Arsenic is a known human
carcinogen. We have reported that brief exposure of pregnant C3H mice to
arsenite in their
drinking water during gestation induced
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 nontumorous 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 nontumorous 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. 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.