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Lori A.
White
Associate Professor
Rutgers University
Dept. of Biochemistry and Microbiology
Lipman Hall
School of Env & Biol Sciences
New Brunswick. NJ 08903
(732) 932-9763. Ext. 128
FAX - 8965
lawhite@aesop.rutgers.edu |
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.
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