Animal models for arsenic carcinogenesis: inorganic arsenic is a transplacental carcinogen in mice

Inorganic arsenic is a known human carcinogen causing tumors of the skin, urinary bladder, lung, liver, kidney, and possibly other organs. However, the animal models for inorganic arsenic carcinogenesis have been limited and development has been problematic. Gestation is often a period of high sensitivity to carcinogenesis so we investigated inorganic arsenite as a transplacental carcinogen in mice. Pregnant C3H mice were exposed to sodium arsenite (0, 42.5, and 85 ppm as arsenic) in the drinking water for a brief period during gestation (from Gestation day 8 to 18), with no further arsenic exposure or other treatments. The offsprings were monitored up to 90 weeks. Transplacental inorganic arsenic exposure produced a dose-dependent induction of tumors in the liver, adrenal, lung, and ovary in the offsprings after they had reached adulthood. This included hepatocellular carcinoma (HCC), a tumor associated with arsenic exposure in humans. These tumors Occurred when mice became adults in the absence of any other treatments and well after arsenic exposure had ended. Genomic analysis of liver tumors and tumor-surrounding tissues revealed several patterns of aberrant gene expression associated with transplacental arsenic carcinogenesis. This animal model demonstrated that inorganic arsenic could act as a "complete" transplacental carcinogen in mice. In addition, other important animal models for inorganic arsenic as a skin tumor co-promoter or as a co-carcinogen are discussed. The development of these animal models should advance our understanding of the mechanisms of inorganic arsenic carcinogenesis. (C) 2004 Elsevier Inc. All rights reserved.