http://www.dartmouth.edu/~dcsbrp/p2.html
Project 2 
Molecular Basis for Effects of Carcinogenic Metals 
on Inducible Gene Expression 

Joshua W. Hamilton, Ph.D., Principal Investigator
Associate Professor of Pharmacology and Toxicology
Adjunct Associate Professor of Chemistry


Department of Pharmacology and Toxicology
Dartmouth Medical School 
7650 Remsen
Hanover NH 03755-3835
(603) 650-1316
fax (603) 650-1129
e-mail: josh.hamilton@dartmouth.edu


Project Description 

The overall goal of this project is to determine the mechanistic basis for 
the preferential effects of carcinogenic metals on inducible gene expression. 
Four of the eight heavy metals on the OSWER list of twenty-two agents of 
concern, namely, chromium, nickel, arsenic and cadmium, are considered human 
carcinogens. However, the mechanism(s) by which these metals exert their 
carcinogenic effects is poorly understood. Previous studies in our lab have 
demonstrated that a variety of organic and inorganic genotoxic chemical 
carcinogens, including the metals chromium and nickel, have strong 
preferential effects on the expression of several inducible genes. The 
effects of these agents appear to be a result of a unique response of the 
cell to low overall levels of DNA damage. Other studies have suggested that 
the carcinogenic but non-genotoxic metals, arsenic and cadmium, can also have 
profound effects on inducible gene expression. However, since these metals do 
not cause appreciable DNA damage, they appear to be acting through different 
and currently poorly understood mechanisms. 

The principal objective of this research is to determine the molecular basis 
for the various effects of individual metals on expression of a model 
inducible gene, and to investigate the interactions of these pathways when 
exposure to combinations of carcinogenic metals occurs.

Our specific aims are to determine whether specific DNA regulatory regions 
within an inducible gene are responsible for the preferential effects of the 
DNA-damaging metals, and to determine whether functional alterations in 
specific transcriptional factors are responsible for the effects of the 
non-DNA-damaging metals on gene expression. We will also examine the effects 
of combinations of metals on gene expression, to determine whether 
preferential effects can occur as a result of interactions between these 
pathways. Determining the mechanisms by which these carcinogenic metals 
selectively alter gene expression would have important implications for 
understanding the molecular basis for the impact of these agents on the 
cancer process. While each of these agents may have specific effects and act 
through independent mechanisms, they may have profound, but different effects 
when present in different combinations in the environment. Understanding 
these interactions at the molecular level is critical for an accurate 
assessment of the overall health effects of these substances on the human 
population.

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Other Personnel on Project 2:

Olga V. Bajenova, Ph.D., Postodoctoral Research Associate
Ronald C. Kaltreider, Graduate Research Assistant
Jean P. Lariviere, Research Assistant
Carrie A. Pesce, Undergraduate Research Associate