Carcinogenicity of dimethylarsinic acid in p53 heterozygous knockout and wild-type C57BL/6J mice.

Abstract

There is abundant epidemiological evidence that arsenic is an environmental carcinogen related to human cancers of the skin, lung, liver and urinary bladder, in particular. Dimethylarsinic acid (DMA) has also been reported to act as a carcinogen/or a promoter in rat models. To elucidate molecular mechanisms, we conducted an 18 month carcinogenicity study of DMA in p53 heterozygous (+/–) knockout mice, which are susceptible to early spontaneous development of various types of tumors, and wild-type (+/+) C57BL/6J mice. Totals of 88–90 males, 7–8 weeks of age, were divided into three groups each administered 0, 50 or 200 p.p.m. DMA in their drinking water for 18 months. Mice that were found moribund or died before the end of the study were autopsied to evaluate the tumor induction levels, as well as those killed at the end. Both p53 ^+/– knockout and wild-type mice demonstrated spontaneous tumor development, but lesions were more prevalent in the knockout case. Carcinogenic effect of DMA was evident by significant early induction of tumors in both treated p53 ^+/– knockout and wild-type mice, significant increase of the tumor multiplicity in 200 p.p.m.-treated p53 ^+/– knockout mice, and by significant increase in the incidence and multiplicity of tumors (malignant lymphomas) in the treated wild-type mice. By the end of 80 weeks, tumor induction, particularly malignant lymphomas and sarcomas, were similar in treated and control p53 ^+/– knockout mice. No evidence for organ-tumor specificity of DMA was obtained. Molecular analysis using PCR–SSCP techniques revealed no p53 mutations in lymphomas from either p53 ^+/– knockout or wild-type mice. In conclusion, DMA primarily exerted its carcinogenic effect on spontaneous development of tumors with both of the animal genotypes investigated here.