Environmental & Occupational Health

Faculty Profile

  • Helmut Zarbl, PhD, ATS Fellow

  • Director, Environmental and Occupational Health Science Institute
    Chair & Professor

  • Department of Environmental and Occupational Health

  • CV

Keywords
Environmental and occupational health; environmental carcinogenesis; mutagenesis; toxicogenomics; chemoprevention; circadian rhythm; shift work; endocrine disruptors; zeranol; genetics; epigenetics; toxicogenetics; DNA repair; transactional regulation; community engagement.

Biography
1987-1992: Assistant Professor, Department Applied Biological Sciences, Massachusetts Institute of Technology, Cambridge, MA. 1992-1994: Associate Professor, Division of Toxicology, Whitaker College of Health Sciences and Technology Massachusetts Institute of Technology, Cambridge, MA. 1994-2006: Member, Divisions of Human Biology & Public Health Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA. 1995- 2006: Member, Center for Ecogenetics and Environmental Health, UW, Seattle, WA. 1996-2006: Affiliate Professor, Departments of Environmental and Occupational Health & Pathology, University of Washington, Seattle, WA. 1998-2002: Scientific Director, DNA Microarray Shared Resource, FHCRC, Seattle, WA. 1998-2002: Director, Public Health Sciences Core Laboratory, FHCRC, Seattle, WA. 2002-2004: Director, Industrial Liaison Program, FHCRC, Seattle, WA. 2000-2006: Director, NIEHS - FHCRC/UW Toxicogenomics Research Consortium, Seattle, WA. 2000: Visiting Professor of Genetics, China Medical University, Shenyang, China. 2006: Professor, Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Rutgers, Piscataway, NJ. 2008-2013: Associate Director, Division of Public Health Sciences, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. 2007: Director, Rutgers NIEHS Center for Environmental Exposures and Disease. 2017: Chair, Environmental and Occupational Health, Rutgers School of Public Health, Piscataway, NJ. 2017: Director, Institute for Environmental and Occupational Health, Rutgers, Piscataway, NJ.

Research Interests
Dr. Zarbl focuses his research on understanding the molecular, genetic, genomic and epigenetic mechanisms that contribute to toxicity, mutagenesis, carcinogenesis, genetic susceptibility, and chemoprevention. He uses in vitro model systems, animal models and population-based studies to understanding the molecular mechanisms of environmental and occupational carcinogenesis, and develop interventions to reduce risk of cancer in exposed individuals and populations. His research has identified new cancer susceptibility genes that serve as new biomarkers for cancer diagnosis and prognosis, new epigenetic biomarkers of risk associated with disruption of circadian rhythm, and biomarkers for transgenerational effects of endocrine disruptors that alter sexual development, reproduction and cancer risk. Epidemiologic studies indicate that about 10% of breast cancer show a familial pattern of inheritance. Decades of genetic linkage studies demonstrated that variants of BRCA1 and BRCA2 tumor suppressor genes account for half of familial breast cancers. Studies also indicated that the remaining genetic susceptibilities are probably due to multiple low penetrance genes that are difficult to map in human populations. His lab therefore used animal models of breast cancer to identify additional susceptibility genes. Rats strains show dramatic differences in susceptibility mammary carcinogenesis in response to hormone, radiation and chemical exposures. Dr. Zarbl used quantitative trait locus (QTL) mapping in a genetic cross between the susceptible Fischer 344 (F344) and the resistant Copenhagen (Cop) strains to identify candidate susceptibility genes. He identified the Fry gene, a regulator of epithelial cell differentiation as candidate gene that is mutated in the susceptible F344 strains. Subsequent in silico and molecular analyses of human breast cancer cell lines and samples from thousands of clinically-annotated breast cancer patients demonstrated that the human FRY is mutated and/or epigenetically silenced in a significant fraction of breast cancers. Moreover, the decreased FRY expression and function are associated with tumor progression, metastasis and poor clinical outcomes. Ongoing studies are focused and elucidating the epigenetic mechanisms of FRY silencing during tumor progression. Endocrine disruptors are chemicals that mimic or interfere with the normal function of hormones within the body. Zeranol, a semi-synthetic derivative of the myco-estrogen zearalenone, is a potent xeno-estrogen that is widely used as a growth promoter in cattle across the US, Canada and South America, but is banned in certified organic cattle and in much of Europe and Asia. To assess the effects of Zeranol on sexual development, reproduction and susceptibility to breast cancer, he exposed pregnant rats to doses that are permitted in meat by the USFDA. The results indicated that perinatal exposure to these low doses has significant effects on both male and female sexual development and fecundity in the F1 offspring and increase the susceptibility of female progeny to mammary carcinogenesis. Moreover, these traits were passed on to the subsequent generations when both the male and female parents were perinatally exposed to Zeranol ingested by the pregnant dam. In collaborative studies with Dr. Elisa Bandera, he next examined the levels of Zeranol in prepubescent girls enrolled in the Jersey Girl Study, a prospective study investigating the effect of diet on the onset puberty. A cross-sectional study of 150 indicated that Zeranol and its metabolites could be detected in a large fraction of the girls, and that the levels were correlated with the consumption of beef. Moreover, Zeranol levels were associated with the delayed onset of puberty, BMI and growth, indicating that low doses of Zeranol also have significant endocrine disrupting effects in humans. His laboratory is also interested in elucidating the mechanisms by which natural products and drugs prevent carcinogenesis induced by exposure to specific environmental or occupational agents. Methylseleocysteine (MSC) is a potent chemopreventive agent that reduces the incidence of mammary carcinomas in rats exposed to carcinogens by as much as 80%. Understanding MSC’s mechanism of action can lead to the development of additional preventive agents and allow targeting to exposures that involve the same of mechanisms of carcinogenesis. Toxicogenomic analyses indicated that mediates MSC its effects by restoring circadian rhythm disrupted in mammary cells by chemical carcinogens. These were the first studies to provide a mechanistic link between chemo prevention and circadian rhythm. Further studies with Dr. Mingzhu Fang elucidated the mechanisms by which a chemo preventive regimen of MSC restores circadian gene expression. These results showed that many hormone receptors, growth promoting genes and DNA damage response and repair genes are regulated by circadian rhythm. Dr. Zarbl further showed that MSC mediates its effects on circadian gene expression via epigenetic mechanism that restore circadian regulation of Sirtuin 1 histone deacetylase activity. Shift work and exposure to light at night are classified as probable human mammary carcinogens by IARC. Studies indicate that these occupational exposures disrupt circadian gene expression via the same Sirtuin 1-mediated epigenetic mechanisms. Ongoing intervention studies are designed to develop biomarkers of circadian disruption and assess the ability of MSC to restore circadian rhythm and reduce cancer risk associated with chronic shift work and jet lag.

Research Highlights

Among the first to demonstrate that mutagenic chemicals induce both genetic and epigenetic changes in oncogenes to contribute to carcinogenesis. Developed and used in vitro assays and genetic linkage analysis to identify tumor suppressor/susceptibility genes that confer susceptibility to mammary carcinogenesis. Identified FRY mammary carcinogenesis susceptibility gene which is being developed as a novel tool for cancer diagnostics and prognosis. Among the first to use genomics in mechanistic studies of toxicity, carcinogenesis and chemoprevention studies on health effects of zeranol, a mycotoxin used as a growth enhancer in cattle, revealed transgenerational effects on rats mammary carcinogenesis and development.   Population-based, cross-sectional studies on developmental effects of dietary zeranol on prepubescent girls. - First to provide a mechanistic link between chemoprevention and circadian rhythm and elucidate the epigenetic mechanisms by which a chemopreventive regimen of MSC restores circadian gene expression. Intervention studies assessing the ability of methyl selenocysteine to restore circadian rhythm and reduce cancer risk are shift workers.

Select Publications
Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature. 1985;315(6018):382-5. PMID: 3923365

Zarbl H, Latreille J, Jolicoeur P. Revertants of v-fos-transformed fibroblasts have mutations in cellular genes essential for transformation by other oncogenes. Cell. 1987;51(3):357-69. PMID: 3664639

Cha RS, Thilly WG, Zarbl H. N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(9):3749-53. PMID: 8170982; PMCID: 43659

Jin Z, Houle B, Mikheev AM, Cha RS, Zarbl H. Alterations in H-ras1 promoter conformation during N-nitroso-N-methylurea-induced mammary carcinogenesis and pregnancy. Cancer Research. 1996;56(21):4927-35. PMID: 8895746

Athanassiou M, Hu Y, Jing L, Houle B, Zarbl H, Mikheev AM. Stabilization and reactivation of the p53 tumor suppressor protein in nontumorigenic revertants of HeLa cervical cancer cells. Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research. 1999;10(11):729-37. PMID: 10593649

Mikheev AM, Inoue A, Jing L, Mikheeva SA, Li V, Leanderson T, Zarbl H. Frequent activation of CArG binding factor-A expression and binding in N-methyl-N-nitrosourea-induced rat mammary carcinomas. Breast Cancer Research and Treatment. 2004;88(1):95-102. doi: 10.1007/s10549-004-1280-5. PMID: 15538050  

Mikheev AM, Mikheeva SA, Liu B, Cohen P, Zarbl H. A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation. Carcinogenesis. 2004;25(1):47-59. doi: 10.1093/carcin/bgg190. PMID: 1455561

Bammler T, Beyer RP, Bhattacharya S, Boorman GA, Boyles A, Bradford BU, Bumgarner RE, Bushel PR, Chaturvedi K, Choi D, Cunningham ML, Deng S, Dressman HK, Fannin RD, Farin FM, Freedman JH, Fry RC, Harper A, Humble MC, Hurban P, Kavanagh TJ, Kaufmann WK, Kerr KF, Jing L, Lapidus JA, Lasarev MR, Li J, Li YJ, Lobenhofer EK, Lu X, Malek RL, Milton S, Nagalla SR, O'Malley J P, Palmer VS, Pattee P, Paules RS, Perou CM, Phillips K, Qin LX, Qiu Y, Quigley SD, Rodland M, Rusyn I, Samson LD, Schwartz DA, Shi Y, Shin JL, Sieber SO, Slifer S, Speer MC, Spencer PS, Sproles DI, Swenberg JA, Suk WA, Sullivan RC, Tian R, Tennant RW, Todd SA, Tucker CJ, Van Houten B, Weis BK, Xuan S, Zarbl H, Members of the Toxicogenomics Research C. Standardizing global gene expression analysis between laboratories and across platforms. Nature Methods. 2005;2(5):351-6. doi: 10.1038/nmeth754. PMID: 15846362 (Presented on the Cover)

Ricicki EM, Luo W, Fan W, Zhao LP, Zarbl H, Vouros P. Quantification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl adducts in human lymphoblastoid TK6 cells dosed with N-hydroxy-4-acetylaminobiphenyl and their relationship to mutation, toxicity, and gene expression profiling. Analytical Chemistry. 2006;78(18):6422-32. doi: 10.1021/ac0607360. PMID: 16970317

Beyer RP, Fry RC, Lasarev MR, McConnachie LA, Meira LB, Palmer VS, Powell CL, Ross PK, Bammler TK, Bradford BU, Cranson AB, Cunningham ML, Fannin RD, Higgins GM, Hurban P, Kayton RJ, Kerr KF, Kosyk O, Lobenhofer EK, Sieber SO, Vliet PA, Weis BK, Wolfinger R, Woods CG, Freedman JH, Linney E, Kaufmann WK, Kavanagh TJ, Paules RS, Rusyn I, Samson LD, Spencer PS, Suk W, Tennant RJ, Zarbl H, Members of the Toxicogenomics Research C. Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses. Toxicological Sciences : an official journal of the Society of Toxicology. 2007;99(1):326-37. doi: 10.1093/toxsci/kfm150. PMID: 17562736

Ren X, Zhang X, Kim AS, Mikheev AM, Fang M, Sullivan RC, Bumgarner RE, Zarbl H. Comparative genomics of susceptibility to mammary carcinogenesis among inbred rat strains: role of reduced prolactin signaling in resistance of the Copenhagen strain. Carcinogenesis. 2008;29(1):177-85. doi: 10.1093/carcin/bgm224. PMID: 17916903

Fang M, Zhang X and Zarbl. H (2010). Methylselenocysteine Inhibits Carcinogenesis by Enhancing Circadian Expression of Melatonin Receptor 1α and Estrogen Receptor β in Rat Mammary Epithelial Cells. Cancer Prevention Research 3(5): 640-652, 2010. PubMed # 20424134  PMCID: PMC2865563

Bandera EV, Chandran U. Buckley B, Lin Y, Isukapalli S, Marshall I, King M, Zarbl H. Urinary mycoestrogens, body size and breast development in New Jersey girls. The Science of the Total Environment. 2011;409(24):5221-7. Epub 2011/10/07. doi: 10.1016/j.scitotenv.2011.09.029. PMID: 21975003; PMCID: 3312601

Ren X, Graham JC, Jing L, Mikheev AM, Gao Y, Lew JP, Xie H, Kim AS, Shang X, Friedman C, Vail G, Fang MZ, Bromberg Y, Zarbl H. Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene. PloS One. 2013;8(9):e70930. doi: 10.1371/journal.pone.0070930. PMID: 24023717; PMCID: 3759375

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG. Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study. PloS One. 2014;9(12):e113632. doi: 10.1371/journal.pone.0113632. PMID: 25474635; PMCID: 4256163

Lewis, CA, Gallo, MA, Reuhl, K, Zarbl, H.  In utero Exposure of Fisher 344 Rats to Low Doses of Zeranol via the Maternal Diet Produces Dose-Dependent Effects on Sexual Development and Reproduction. International Proceedings of Nutrition and Food Sciences 2015;86:62-68 DOI: 10.7763/IPCBEE. 2015. V86. 10.

Fang MZ, Ohman-Strickland P, Kelly-McNeil K, Kipen H, Crabtree BF, Lew JP, Zarbl H. Sleep interruption associated with house staff work schedules alters circadian gene expression. Sleep Medicine. 2015;16(11):1388-94. Epub 2015/10/27. doi: 10.1016/j.sleep.2015.06.011. PMID: 26498241; PMCID: 4621493.

Fang MZ, Guo WR, Kang H-G, Zarbl H. Enhancement of NAD+-dependent SIRT1 Deacetylase Activity by Methylselenocysteine Resets Circadian Clock in Carcinogen-Treated Mammary Epithelial Cells. Oncotarget 2015;6(40):42879-91. DOI: 10.18632/oncotarget.6002. PMID: 26544624. PMCID: PMC4767478

Fang MZ, Kang HG, Ohman-Strickland P, Zarbl H. Uncoupling Genotoxic Stress Responses from Circadian Control Increases Susceptibility to Mammary Carcinogenesis. Oncotarget 2017;8(20):32752-32768. PMCID: PMC5464825

Scholarly Activities
Cancer Research (AACR), Associate Editor (2000)

Environmental Health Perspectives: Toxicogenomics, Associate Editor (2002)

The Open Toxicology Journal, Editorial Board (2008)

Biological Procedures Online, Editor-In Chief (2006)

Frontiers in Toxicogenomics, Editorial Board (2011)

Toxicology and Applied Pharmacology, Editorial Board (2010)

Toxicological Sciences Associate Editor for Carcinogenesis, Editorial Board (2017)

National Research Council: Committee on Applications of Toxicogenomics to Predictive Toxicology (2004)

NIEHS Superfund Basic Research Program External Advisory Board (2008)

EPA-IRIS Peer Review Panel: Toxicological Review of 1,2,3-Trichlropropane (CAS No. 96-18-4) (2008)

NIEHS Superfund Basic Research Program, External Advisory Panel (2009)

National Academies, National Research Council Committee on Applications of Toxicogenomics to Predictive Toxicology (2004)

External Scientific Advisory Board Member, Research Center for Minority Institutions, Clark Atlanta University, Atlanta (1999)

Chair, External Scientific Advisory Board Member, Center for Cancer Research and Therapeutic Development, Clark Atlanta University (2005)

External Scientific Advisory Board, NIEHS Center, University of Michigan (2009)

External Scientific Advisory Board Superfund Basic Research Program University of North Carolina (2009)

External Scientific Advisory Board, NIEHS Center, University of Cincinnati (2015)

External Scientific Advisory Board, NIEHS Center, Emory University Atlanta (2015)

National Academy of Sciences, National Research Council Standing Committee on “Emerging Science for Environmental Health Decisions,” (2009)

Awards
Women in Toxicology Mentoring Award - Society of Toxicology (2012) - This award is given to an individual (male or female) in academia, government, industry, or a related field who has been a major influence in the mentoring of women scientists entering the field of toxicology and/or whose leadership and service have provided career development opportunities for women toxicologists or encouraged women to achieve their professional goals.

Fellow of the Academy of Toxicological Sciences - Academy of Toxicological Sciences (2008) - A Fellow of the Academy must have an exemplary record of professional accomplishment as well as extensive evidence of recognition by peers of competency and sound scientific judgment in toxicology as reflected by appointment or election to councils, committees, etc.

Robert A. Swanson Assistant Professor in Life Sciences - University of Washington (1998) - In recognition of extraordinary work in the field.

Social Media & Websites
LinkedIn: https://www.linkedin.com/in/helmut-zarbl-0a099770/