The repeated administration of the hypolipidemic agent Su-13 437 (nafenopin) to neonatal rats roughly doubled the number of peroxisomes in the liver tissue and caused a sixfold volumetric expansion of the peroxisomal compartment. During the proliferative response, the size-distribution of the peroxisomes was reversibly altered, enlarged particles appearing in numbers varying according to the dose given. By means of a new method for quantitative autoradiography, it was shown that (a) the concentration of silver grains over peroxisomes was comparable to that found over the endoplasmic reticulum; (b) the peak incorporation of [aH]arginine into the peroxisomes was delayed in comparison with that into the endoplasmic reticulum; (c) the label, once incorporated into the expanding peroxisomal compartment, displayed the same shift to large particles as did the whole population. These results are compatible with the biosynthetic pathway for peroxisomal catalase proposed earlier (cf. reference 12), and with the notion that the druginduced size-shift might have resulted from progressive growth of a particular class of peroxisomes formed in the presence of the agent. Evidence is presented to show that during the recovery period the larger peroxisomes are removed preferentially.In a series of reports, we have shown that two hypolipidemic drugs of the a-aryloxyisobutyric acid type, clofibrate (CPIB) 1 and CIBA Su-13 437, are endowed with the capacity to elicit the induced state and to expand the peroxisomal compartment of male rat liver parenchymal cells (24-1Abbreviations used in this paper: CPIB, clofibrate, Atromid S; DAB, diaminobenzidine; ER, endoplasmic reticulum; PO, peroxisome(s) (microbody); RER, rough-surfaced endoplasmic reticulum, SER, smoothsurfaced endoplasmic reticulum; Su-13 437, CIBA Su-13 437 (nafenopin). 26, 69). These observations were subsequently confirmed and extended by several research groups (reviewed in references 2, 30, 56, 70). The biosynthesis and precise metabolic function(s) of peroxisomes (microbodies) in normal or in experimentally altered mammalian cells are still not fully understood (12,13,56,70), although in the past few years considerable progress has been achieved with regard to the biosynthesis of peroxisomal constituents (37,38,62). In addition, interest in the biology of peroxisomes has been rekindled by a large number of morphological observations leading to the concept of the ubiquitous distribu-
Gamma-glutamyltranspeptidase-positive hepatocyte foci were produced in female rats given a single dose of diethylnitrosamine neonatally after birth and, after weaning, a diet containing phenobarbitone for 30 wk. The nucleator method, a new stereological approach, provided an efficient, unbiased estimate of mean cell volume in focal lesions and extrafocal areas. It also provided an unbiased sample of cells to estimate hepatocyte nuclear volume and the percentage of binucleated cells. The results showed an increase in the mean volume of mononucleated cells--from 4,700 micron3 in extrafocal areas to 12,700 micron2 in foci--and of binucleated cells--from 6,900 micron3 to 25,000 micron3. This demonstrated the hypertrophic effect of the carcinogenic treatment in focal lesions. A striking reduction in the proportion of binucleated cells was also observed in the preneoplastic lesions. Nuclear volume measurements from mononucleated and binucleated hepatocytes were used to assess ploidy. An apparent increase in nuclear ploidy, with no change in cellular ploidy, was noted in focal tissue when compared with nonfocal tissue. This appeared to be caused by an increase in mononucleated tetraploid cells and a reduction in binucleated cells with two diploid nuclei, indicating an altered mitotic mechanism in focal lesions. The significance of these changes in cell volume, apparent ploidy levels and binuclearity in preneoplastic foci is discussed in relation to the hepatocarcinogenic process.
Ultrastructural changes were investigated and quantified, using a stereological approach, in early gamma-glutamyltranspeptidase (GGT)-positive focal lesions, induced in the rat liver by treatment with a single initiating dose of diethylnitrosamine (DENA) followed by promotion with phenobarbitone (PB) for 30 weeks. Within the extra-hepatocyte environment of focal tissue, the mean volume occupied by Ito cells was markedly decreased, whilst that occupied by endothelial and Kupffer cells was increased, when compared to unlnvolved tissue from the same rat livers. The bile canalkuli were dilated, but no significant differences in the mean volume occupied by the sinusoidal and Disse spaces were noted. In focal hepatocytes there was a striking overproduction of lipid droplets and proliferation of smooth endoplasmlc retkulum (sER). Whorls of concentrically arranged, parallel ER membranes were found only in the hepatocytes of preneoplastk foci, in association with the proliferated sER, and never in the surrounding, uninvolved tissue. The increase hi mean volume of the sER, lipid droplet and cytoplasmk matrix compartments, together with the appearance of whorls, were the major contributing factors to the marked hypertrophy seen in focal hepatocytes. The mean volume of the rough endoplasmic reticulum, mitochondrial, lysosomal, peroxisomal and nuclear compartments per hepatocyte also increased, but contributed to a lesser extent to the cellular hypertrophy. It is speculated that whorls may be structural adaptations, resulting from a possible alteration in the normal feedback control of cholesterol synthesis, for the production of sterols and the biogenesis of sER in eosinophilk-ty pe focal cells. The significance of changes observed in focal tissue, and the high biological variation noted between foci, is discussed in relation to the hepatocarcinogenic process.
Atrophy of the L4 dorsal and ventral spinal roots was experimentally induced by unilateral sciatic neurectomy in groups of young (2 and 4 months) and older (12 months) albino rats. During the 4 months following neurectomy, the occurrence of infolded myelin loops (IMLs) was quantitatively examined in transverse sections prepared using perfusion fixation with glutaraldehyde and embedding in epoxy resin. The number of IMLs was higher on the operated side and increased with the time of survival and the age of the animals.The formation of IMLs is a characteristic early response of a large-caliber myelin sheath to axonal atrophy, probably reflecting the presence of redundant myelin.
Naturally occurring degenerative lesions of nerve fibers in the spinal cord, spinal roots and peripheral nerves in nine male rats 877 days old were swollen myelin sheaths, forming "myelin bubbles." The myelin swellings were distributed throughout the spinal tracts and the peripheral nerves, but most frequently in the lumbar ventral spinal roots. Although most axons surrounded by swollen myelin were intact, some were constricted and degenerated, while others showed signs of remyelination.
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