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.  Epigenetic changes may occur in no-dividing cells, too. 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.

Gene expression may be regulated in an epigenetic fashion by DNA methylation (the presence of 5-methyl cytosine (5MeC) in place     of cytosine), the histone code and non-coding RNAs.  My laboratory focuses on   DNA methylation as an epigenetic mechanism controlling gene activity.  Changes in methylation are not mutations because both 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 and, possibly, other toxicities.

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. What excites me most about toxicological research is that it combines the theoretical with the practical. Specifically, as we discern events involved in the mechanism of action of chemicals of interest we learn more about basic biology and this information is necessary to enhance science-based safety assessment by addressing key issues e.g., appropriate extrapolation from test species to humans and dose-response relationships.

Selected Achievements

Editorial Boards:
Toxicological Sciences, 1995-2000, Associate Editor, 2001-2007; Regulatory Toxicology and Pharmacology, 2000-present; Associate Editor, 2004-present
  

Memberships on Advisory Committees:
Member of the Board of Scientific Counselors, National Toxicology Program, Department of Health and Human Services, 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 Council, International Society of Regulatory Toxicology and Pharmacology, 2001-present

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

 
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

Honors/Awards:
Recipient of the John Barnes Prize Lecture, awarded by the British Toxicology Society, 2005
Recipient of the George H. Scott Memorial Award, awarded by the Toxicology Forum, 2007

Presentations at National/International Meetings, selected recent examples

“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.

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

“Epigenetics and transgenerational effects: Implications for safety assessment,” CEFIC (European Chemistry Industry Council) Long-Range Workshop, Brussels, Belgium, November, 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, 2007

“Altered DNA Methylation: An Epigenetic Mechanism Underlying Carcinogenesis,” Gordon Conference on Toxicogenomics, Colby-Sawyer College, New Long, NH, June, 2007.

“What We Need to Know Prior to Considering Incorporating An Epigenetic Evaluation Into Human Health Assessments,” The Toxicology Forum, Aspen, CO, July, 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.

“Genotoxicity and Carcinogenicity Testing: What are we Doing and What Should we be Doing?”  The Toxicology Forum, Annual Winter Meeting, University of Delaware, Washington, DC, January, 2008.

“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.

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., Kronenberg, 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.