Proliferative Response in the Rat Kidney Induced by a Single, Carcinogenic Dose of Dimethylnitrosamine

Abstract

With the application of autoradiography, the pattern of DNA synthetic activity in the rat kidney following a carcinogenic dose of DMN was traced during the 3 weeks following treatment. Depending on cell class and location, DNA synthesis was constantly depressed for the first 1 or 2 days throughout all zones of the kidney. Mesenchymal cells of the cortex and outer band of the outer medulla commenced a wave of stimulated activity at the third day with a peak of response at the sixth day. Epithelial cells of these same two zones were slower to respond, attaining a peak of DNA synthetic activity at the tenth day. By the start of the third week, activity had returned to normal or near‐normal levels. The observations are discussed in relation to the known morphological events which occur in the kidneys of DMN‐treated rats prior to the development of neoplasia.

Thymus-Dependent Lymphocyte Function in Dimethylnitrosamine-Induced Renal Carcinogenesis is Not Depressed

“…Four of these occurred during the acute phase of toxicity within the first week of treatment. Previous studies have shown that the First 2 -3 weeks of DMN-renal carcinogenesis are marked by a diffuse inflamma tory response within the intertubular spaces of the renal cortex, a reaction which peaks at 7 days and resolves by 2 or 3 weeks (14,15). During this period there is also a substantial mortality from acute liver injury and at least 2 of the 4 rats with a depressed immune response were considered from their general appear ance before testing, to be likely non-survivors.…”

“…These lesions consist predominantly of lymphocytes and plasma cells together with frequent macro phages and lymphoblasts, but occasional fibroblast-like cells of abnormal struc ture which appear to be the targets of macrophage interaction are also present (14,15). During this chronic phase, no individual rat possessed a depressed lymphocyte response to PHA.…”

“…At 12 weeks, hypercellular lesions consisting of immunological cell types are no longer conspicuous in the renal tissue and from 12 to 16 weeks, in every surviving rat, microscopic foci of tumour cells, derived either from renal tubule epithelium or fibroblast-like interstitial cells, can be found (14,15,16). Signifi cantly, at neither of these time points did lesion-bearing rats possess depressed responses to PHA nor at 20 weeks when the extent of proliferation of renal tumour cells enabled the foci to be perceived by the naked eye as small spots or nodules.…”

“…Firstly, DMN is eliminated from the body tissues within 24 h of administration (13) so that the integrity of the immune system can be analysed without perturbation from the effects of continued toxic pressure, unlike the situation that exists in some models dependent on continuous or repeated ex posure to carcinogen. In additon, the morphological sequence of events from the time of dosing with DMN up to the appearance of macroscopic renal neoplasms has been recorded at both light-and electron-microscopic levels (14)(15)(16). Furthermore, the nature of certain lesions during the latent period of induction implicates active involvement of the immune system.…”

Length of In Vivo Exposure to a Carcinogenic Dose of Dimethylnitrosamine Necessary for Subsequent Expression of Morphological Transformation by Rat Kidney Cells In Vitro

“…DMN, naturally converted within the host (thus dispensing with the need for addition of appropriate enzyme systems in vitro) but the subsequent in vitro events can be interpreted against a background of in vivo phenomena relevant to the actual cancer induction process. I'n the case of DMN, the single pulse results in the long term development of renal neoplasms in every surviving rat, and information concerning the sequence of morphological and biochemical events commencing 24 hours after the dose and leading up to the macroscopic presence of these tumours in available [5][6][7][8]17], The present study confirms our previous report [10], that kidney cells isolated from rats treated with a single car cinogenic dose of DMN acquire the growth properties of renal tumour cells in vitro [12,13]. The observations are extended here to show that kidney cells acquire this potential long before the chemical is eliminated from the host tissues and as early as one hour following that carcinogenic stimulus.…”