., Gulland, F.M.D., Bozza, M., Atkinson, S., and Thompson, W.D. Chromium Cytotoxicity in Steller Sea Lion Lung, Skin and Testes Cells. In Trites, A.W., Atkinson, S.K., DeMaster, D.P., Fritz, L.W., Gelatt, T.S., Rea, L.D., and Wynne, K.M. (Eds), Sea Lions of the World Conservation and Research in the 21st Century. Alaska Sea Grant College Program, pp. 57-68, 2006.
• Duzevik, E.G., Wise, S.S., Munroe, R.C., Thompson, W.D., and Wise, Sr., J.P. XRCC1 Protects against Particulate Chromate-Induced Chromosome Damage and Cytotoxicity in Chinese Hamster Ovary Cells. Toxicological Sciences, 92(2): 409-415, 2006.
• Wise, S.S., Holmes, A.L., and Wise, Sr., J.P. Particulate and Soluble Hexavalent Chromium Are Cytotoxic and Genotoxic to Human Lung Epithelial Cells. Mutation Research, 610(1-2): 2-7, 2006.
• Holmes, A.L., Wise, S. S., Sandwick, S.J., and Wise, Sr., J.P. The Clastogenic Effects of Chronic Exposure to Particulate and Soluble Cr(VI) in Human Lung Cells. Mutation Research, 610(1-2): 8-13, 2006.
• Grlickova-Duzevik, E., Wise, S.S., Munroe, R.C., Thompson, W.D., and Wise, Sr., J.P. XRCC1 Protects Cells from Chromate-Induced Chromosome Damage, but Does Not Affect Cytotoxicity Mutation Research, 610(1-2): 31-37, 2006.
• Wise, S.S., Holmes, A.L., Xie, H., Thompson, W.D., and Wise, Sr., J.P. Chronic Exposure to Particulate Chromate Induces Spindle Assembly Checkpoint Bypass in Human Lung Cells. Chemical Research in Toxicology, 19(11):1492-1498, 2006.
• Wise, Sr., J.P. Genotoxic and Carcinogenic Effects of Lead. In, U.S. EPA. Air Quality Criteria for Lead (Final). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-05/144aF-bF, 5-125 – 5-147, 2006.
• Holmes, A.L., Wise, S.S., Xie, H., Gordon, N., Thompson W.D., and Wise, Sr., J.P. Lead Ions Do Not Cause Human Lung Cells to Escape Chromate-Induced Cytotoxicity. Toxicology and Applied Pharmacology, 203:167– 176, 2005.
• Xie, H., Wise, S.S., Holmes, A.L., Xu, B., Wakeman, T., Pelsue, S.C., Singh, N.P., and Wise, Sr., J.P. Carcinogenic Lead Chromate Induces DNA Double-Strand Breaks in Human Lung Cells. Mutation Research, 586(2): 160-172, 2005.
• Wise, S.S., Holmes, A.L., Moreland, J.A., Xie, H., Sandwick, S.J., Stackpole, M.M., Fomchenko, E., Teufack, S., May, Jr., A.J., Katsifis, S.P., and Wise, Sr., J.P. Human Lung Cell Growth Is Not Stimulated by Lead Ions after Lead Chromate-Induced Genotoxicity. Molecular and Cellular Biochemistry, 279(1-2): 75-84, 2005.
• Wise, S.S., Elmore, L.W., Holt, S.E., Little, J.E., Antonucci, P.G., Bryant, B.H., and Wise, Sr., J.P. Telomerase-Mediated Lifespan Extension of Human Bronchial Cells Does Not Affect Hexavalent Chromium-Induced Cytotoxicity or Genotoxicity. Molecular and Cellular Biochemistry, 255:103-111, 2004.
• Wise, S.S., Schuler, J.H.C., Katsifis, S.P., and Wise, Sr., J.P. Barium Chromate Is Cytotoxic and Genotoxic to Human Lung Cells. Environmental and Molecular Mutagenesis, 42:274-278, 2004.
• Wise, S.S., Holmes, A.L., Ketterer, M.E., Hartsock, W.J., Fomchenko, E., Katsifis, S.P., Thompson, W.D., and Wise, Sr., J.P. Chromium Is the Proximate Clastogenic Species for Lead Chromate-Induced Clastogenicity in Human Bronchial Cells. Mutation Research, 560:79-89, 2004.
• Wise, S.S., Schuler, J.H.C., Holmes, A.L., Katsifis, S.P., Ketterer, M.E., Hartsock, W.J., Zheng T., and Wise, Sr., J.P. A Comparison of Two Carcinogenic Particulate Hexavalent Chromium Compounds: Barium Chromate Is More Genotoxic than Lead Chromate in Human Lung Cells. Environmental and Molecular Mutagenesis, 44:156-162, 2004.
• Zhang, Y, Wise, Sr., J.P., Holford, T.R., Xie, H., Boyle, P., Zahm, S.H., Zou, K.Y., Zhang B., Owens, P.H., Zheng, T. Serum Polychlorinated Biphenyls, Cytochrome P4501A1 Polymorphisms, and Risk of Breast Cancer in Connecticut Women. American Journal of Epidemiology, 160(12):1177-1183, 2004.
• Xie, H., Holmes, A.L., Wise, S.S., Gordon, N., and Wise, Sr., J.P. Lead Chromate-Induced Chromosome Damage Requires Extracellular Dissolution to Liberate Chromium Ions but Does Not Require Particle Internalization or Intracellular Dissolution. Chemical Research in Toxicology, 17(10):1362-1367, 2004.
• Zheng, T., Holford, T.R., Zahm, S.H., Owens, P.H., Boyle, P., Zhang, Y., Wise, Sr., J.P., and Ali-Osman, F. Glutathione S-transferase M1 and T1 Genetic Polymorphisms, Alcohol Consumption and Breast Cancer Risk. British Journal of Cancer, 88: 58-62, 2003.
• Zheng, T., Boyle, P., Zhang, B., Zhang, Y., Owens, P.H., Lan, Q., and Wise, J. Tobacco Use and Risk of Oral Cancer . In: Boyle P, ed. Tobacco: The public health disaster of the 20th century. Oxford University Press, Oxford, UK., 2003
• Wise, Sr., J.P., Winn, R.N., and Renfro, J.L. Generating New Marine Cell Lines and Transgenic Species. Journal of Experimental Zoology, 292: 271-220, 2002.
• Wise, Sr., J.P., Wise, S.S., and Little, J.E. The Cytotoxicity and Genotoxicity of Particulate and Soluble Hexavalent Chromium in Human Lung Cells. Mutation Research, 517: 221-229, 2002.
• Rabinowitz, P.M., Wise, Sr., J.P., Antonucci, P.G., Mobo, B.H. Glutathione-S-Transferase Polymorphism and High Frequency Otoacoustic Emissions in Noise-Exposed Workers. Hearing Research,173: 164-171, 2002.
• Zheng, T., Holford, T.R., Zahm, S.H., Owens, P.H., Boyle, P., Zhang, Y., Wise, Sr., J.P., Stephenson, L.P., Ali-Osman, F. Cigarette Smoking, Glutathione S-Transferase M1 and T1 Genetic Polymorphisms, and Breast Cancer Risk (United States). Cancer Causes Control, 13: 637-645, 2002.