From avakian at niehs.nih.gov  Wed Jun  1 10:20:05 2005
From: avakian at niehs.nih.gov (Avakian, Maureen (NIH/NIEHS))
Date: Wed Jun  1 10:26:21 2005
Subject: [SBRP-brief] SBRP Research Brief 126: Clues to the Genotoxicity of
	Arsenic
Message-ID: <97A32A5EB720C84F90D76AC8BA06C1E30B0923E6@nihexchange21.nih.gov>

Research Brief 126: Clues to the Genotoxicity of Arsenic

The metalloid arsenic, a natural component of the earth's crust and an
anthropogenic soil, sediment and water pollutant, is a serious environmental
concern and a global health threat impacting millions of people.
Epidemiologic data have shown that chronic exposure of humans to inorganic
arsenic is associated with liver injury, peripheral neuropathy, and an
increased incidence of cancer of the lung, skin, bladder, and liver.
However, the mechanism underlying arsenic's carcinogenicity is poorly
understood.  Dr. Tom Hei of the Columbia University SBRP believes that a
better understanding of arsenic's mutagenic/carcinogenic mechanism(s) could
increase the accuracy of risk assessments and provide a basis for better
interventional approaches for both treatment and prevention of
arsenic-related diseases.

Dr. Hei and researchers in his laboratory are conducting a series of studies
aimed to increase our understanding of arsenic's carcinogenic mechanism.  In
earlier SBRP-funded studies, Dr. Hei found that arsenite is a potent gene
and chromosomal mutagen, debunking the characterization of arsenic as a
nongenotoxic carcinogen.  He also showed that reactive oxygen species
(superoxides and hydrogen peroxides) are important mediators in the
genotoxicity of arsenic.  This was the first clear-cut evidence of an
environmental carcinogen acting predominantly through a free radical
pathway.  
(See Research Brief 78:
http://www-apps.niehs.nih.gov/sbrp/researchbriefs/view.cfm?Brief_ID=78)  

In recent studies, Dr. Hei has worked to uncover the origin of the
oxyradical species and to determine if other secondary radical species are
involved in the processes mediating the genotoxic effects of arsenic.  The
researchers used enucleation and fusion techniques with human-hamster hybrid
(AL) cells to test the hypothesis that mitochondria are an important target
of arsenic-induced genotoxicity.  As the metabolic center of a cell,
mitochondria are intimately involved in the production of reactive oxygen
species, mainly superoxides and hydrogen peroxides.  

Dr. Hei and his research team conducted experiments to determine if the
nucleus is the critical target for arsenite-induced genotoxicity.  First,
they removed the nuclei of AL cells, yielding enucleated cytoplasts.  They
exposed the cytoplasts to 2 ppm arsenite and determined that the cytoplasts
were able to generate reactive oxygen species, even in the absence of
nuclei.  

In a second experiment, they exposed enucleated cytoplasts to 2 ppm arsenite
and later fused the treated cytoplasts with untreated nuclei to see if gene
mutations would be induced.  They detected significant mutant induction,
indicating that, even in the absence of direct nuclear damage by arsenite,
cytoplasts can initiate the signaling pathways that result in genotoxic
damage. 

To assess the role of the mitochondria in mediating the genotoxic response,
Dr. Hei exposed AL cells either lacking mitochondrial DNA (rho zero cells)
or having diminished mitochondrial membrane potential to arsenite.  The
treatments produced few or no mutations.  These data strongly suggest that
mitochondrial function is necessary for arsenic-induced genotoxicity.

They also determined that mitochondrial damage can lead to the release of
superoxide anions which then react with nitric oxide in the cytoplasm to
produce the highly reactive peroxynitrites (ONOO-), which are potent and
versatile oxidants that can attack a wide range of biological molecules
including DNA, proteins, and lipids.  

These studies lead to several important conclusions:
(1)  The nucleus is not necessarily the only and sufficient target for
environmental carcinogens.
(2)  Mitochondria are a primary target in arsenic-induced genotoxic
response.
(3)  The genotoxicity of arsenic is mediated by a combination of reactive
oxygen species and reactive nitrogen species.

Dr. Hei believes that mitochondria are an important target for
arsenic-induced genotoxicity and the current findings should provide an
additional impetus for focusing on mitochondria as an interventional target
in the management of arsenic-induced diseases.

For More Information Contact:
Tom K. Hei, Ph.D.
Professor of Radiation Oncology and Environmental Health Sciences 
Columbia University
Center for Radiological Research 
VC 11-205/218
622 W. 168th St.
New York, NY 10032
Tel: (212) 305-8462
Fax: (212) 305-3229
Email:  tkh1@columbia.edu 

To learn more about this research, please refer to:

Liu S-X, M.M. Davidson, X. Tang, W. F. Walker, M. Athar, V. Ivanov and T. K.
Hei.  April 15, 2005.  Mitochondrial Damage Mediates Genotoxicity of Arsenic
in Mammalian Cells.  Cancer Research 65(8):3236-3242.