Helmut Zarbl, PhD
Helmut Zarbl, Ph.D., is the director of the Environmental and Occupational Health Science Institute. He is also the chair and professor of the Department of Environmental and Occupational Health and Justice at the Rutgers School of Public Health.
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.