Contact Info:Email: goodman3@msu.edu Phone: (517) 353-9346 Fax: (517) 353-8915

Toxicology: A Personal Perspective
My research interests are focused upon discerning mechanisms underlying the ability of chemicals to cause adverse effects. What excites me about research in toxicology is that it combines the theoretical with the practical. While pursuing research aimed at understanding the mechanism(s) of action of the chemical of interest, we learn more about fundamental aspects of biology. Thus, toxicology is a basic biomedical science. On the practical side, the new knowledge gleaned facilitates the enhancement of science-based safety assessment of chemicals. This permits a rational approach towards resolving key issues, e.g., dose-response relationships and appropriate extrapolation from test species to humans. Thus toxicological research plays a key role by facilitating our ability to safely use chemicals (including, but not limited to, medicines, consumer products and agricultural chemicals) to enhance the quality of people’s lives. Therefore, I view toxicology as “part of the solution.” This is a theme that I began advocating when I was President of the Society of Toxicology (1999-2000): http://www.toxicology.org/AI/PO/video/jay.asp

Research Synopsis:

The involvement of mutagenesis in carcinogenesis needs to be reconciled with the fact that not all carcinogens are mutagens and the view that nonmutagenic events also play key roles in the transformation of a normal cell into a cancer cell. This apparent paradox can, in part, be resolved by considering the roles that altered DNA methylation, an epigenetic mechanism, play in carcinogenesis.

Gene expression is not determined only by DNA base sequence; it also depends on epigenetic mechanisms, i.e., heritable gene-regulating mechanisms not involving a change in DNA base sequence. Inheritance occurs on two levels. The transmission of genes either in the somatic sense or from generation to generation is distinct from mechanisms involved in transmission of alternative states of gene activity.

Epigenetics describes the latter and involves regulation of temporal and spatial control of gene activity, e.g., changes in gene expression during development, imprinting, segregation of gene activities such that daughters of a cell exhibit different patterns of gene expression, and mechanisms that permit the somatic inheritance of a specific set of active and quiescent genes.

DNA methylation (the presence of 5-methylcytosine (5MeC) as compared to cytosine) is an epigenetic mechanism controlling gene activity. Changes in DNA methylation are not mutations because 5MeC and cytosine base pair with guanine. In general, increased methylation of a gene is associated with deceased transcription (e.g., may silence tumor suppressor genes, functionally equivalent to inactivation due to point mutation or allelic loss) and decreased methylation may up-regulate gene expression (e.g., may increase expression of oncogenes). Thus, altered DNA methylation can facilitate the aberrant gene expression underlying carcinogenesis.

The hypothesis being tested in my laboratory is that susceptibility to carcinogenesis, and perhaps other toxicities, is related inversely to the capacity to maintain normal patterns of DNA methylation. Particular emphasis is being placed on discerning novel genes that are involved in carcinogenesis due to aberrant methylation.

 

 

SELECTED ACHIEVEMENTS
Editorial Boards:

• Regulatory Toxicology and Pharmacology, 2000-present; Associate Editor, 2004-present
• Nonlinearity in Biology, Toxicology and Medicine, 2000-present
• Toxicology, 2008-present

Associate Editor

• Toxicological Sciences, 1997-2007

Membership on Advisory Committees:

• Member of the Board of Scientific Counselors, National Toxicology Program, 1989-1992
• Member of the Board of Directors, American Board of Toxicology, Inc., 1992-1996
• Member of the Nonclinical Studies Subcommittee of the Advisory Committee for Pharmaceutical Science, U.S. Food and Drug Administration, 1999-2002
• Member of the Global Environmental Advisory Council, Dow AgroSciences, 2000-2004
• Member of Council, International Society of Regulatory Toxicology and Pharmacology, 2001-2008
• Member, Alumni Steering Committee, Department of Pharmacology, The University of Michigan, 2001-
• Chairperson of the Executive Committee, International Life Sciences Institute, Health and Environmental Sciences Institute, 2002-2004; currently, member of the Board of Trustees and member of the Executive Committee
• Member of Council, Academy of Toxicological Sciences, 2002-2005
• Participant in the Strategic Implementation Leadership Committee Meeting, American Chemistry Council, Chlorine Chemistry Council, 2004
• Member of the International Scientific Program Planning Committee for the International Congress of Toxicology (ICT XI), Montreal, Canada, July, 2007, 2005-2007
• Member of the Advisory Committee to the Director, Centers for Disease Control and Prevention, Atlanta, GA, 2005-2008
• Member of the Board of Scientific Counselors, NIH, National Institute of Environmental Health Sciences, 2008-2011

Society of Toxicology Activities:

• President, 1999-2000
• Member of the Task Force to Improve the Scientific Basis for Risk Assessment, 1996-1999
• Chairperson of the Steering Committee of the Mixtures Project, 2001-2003
• Member, Awards Committee, 2009-2012

Honors/Awards:

• Distinguished Alumnus Award, Long Island University College of Pharmacy, 1998
• Distinguished Alumnus Award, Doctoral Program in Pharmacology, the University of Michigan, 2000
• Recipient of the John Barnes Prize Lecture, awarded by the British Toxicology Society, 2005
• Invited speaker, Annual John Doull Symposium, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas, 2007
• Recipient of the George H. Scott Memorial Award, awarded by the Toxicology Forum, 2007
• Plenary Lecture, Annual Meeting of the European Societies of Toxicology (EUROTOX), 2009

Presentations at National and International Meetings, Selected recent examples:

“Altered DNA methylation and carcinogenesis: Implications for safety assessment.” AstraZeneca, Ltd., Central Research Laboratory, Manchester, United Kingdom, February, 2000.

“Altered DNA methylation: An epigenetic, secondary mechanism involved in carcinogenesis.” Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN, May, 2000.

“Threshold-exhibiting events in carcinogenesis: Epigenetics and secondary mechanisms.” Annual Summer meeting of the Toxicology Forum, Aspen, CO, July, 2000.

“Toxicogenomics: Making progress by maintaining a focus on the fundamentals of toxicology.” Toxicogenomics International Forum 2001, National Institute of Health Sciences, Tokyo, Japan, October, 2001.

“Toxicogenomics: Making progress by focusing on the fundamentals of toxicology.” Symposium on “Genomics and Toxicology,” Annual Meeting of the Society of Toxicology of Canada, Montreal, Quebec, Canada, December, 2001.

Plenary lecture, “Results of the Society of Toxicology’s Expert Panel Workshop, Risk Assessment of Mixtures Development of Testable Hypotheses as Science Input into Policy Decisions.” Sponsored by the Agency for Toxic Substances and Disease Registry, Atlanta, GA, September, 2002.

“Altered DNA methylation: A secondary mechanism involved in carcinogenesis.” American Cancer Society, Shilling Conference 2002, “From the Cancer Cell to a Tumor: Tumors as Outlaw Organs,” Santa Cruz, CA, September, 2002.

“Use of alternative models for carcinogen risk assessment: Areas of agreement and disagreement in the United States, Europe and Japan.” International Life Sciences Institute, Health and Environmental Science Institute Workshop on Alternatives for Carcinogen Testing, Washington, DC, February, 2003.

“Altered DNA methylation: A secondary mechanism involved in carcinogenesis.” Continuing Education course entitled “Epigenetics of Cancer,” Annual Meeting of the Society of Toxicology, Salt Lake City, UT, March, 2003.

“Epigenetics, Altered DNA Methylation and Carcinogenesis: Implications for Safety Assessment.” Millenium Pharmaceuticals, Boston, MA, September, 2004.

“Altered DNA methylation: An epigenetic, secondary mechanism involved in carcinogenesis.” Annual Meeting of the Genetic and Environmental Mutagenesis Society, “DNA Methylation and Its Toxicological Consequences,” Chapel Hill, NC, November, 2004.

Plenary lecture, “Epigenetics, DNA Methylation and Carcinogenesis: Implications for Safety Assessment.” The John Barnes Prize Lecture, Annual Meeting of the British Toxicology Society, The University of Warwick, England, March, 2005.

“Mode of action-based framework for risk assessment.” Roundtable Discussion on Large Granular Lymphocyte Leukemia in F344 Rats: Relevance for Human Cancer Risk Assessment, University of Pennsylvania Medical Center, Hershey, PA, June, 2005.

Invited participant, Workshop on Framework Approaches to Risk Assessment: Rodent Liver Tumors as a Predictor of Human Cancer Risk? International Life Sciences Institute, Health and Environmental Sciences Institute, EuroForum, Nice, France, November, 2005.

“Identification of Regions of Altered DNA Methylation Which May Lead to Carcinogenesis: Implications for Safety Assessment.” Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, United Kingdom, May, 2006.

“Altered DNA Methylation: An Epigenetic Mechanism Underlying Carcinogenesis.” Symposium on Epigenetic Mechanisms in Toxicology, Eurotox Meeting, Cavtat, Croatia, September, 2006.

“Epigenetics and Carcinogenesis: The Role of Altered DNA Methylation.” Symposium entitled “Epigenetic Regulation in Development, Reproduction and Disease. Annual Meeting of the Society of Toxicology, Charlotte, NC, March 25-29, 2007.

“A Novel Approach to Identify Genes Involved in Carinogenesis Due to Altered DNA Methylation.” The Annual John Doull Symposium, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas, Kansas City, KS, September, 2007.

“Altered DNA Methylation: An Epigenetic Mechanism Underlying Carcinogenesis.” Symposium entitled: “The Interface of Chemistry and Biology in the “Omics” Era: Environment and Health and Drug Discovery,” The 6th Princess Chulabhorn International Science Congress, Bangkok, Thailand, November, 2007.

“Transgenerational Epigenetics: What do we Need to Know Before Altering the Risk Assessment Paradigm?” Workshop on Transgenerational Epigenetics, sponsored by the United Kingdom Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, Cheshire, United Kingdom, February, 2008.

“Orphan Nuclear Receptor Constitutive Active/Androstane Receptor (CAR)-mediated Alterations in DNA Methylation During Phenobarbital (PB) Promotion of Liver Tumorigenesis.” Symposium entitled “New Developments in Liver Tumor Biology,” Annual Meeting of the Society of Toxicology, Seattle, WA, March, 2008.

Invited participant, workshop on Alternative Approaches to Assessment of Systemic Toxicity Without the Use of Animals, sponsored by The European Partnership for Alternative Approaches for Animal Testing, Brussels, Belgium, April, 2008.

“Identification of Genes Involved in Phenobarbital-Induced Tumorigenesis Due to Altered DNA Methylation.” U.S. Food and Drug Administration, National Center for Toxicological Research, Jefferson, AK, May, 2008.

“Genotoxicity and Carcinogenicity Testing: What are we Doing and What Should we be Doing?” Genetic Toxicology Association, Annual Meeting, University of Delaware, Newark, DE, September 2008.

“Identification of Genes Involved in Carcinogenesis Due to Altered DNA Methylation.” Department of Pharmacology, East Carolina University, Greenville, NC, November, 2008.

“Epigenetic Regulation of Gene Expression.” Symposium entitled “Epigenetic Implications to Toxicology,” Annual Meeting of the Society of Toxicology, Baltimore, MD, March, 2009.

“Identification of genes involved in phenobarbital-induced tumorigenesis: Emphasis on altered DNA methylation.” Symposium entitled “Biological Factors that Impact Assessment of Human Relevance of Animal Neoplasia.” Annual Meeting of the Society of Toxicologic Pathology, Washington, DC, June, 2009.

Plenary Lecture: Identification of genes involved in phenobarbital-induced tumorigenesis: Emphasis on altered DNA methylation and Expression. Annual EUROTOX meeting, Dresden, Germany, September, 2009.

Selected Publications:

Counts, J.L. and Goodman, J.I.: Alterations in DNA methylation may play a variety of roles in carcinogenesis. Cell 83: 13-15, 1995.

Watson, R.E. and Goodman, J.I.: Epigenetics and DNA methylation come of age in toxicology. Toxicol. Sci. 67(1): 11-16, 2002.

Goodman, J.I. and Watson, R.E.: Altered DNA methylation: A secondary mechanism involved in carcinogenesis. Ann. Rev. Pharmacol. Toxicol. 42: 501-525, 2002.

Carnell, A.N. and Goodman, J.I.: The long (LINEs) and short (SINEs) of it: Altered methylation as a precursor to toxicity. Toxicol. Sci. 75(2): 229-235, 2003.

Watson, R.E., Curtin, G.M., Hellmann, G.M., Doolittle, D.J. and Goodman, J.I.: Increased DNA methylation in the Hox45 promoter region correlates with decreased expression of the gene during tumor promotion. Molec. Carcinogen. 41(1): 54-66, 2004.

MacDonald, J., French, J.E., Gerson, R., Goodman, J., Inoue, T., Jacobs, A., Kasper, P., Keller, D., Lavin, A., Long, G., McCullough, B., Sistare, F., Storer, R. and van der Laan, J.W.: The utility of transgenic mouse assays for identifying human carcinogens: A basic understanding and path forward. Toxicol. Sci. 77: 188-194, 2004.

Moggs, J.G., Goodman, J.I., Trosko, J.E. and Roberts, R.A.: Epigenetics and cancer: Implications for drug discovery and safety assessment. Toxicol. Appl. Pharmacol. 196(3): 422-430, 2004.

Watson, R.E., McKim, J.M., Cockerell, G.L. and Goodman, J.I.: The value of DNA methylation analysis in basic, initial toxicity assessments. Toxicol. Sci. 79(1): 178-188, 2004.

Doe, J.E., Boobis, A.R., Blacker, A., Dellarco, V., Doerrer, N.G., Franklin, C., Goodman, J.I., Kro-nenberg, J.M., Lewis, R., McConnell, E.E., Mercier, T., Moretto, A., Nolan, C., Padilla, S., Phang, W., Solecki, R., Tilbury, L., van Ravenzwaay, B. and Wolf, D.C.: A tiered approach to systemic toxicity testing for agricultural chemical safety assessment. Crit. Rev. Toxicol. 36: 37-68, 2006.

Bachman, A.N., Kamendulis, L.M. and Goodman, J.I. Diethanolamine and phenobarbital produce an altered methylation in GC-rich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency. Toxicol. Sci. 90: 317-325, 2006.

Bachman, A.N., Phillips, J.M. and Goodman, J.I.: Phenobarbital induces unique time-dependent patterns of GC-rich and gene-specific altered methylation in the liver of tumor-prone B6C3F1 mouse as compared to the relatively resistant C57BL/6 mouse. Toxicol. Sci. 91: 393-405, 2006.

Bachman, A.N., Curtin, G.M., Doolittle, D.J. and Goodman, J.I.: Altered methylation in gene-specific and GC-rich regions of DNA is progressive and non-random during promotion of skin tumorigenesis. Toxicol. Sci. 91: 406-418, 2006.

Phillips, J.M., Yamamoto, Y., Negishi, M., Maronpot, R.R. and Goodman, J.I.: Orphan nuclear receptor constitutive active/androstane receptor (CAR)-mediated alterations in DNA methylation during phenobarbital (PB) promotion of liver tumorigenesis. Toxicol. Sci. 96: 72-82, 2007.

Thomas, J., Spencer, P.J., Haseman, J.K., Goodman, J.I., Ward, J.M. and Loughran Jr., T.P.: A review of large granular lymphocytic leukemia (LGLL) in Fischer 344 rats as an initial step toward evaluating the relevance of the endpoint to human cancer risk assessment. Toxicol. Sci. 99: 3-19, 2007.

Phillips, J.M. and Goodman, J.I.: Identification of genes that may play critical roles in Phenobarbital (PB)-induced liver tumorigenesis due to altered methylation. Toxicol, Sci. 104: 86-99, 2008.

Phillips, J.M. and Goodman, J.I.: Multiple Genes Exhibit Phenobarbital (PB)-Induced Constitutive Active/Androstane Receptor (CAR)-Mediated DNA Methylation Changes During Liver Tumorigenesis and in Liver Tumors. Toxicol. Sci., Submitted, 2008.

Phillips, J.M., Burgoon, L.D. and Goodman, J.I.: Phenobarbital (PB) Elicits Unique, Early Changes in the Expression of Hepatic Genes That Affect Cricial Pathways in Tumor-Prone B6C3F1 Mice. Toxicol., 109: 193-2009, 2009.

Philips, J.M., Burgoon, L.D. and Goodman, J.I.: The Constitutive Active/Androstane Receptor (CAR) Facilitates Unique Phenobarbital (PB)-Induced Expression Changes of Genes Involved in Key Pathways in Precancerous Liver and Liver Tumors. Toxicol. Sci., 110: 319-333, 2009.