Dept. of Biochemistry and Microbiology
School of Env & Biol Sciences
New Brunswick, NJ 08903
Molecular mechanisms of xenobiotic-induced pathologies
The focus of my laboratory is to investigate the molecular mechanisms of xenobiotic exposure and to link these molecular changes to xenobiotic-induced pathologies. The polycyclic aromatic hydrocarbon (PAH) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a byproduct of industrial combustion processes. Exposure results in a variety of pathologies in humans, including alterations in the immune and neurological systems, liver dysfunction, and increases in bladder and skin cancer. It is believed that these pathologies are mediated by TCDD binding to the AhR (aryl hydrocarbon receptor) which heterodimerizes with Arnt to function as a transcription factor and alter gene expression. Although this pathway has been well characterized, it is unclear how TCDD activation of the AhR pathway results in the pathological effects of exposure. Using skin as a model system, we aim to identify the molecular pathways that are involved in mediating PAH-induced pathologies, and to better understand the role these chemicals play in skin carcinogenesis. One area of interest is to identify biologically relevant targets of the AhR/Arnt pathway. To this end, we have shown that exposure to TCDD results in an increase in expression and activity of matrix metalloproteinases in normal human keratinocytes. These enzymes mediate the degradation of the extracellular matrix and basement membrane proteins during processes of tissue remodeling and cell migration, and inappropriate expression of these enzymes is associated with tumor metastasis. Another project is aimed at understanding the regulation of an AhR responsive gene, cytochrome p-450 1B1 (CYP1B1). CYP1B1 is a monoxygenase that metabolizes xenobiotic compounds and endogenous steroids to carcinogenic compounds. We have recently found that expression of this gene is influenced by cell-cell interactions in murine keratinocytes. By utilizing both human and mouse model systems, we aim to gain a better understanding of the molecular mechanisms that are important for PAH-induced carcinogenesis in skin.