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Our laboratory is testing the hypothesis that hypomethylation of DNA [a decreased content of 5-methylcytosine (5MeC) compared with cytosine] facilitates aberrant oncogene expression involved in tumorigenesis, using a model system of mouse strains with differing susceptibilities to liver tumorigenesis. The B6C3F1 (C57BL/6 x C3H/He) mouse serves as the relatively susceptible strain and C57BL/6 serves as the relatively resistant strain. Phenobarbital (PB) and/or administration of a choline-devoid, methionine-deficient diet (CMD) were employed as non-genotoxic hepatocarcinogens. We have examined hepatocyte and nonhepatocyte proliferation in conjunction with an assessment of global methylation changes in liver DNA of B6C3F1 and C57BL/6 mice following these promoter treatments. Bromodeoxyuridine incorporation into DNA, used to measure cell proliferation indirectly, was visualized by immunohistochemistry and quantified by a Macintosh-based image analysis system. Increased hepatocyte proliferation was demonstrated following all three treatments. This increase was larger in C57BL/6 (the relatively resistant strain) as compared with B6C3F1. In contrast, global hypomethylation was evident to a larger extent in the B6C3F1 mouse, as compared with C57BL/6. PB led to hypomethylation (>20% decrease as compared with controls) at weeks 1, 2 and 4 in B6C3F1, but not in C57BL/6 at the same time points. CMD diet administration led to hypomethylation in both strains. At week 1, 21 and 9% decreases in global methylation status were observed in B6C3F1 and C57BL/6 respectively. Evaluation of these data suggests that the heightened sensitivity of the B6C3F1 mouse compared with the C57BL/6 is due, in part, to a decreased capacity for, or fidelity of, maintaining normal methylation status. The relatively resistant strain is better able to maintain the normal methylation status of DNA in the face of a higher level of cell proliferation.

Abstract. Clinical and postmortem materials from six dogs with a diagnosis of malignant mesothelioma were studied retrospectively. The dogs were urban pets with clinical signs of malignant effusions. Two mesotheliomas were pleural, one pericardial, and one peritoneal. Both pleura and pericardium were involved in one dog, and the pleura and peritoneum in another. On gross examination at necropsy, diffuse granular or velvety plaques covering mesothelial surfaces were found in all dogs; firm discrete pleural nodules also were present in two dogs. Neither distant mestastases nor areas of deep lung invasion were found. The tumors varied histologically, but the most common type was epithelial with a papillary pattern. Ultrastructurally, the neoplastic cells had prominent surface microvilli, numerous desmosomes, and tonofilaments.Lung tissue from these dogs and from control dogs was evaluated for the presence of ferruginous bodies. Asbestos bodies were found in three of five dogs with mesotheliomas but rarely were found in control dogs. As a group, the mesothelioma cases had significantly more asbestos bodies and total ferruginous bodies than controls. The clinical and morphologic appearance of canine mesothelioma is similar to human mesothelioma and also may be associated with exposure to airborne fibers.