University of Arizona

Southwest Environmental Health Sciences Center

Serrine S Lau, Ph.D.
lau@pharmacy.arizona.edu
http://swehsc.pharmacy.arizona.edu/index.html

Project Description

The theme that unites the research activities of the Southwest Environmental Health Sciences Center (SWEHSC) is the need to understand the mechanisms by which exposures to environmental agents contribute to human disease. Identifying factors that contribute to human diseases that arise as a consequence of environmental exposures is a prerequisite for the development of strategies designed to minimize both the environmental exposure, and the adverse effects of such exposures. The SWEHSC is a dynamic organization that promotes collaborative, interdisciplinary research, with an emphasis on the detection and prevention of environmentally-mediated diseases. Members of the SWEHSC are organized into three Research Cores (RC) with overlapping spheres of interest; Mechanisms of Environmental Chemical Toxicity (RC1), Pulmonary Toxicology and Lung Disease (RC2), and Chemical-Chromatin Interactions (RC3). The Research Cores provide the scientific foundation that provides the basis for strategies designed to treat or prevent environmental diseases. The research efforts of SWEHSC are complemented by five Facility Cores (FC); Cellular Imaging, Genomics, Proteomics, Synthetic Chemistry, and Bioinformatics. The Facility Cores offer state-of-the-art instrumentation and expertise to assist investigators in developing and utilizing cutting-edge technologies. The Administrative Core provides enrichment programs, including seminars, workshops, an annual Science Fair, newsletters, and supports the activities of the Internal and External Advisory Boards.

The SWEHSC is also actively involved in promoting innovative research through the Pilot Project Program, and in the recruitment of new investigators. The Community Outreach and Education Program (COEP) offers environmental health science and toxicology based educational programs that are geared to students (K-12), health professionals, and the public. Through the COEP, the SWEHSC provides service to health organizations, government agencies, and the private sector. Three major inter-dependent goals will provide the focus for the next 5 years of support. The SWEHSC will (1) Facilitate the utilization and integration of "global" systems-centered toxicological approaches (proteomics, toxicogenomics, SNP's, cell and tissue imaging) to basic environmental health science research questions. (2) Facilitate the extension of basic research discoveries into the clinical and public health arenas. SWEHSC faculty, in collaboration with faculty in the Colleges of Public Health, Medicine, Pharmacy, and Nursing, will focus in the general area of novel biomarkers (SNP's, proteins, protein adducts, etc) of susceptibility, particularly within minority populations (Hispanic, Native American). Emerging border health initiatives will play an integral role in developing these new areas of emphasis. (3) Initiate and expand collaborations with sister Centers of Excellence on the University of Arizona Health Sciences Center campus (e.g., Arizona Respiratory Center, The University of Arizona Sarver Heart Center, Arizona Cancer Center, Arizona Center on Aging, Steele Memorial Children's Research Center and the BIOS Institute). This last goal is synergistic with the objective of extending basic research discoveries into the clinical and public health arenas.

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Program Highlights

Searching for a Biomarker for Nonalcoholic Fatty Liver Disease

With changes to Western diet and lifestyle, more than 20% of all adults have some form of nonalcoholic fatty liver disease (NAFLD). The risk factors involved in NAFLD are identical to those identified for developing severe adverse chemical reactions. Dr. Chemington's group is trying to understand the effect of NAFLD on the capacity of the liver to metabolize and eliminate chemicals from the body. Their data demonstrates dramatic alterations in both the mRNA and protein expression profiles of important metabolizing enzymes and transporters resulting in the decreased hepatic uptake, reduced metabolic biotransformation, and altered disposition of chemicals. For example, hepatic expression of two specific cell proteins, transporters Mrp3 and Mrp4, is increased in rats with steatohepatitis. As a likely consequence of the increased levels of these proteins, pharmacokinetic studies revealed a shift from biliary elimination to plasma retention and urinary elimination of xenobiotic metabolites. In other words, there was a build-up of undesirable metabolites in the blood. Preliminary results using liver samples from patients diagnosed with increasingly severe forms of NAFLD indicate that human Mrp4 is similarly increased by the disease. These clues will assist in improved biomarkers for prediction and therapy for NAFLD.

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New approaches to Understanding Arsenic Exposure

While arsenic is recognized as a human carcinogen, the mechanism of action of arsenic is not understood. Arsenic is not a direct-acting genotoxicant and is at best only weakly mutagenic. While inhalation is an important route of exposure, the major cancerous and non-cancerous health effects are since following ingestion of arsenic. While investigators have examined the effects of inhaled arsenicals, research currently uses ingestion as the route of exposure. To understand mechanisms and to identify biomarkers and adverse health effects, an integrated research approach has been developed that includes in vitro assessment of the effects of arsenic exposure on human airway epithelial cells analysis of in vivo effects of arsenic in model animal systems and validation of arsenic induced effects in human populations (Drs. Lantz, Boitano, and Burgess).

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Epigenetics and Breast Cancer

Using sophisticated computer software, to profile gene expression and chemical changes in the genome, known as epigenetics, Dr. Futscher has found aberrant chemical changes resulting in “silenced” (or turned off) genes in a small contiguous neighborhood - the HOXA gene cluster, associated with human breast cancer. The observed transcriptional repression was localized to a select region (approximately 100kb) of the HOXA gene cluster and did not extend to genes located upstream or downstream of the cluster. Further studies confirmed that the loss of expression of the HOXA gene cluster occurs in human breast cancer in a manner consistent with the chemical changes described. Overall, these data suggest that inactivation of the HOXA gene cluster in breast cancer may represent a new type of genomic lesion - termed an epigenetic micro-deletion. Dr. Futscher predicts epigenetic micro-deletions are common in human cancer. Importantly, the nature of these regions suggests that they are not very stable and may be reversible under the proper conditions, suggesting new forms of therapy or prevention.

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