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Jie Liu,¹ Yaxiong Xie,¹ Danica M.K. Ducharme,² Jun Shen,¹ Bhalchandra A. Diwan,³ B. Alex Merrick,² Sherry F. Grissom,² Charles J. Tucker,² Richard S. Paules,² Raymond Tennant,² and Michael P. Waalkes¹

¹Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, and ²National Center For Toxicogenomics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ³Basic Research Program, Science Applications International Corporation, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Frederick, Maryland, USA

Abstract
Our previous work has shown that exposure to inorganic arsenic in utero produces hepatocellular carcinoma (HCC) in adult male mice. To explore further the molecular mechanisms of transplacental arsenic hepatocarcinogenesis, we conducted a second arsenic transplacental carcinogenesis study and used a genomewide microarray to profile arsenic-induced aberrant gene expression more extensively. Briefly, pregnant C3H mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from days 8 to 18 of gestation. The incidence of HCC in adult male offspring was increased 4-fold and tumor multiplicity 3-fold after transplacental arsenic exposure. Samples of normal liver and liver tumors were taken at autopsy for genomic analysis. Arsenic exposure in utero resulted in significant alterations (p < 0.001) in the expression of 2,010 genes in arsenic-exposed liver samples and in the expression of 2,540 genes in arsenic-induced HCC. Ingenuity Pathway Analysis revealed that significant alterations in gene expression occurred in a number of biological networks, and Myc plays a critical role in one of the primary networks. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis of selected genes/proteins showed > 90% concordance. Arsenic-altered gene expression included activation of oncogenes and HCC biomarkers, and increased expression of cell proliferation-related genes, stress proteins, and insulin-like growth factors and genes involved in cell-cell communications. Liver feminization was evidenced by increased expression of estrogen-linked genes and altered expression of genes that encode gender-related metabolic enzymes. These novel findings are in agreement with the biology and histology of arsenic-induced HCC, thereby indicating that multiple genetic events are associated with transplacental arsenic hepatocarcinogenesis. Key words: Agilent mouse oligo 22K microarray, arsenic, hepatocellular carcinoma, real-time RT-PCR, transplacental exposure, Western blotting. Environ Health Perspect 114:404-411 (2006) . doi:10.1289/ehp.8534 available via http://dx.doi.org/ [Online 6 October 2005]

Address correspondence to M.P. Waalkes, Inorganic Carcinogenesis Section, NCI at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2328. Fax: (919) 541-3970. E-mail: waalkes@niehs.nih.gov

The authors thank W. Qu, J-F. Coppin, and L. Keefer for their critical review of this manuscript.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.

Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, the National Center for Toxicogenomics, and the National Cancer Institute under contract NO1-CO-12400.

The authors declare they have no competing financial interests.

Received 22 July 2005 ; accepted 6 October 2005.