Regine Goth-Goldstein 1 Cyclotron Road Bldg. 70, 108B Berkeley, CA 94720 phone: (510)-486-5897 fax: (510)-486-7303 Email: R_Goth-Goldstein@lbl.gov

The main goal of my research is to establish an informed basis for major forms of cancer that may have an environmental component. Current research in my laboratory addresses human health risk from exposure to polycyclic aromatic hydrocarbons (PAHs). We are conducting studies in molecular epidemiology and genetic toxicology to investigate the interplay of genetic and environmental factors in the development of cancer:

1. environmental factors - hazard identification and exposure assessment Using human cells in culture we are developing bioassays to evaluate the health hazard from exposure to individual PAHs and complex mixtures.

(a) We have used an in vitro cell model (Caco-2 cells) that simulates intestinal conditions to evaluate bioavailability, absorption and presystemic metabolism of ingested PAHs.

(b) We have participated in research that demonstrates that vibrational spectroscopy, when combined with synchrotron radiation-based microscopy is apowerful new analytical tool with high spatial resolution. It detect changes in individual cells in response to treatment with PAHs or dioxin derivatives.

(c) Whereas the current paradigm for cancer induction by products of incomplete combustion is benzo[a]pyrene, there is now considerable evidence that this compound present in complex mixtures plays only a minor role. A new, potentially important compound, 7H-benzo[c]fluorene has been identified. We have initiated studies to evaluate its contributions to the observed health effects. We are measuring 7H-benzo[c]fluorene-DNA adduct formation and repair in human cells in culture.

2. genetic factors - role of PAH-metabolizing enzymes in cancer-susceptibility PAHs like benzo(a)pyrene are potent chemical carcinogens ubiquitous in the environment that require metabolic activation before acting as carcinogens. Two groups of enzymes are responsible for the metabolism, one activates the chemically inert PAH to a reactive intermediate and the other transforms the intermediate to a water-soluble compound that can be excreted. Whereas most carcinogen metabolism leads to detoxification, the reactive intermediates can also bind to cellular DNA. The resulting DNA adducts can lead to mutations that activate oncogenes or inactivate tumor suppressor genes. The detoxifying enzymes compete with the activating enzymes in the metabolism of the carcinogen. A more rapid clearing of intermediates can confer a protective effect, while a more efficient conversion of carcinogen to active intermediate can increase the risk of DNA adduct formation. Large interindividual variations in the efficiency of these processes have been observed. Variability in the activity of these enzymes is attributable in part to mutations in the DNA sequence coding for these genes (genetic polymorphism), and in part to modification of gene expression by genetic and environmental factors. We are testing the hypothesis that interindividual variation in the level of the PAH-metabolizing enzymes represents a risk factor for breast cancer. We are examining the role of genetic polymorphism in several genes. In addition we are measuring the expression of PAH-activating enzymes in a collection of non-tumor breast tissue specimens from breast cancer patients and healthy individuals. We have found recently that one gene coding for a PAH-activating enzyme (CYP1B1) is expressed at statistically significant higher levels in breast cancer patients than in controls.

C.A. Erdmann, M.X. Petreas, M. Caleffi, F.S. Barbosa, R. Goth-Goldstein (1999) "Comparison of Organochlorine Chemical Body Burdens of Female Breast Cancer Cases with Cancer Free Women in Rio Grande do Sul," Brazil - Pilot Study. LBNL report

H.-Y.N. Holman, R.Goth-Goldstein, E.A.Blakely, K.Björnstad, M.C.Martin and W.R.McKinney. "Individual Human Cell Responses to Low Doses of Chemicals Studied by Synchrotron Infrared Spectromicroscopy. In: Biomedical Spectroscopy: Vibrational Spectroscopy and Other Novel Techniques," SPIE Vol. 3918, in press.

R. Goth-Goldstein, M. Russell and H.-Y.N. Holman (2000) Examination of transport and metabolism of benzo(a)pyrene through Caco-2 cells. In: Final Project Report: PERF 94-06 Research Area No.1, ‘Environmentally Acceptable Treatment Endpoints for Hydrocarbon-Contaminated Soils’, Appendix 12B.

H-Y.N. Holman, R. Goth-Goldstein, M.Martin, M.L. Russell, W.R. McKinney. (2000) "Low-dose responses to 2,3,7,8,-tetrachlorodibenzo-p-dioxin in single living cells measured by synchrotron infrared spectromicroscopy," Env. Science & Tech. 34: 2513-2517.

R. Goth-Goldstein, C. Erdmann, M. Russell (2000) "CYP1B1 expression in normal human breast tissue specimen," Proc. Am. Ass. Cancer Res. 41 # 807.

R. Goth-Goldstein, M.R. Stampfer, M.L. Russell. "Interindividual Variation in CYP1A1 Expression in Breast Tissue and the Role of Genetic Polymorphism," Carcinogenesis, in press.