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ToxSci Advance Access published online on December 22, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh055
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 22, 2003; accepted October 21, 2003
© 2003 Society of Toxicology

Carcinogenicity

Toxicogenomic Analysis of Aberrant Gene Expression in Liver Tumors and Non-Tumorous Livers of Adult Mice Exposed in Utero to Inorganic Arsenic

Jie Liu 1*, Yaxiong Xie 1, Jerrold M. Ward 2, Bhalchandra A. Diwan 3, and Michael P. Waalkes 1

1 Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, NC 27709
2 Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, NCI-Frederick, Frederick, MD 21702
3 Basic Research Program, SAIC-Frederick, Frederick, MD 21702

* To whom correspondence should be addressed. E-mail: Liu6{at}niehs.nih.gov.


  Abstract

Arsenic is a known human carcinogen. We have reported that brief exposure of pregnant C3H mice to arsenite in the drinking water during gestation induces hepatocellular carcinoma (HCC) in male offspring after they became adults. Tumor formation is typically associated with multiple gene expression changes, and this study examined aberrant gene expression associated with transplacental arsenic hepatocarcinogenesis. Liver tumors and non-tumorous liver samples were taken at necropsy from adult male mice exposed in utero to either 42.5 or 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to 18 of gestation. Total RNA was extracted and subjected to microarray analysis. Among 600 genes, arsenic-induced HCC showed a higher rate of aberrant gene expression (>2-fold and p < 0.05, 14%) than spontaneous tumors (7.8%). Overexpression of {alpha}-fetoprotein, c-myc, cyclin D1, proliferation-associated protein PAG and cytokeratin-18 were more dramatic in arsenic-induced HCC than spontaneous tumors. In non-tumorous liver samples of arsenic-exposed animals, 60 genes (10%) were differentially expressed, including the increased expression of {alpha}-fetoprotein, c-myc, insulin-like growth factor binding protein-1, superoxide dismutase, glutathione S-transferases, and CYP2A4, and the depressed expression of CYP7B1. Real time RT-PCR analysis largely confirmed these findings. In summary, this toxicogenomic analysis revealed several aberrant gene expression changes associated with transplacental arsenic carcinogenesis. It is indeed remarkable that expression changes occurred in adulthood even though arsenic exposure ended during gestation. Some of these aberrantly expressed genes could play a role in the development of arsenic-induced tumors, at least in the liver.

Key Words: Inorganic arsenic, transplacental exposure, hepatocellular carcinoma, microarray, real-time RT-PCR .


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