Show simple item record

dc.contributor.authorJackson, M. R.en
dc.date.accessioned2018-05-22T12:43:02Z
dc.date.available2018-05-22T12:43:02Z
dc.date.issued1972
dc.identifier.urihttp://hdl.handle.net/1842/30311
dc.description.abstracten
dc.description.abstractThis thesis is concerned with the pathological enlargement of hepatocyte nuclei By increases in DM content.en
dc.description.abstractThe experimental work confirms the mechanism by which carbon tetrachloride brings about this effect and provides novel and detailed information on nuclear enlargement induced by dimethylnitrosamine and thiocetamide. The significance of this effect, which has been shown to be induced by many hepatoxic procedures, is given a broad appraisal.en
dc.description.abstractVariation in nuclear ploidy from birth onwards is reviewed. It becomes apparent that the first three weeks of life is an ideal period for studying the effects of toxins on nuclear enlargement. Attention is then given to toxic substances which induce nuclear enlargement in the liver and the mechanisms which underly this phenomenon. Prom this appreciation there emerges three groups of hepatotoxic chemicals: i) those inducing increased nuclear ploidy during an elevation of mitosis ii) those inducing increased nuclear ploidy during a depression of mitosis and iii) those whose action on the cell cycle is, as yet, obscure so that no firm conclusions about them can be drawn. The hepatotoxic substances which bring about nuclear enlargement during a depression of mitosis are also capable of inducing neoplasia in the liver, and of interaction with DM. The possible association of these three effects is briefly alluded to at this stage.en
dc.description.abstractDimethylnitrosamine, carbon tetrachloride and thiocetamide all produce enlargement of hepatocyte nuclei and the mechanism by which they do so was investigated "by microspectrophotometry, mitotic counts, binucleate counts and autoradiography.en
dc.description.abstractA strain susceptibility of the rat to dimethylnitrosamine was discovered as a result of which definitive experiments were restricted to Ash/Wistar stock. A single injection of 10 mg DMN/kg body weight into 2-day old rats evoked an irregular patchy necrosis associated with central veins. This effect was found to be most pronounced towards the hilus of the organ at this dosage. At 20 mg/kg a diffuse necrosis throughout the organ was observed. The dimethylnitrosamine treatment at both levels of administration also markedly depleted hepatic haemopoietic tissue over the first 48 hours but did not effect other haemopoietic centres. It was concluded from this that necrosis of haemopoietic cells was caused by a toxic metabolite of DMN formed in the liver.en
dc.description.abstractThe administration of 10 mg DMN/kg to 2-day old rats produced an immediate rise in nuclear ploidy so that hyperdiploid nuclei increased from 5 percent to 35 percent by day four following injection. Over the next 17 days the proportion of hyperdiploid cells decreased to approx¬ imately 25 percent. Mitotic activity of the hepatocytes was considerably depressed in DMN" treated animals over the first four days of the experiment although an increase in DM synthesis in hepatocytes occurred over the first two days following injection. The binucleate hepa¬ tocytes were not involved in this ploidy increase and it was concluded that dimethylnitrosamine brought about a blockage in the G2 stage of the cell cycle. Moreover, a single injection of dimethylnitro-samine induced blockage in one cell cycle only; subsequently, normal mitoses were resumed. Further work showed that the increased nuclear ploidy induced by dimethylnitrosamine is proportional to the number of hepatocytes stimulated to enter MA synthesis and that the antimitotic effect persists for at least four days following a single administration. Repeated injections can lead to 'megalocytosis' of hepatocytes due to continued blockage of the cell cycle in G2 during successive attempts at division.en
dc.description.abstractAdditional autoradiographic experiments afforded evidence that there are two populations of hepatocytes in the liver having a short and long generation time respectively. Once an hepatocyte enters the 'proliferative pool' it undergoes a number of divisions in a relatively short space of time. Although hepatocytes with generation times of at least six months were seen in both dimethylnitrosamine treated and control rats dosed at birth, they were, nevertheless, present in significantly greater numbers in the dimethylnitrosamine group at the end of this period. It was concluded however, that no particular significance could be attached to this finding with regard to the carcinogenic effects induced by the compound.en
dc.description.abstractWith carbon tetrachloride, there is a gradual development of susceptibility of the liver to necrosis from birth onwards. This is related to the development of processing enzymes so that by four days of age a maximum necrotoxic response is seen. Injection of carbon tetrachloride to the 4-day old rat induced a reparative wave of mitosis but no increase in ploidy. At this age there are negligible numbers of binucleate hepatocytes. At 28 days of age, however, biimcleate hepatocytes account for JO percent of the parenchymal cell population and a reparative wave of mitosis induced by carbon tetrachloride leads to a sharp drop in the numbers of binucleate cells and a marked increase in nuclear ploidy. From this and other histological evidence it was concluded that carbon tetrachloride brings about an increase in nuclear ploidy via an intermediate binucleate system. That is, the two nuclei of a binucleate cell enter mitosis at the same time but form a common metaphase plate. Two mononucleate cells or one binucleate cell with nuclei of the next ploidy level are then formed.en
dc.description.abstractThe same mechanism was found in the case of thiocetamide but the wave of mitosis induced was very marked in relation to the relatively small amount of necrosis induced and may not therefore be entirely related to repair.en
dc.description.abstractOn this evidence it was concluded that there were two mechanisms of pathological nuclear ploidy increase in the liver. No histological evidence was found for processes other than the two outlined above vis: blockage in G2 of the cell cycle or an intermediate binucleate cell.en
dc.description.abstractA final carcinogenic experiment showed that carbon tetrachloride injected into the 4-day old rat failed to induce neoplasia after 17 months. Injection of dimethylnitrosamine into the 2-day old rat however, resulted in tumours of the kidney, liver and lung over the same period.en
dc.description.abstractThe above results were taken to be in agreement with the initial postulate that substances with an antimitotic activity on liver parenchymal cells were also likely to induce neoplasia in the liver. Circumstantial evidence indicating that damage to DM might explain the antimitotic action of these hepatotoxic substances is discussed. Other mechanisms such as inhibition of protein synthesis are also mentioned. Finally, the ability of mammalian cells to repair damage to DM is also discussed as a possible factor in the varying persistence of the antimitotic action and of other cell cycle effects of some hepatotoxic procedures.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 19en
dc.relation.isreferencedbyAlready catalogueden
dc.titleThe induction of enlargement of rat hepatocyte nuclei by certain toxic chemicalsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record