N-Nitrosomorpholine induced alterations of unscheduled DNA synthesis, mitochondrial DNA synthesis and cell proliferation in different cell types of liver, kidney, and urogenital organs in the rat

Abstract

In order to measure rates of unscheduled DNA synthesis (UDS), mitochondrial DNA synthesis, and cell proliferation, i.e. factors relevant in the early phase of carcinogenesis, young rats received by gavage 200 mg/kg N-nitrosomorpholine (NNM) or vehicle (distilled water), and were injected with 3H-thymidine 24 h later. Autoradiographs from liver, kidney, urethra, prostate, seminal vesicle, and ductus deferens were prepared from deparaffinized sections, using a 250-day exposure time. In the liver, UDS was at least doubled in 2 n and 4 n hepatocytes. Approximately 3% of these hepatocytes exhibited a fourfold increase in UDS. Such strongly labeled cells were only observed in the liver following NNM exposure. With the exception of renal epithelial cells of the proximal tubule, UDS in epithelial cells of bladder, urethra, ductus deferens, seminal vesicle and prostate was decreased in NNM-exposed rats. Mitochondrial DNA synthesis and cell proliferation were significantly increased only in hepatocytes, and were decreased in all other monitored organs in NNM-exposed rats. The strongly increased UDS and more moderately increased mitochondrial DNA synthesis in a subgroup of hepatocytes suggest that possibly some unrepaired damage persists in the DNA of these cells. The latter cells may be the precursors of so-called foci of hepatocellular alteration, which appear later during the process of carcinogenesis. The increased UDS but decreased rate of proliferation in the renal proximal tubule cells might be related to renal carcinogenesis which is observed in NNM-exposed rats after a long latency period.