Ultrastructural changes in Golgi apparatus (GA) during various functional conditions were studied in the rat parotid glands, and their three dimensional configuration was analyzed with the use of computer graphics from serial section electron micrographs. Three dimensional reconstruction confirmed that a normal GA was a connected single structure located in the supranuclear region, although it exhibited markedly complicated and reticulated branches. In contrast when host cells entered into the mitotic phase, underwent postnatal development and were inhibited of transport of secretory materials from rough endoplasmic reticulum, GA became an aggrega-tion of small vesicles or tubules, in which cis and most likely medial, but not trans elements were included. From these observations, we propose a new hypothesis that a GA consists of two components, basic and functional ones. The basic component having small vesicles and tubules of cis and medial natures is the most primitive feature of GA that is recognized in such cellular phases as early development, mitosis, and interruption of inflow. Basic components evolve a functional one that consists of a lamellar structure with cis, medial and trans elements. They are recognized in the usual cells at the active states. The size and overall configuration of GA changes greatly due to the amount of inflow of secretory materials depending upon the functional conditions of the cells.
The carcinogenicity of 5-fluorouracil (5-FU), an antineoplastic drug, was examined in (C57BL/6×C3H)F1 mice. Groups of 51 or 52 mice of each sex were given 5-FU orally in their drinking water at doses of 60 or 30 ppm for 82 weeks and were then observed for 4 weeks. Control mice were given tap water for 86 weeks. Mean total intakes of 5-FU per mouse were 196 and 98mg in males, and 136 and 67 mg in females, respectively. The survival rates of each group at week 86 were more than 80% in both sexes. There were no significant differences between body weights of mice given 5-FU and those of controls in both sexes. Harderian gland adenomas, alveolar adenomas of the lung, lymphoma/leukemias and intestinal tumors in both sexes, liver cell tumors in males, and a few tumors in other organs of both sexes were found. Eight (15%) of 52 male mice treated with the high dose of 5-FU developed Harderian gland adenomas and the incidence was higher than that of controls, but the difference was marginal and no dose-response was found. In other organs, no significant increase of any particular tumor type was observed in the treated groups of both sexes.
Carbon tetrachloride (CCl4) hepatotoxicity to the primary hepatocyte culture of Mongolian gerbils was studied. Transaminase leakage from cultured cells appeared at 3h-exposure to 0.5 or 1.0mM CCl4 remarkably increasing at 24h. With 0.5mM CCl4, there were marked increase of lipid droplets. aggregation of swollen smooth-surfaced endoplasmic reticulums (sER), dilatation of ER lumen, metamor-phosis of mitochondria, and reduction of periodic acid-Schiff (PAS) reactivity. Cholesterol clefts were produced in ER areas at 3h-exposure, increasing in size and number with time course. These mor-phological changes due to CCl4 were enhanced by previous treating of the culture with phenobarbital.
Combination effects of low doses of three carcinogens, N-nitrosobis (2-oxopropyl) amine (BOP), N-methyl-N-nitrosourea (MNU), and diethylnitrosamine (DEN) on initiation of pancreatic ductal carcinogenesis were examined using a rapid production model in female Syrian hamsters. Groups of animals received intraperitoneal injections of BOP, MNU, and DEN at doses of 20, 10, and 20mg/kg body weight, respectively, either alone or in combination as initiators, followed by three cycles of augmentation pressure, established earlier to cause selective growth of initiated cell populations. All hamsters were sacrificed 10 weeks after the commencement and pancreatic duct lesions were histopath-ologically diagnosed. The low single dose of 20mg/kg body weight of BOP still retained relatively strong initiating activity resulting in substantial induction of ductal adenocarcinomas 67%, while neither MNU nor DEN alone exerted significant initiating activity under the present experimental conditions. Combined administration of these three carcinogens either simultaneously or serially at intervals of one day exhibited no significant synergism, with the incidences and mean numbers of ductal lesions being almost the same as those of the BOP alone group. Thus, under the present experimental conditions, BOP, MNU, and DEN exerted no synergism regarding initiation of pancreatic ductal carcinogenesis in hamsters.
Modifying effect of magnesium hydroxide on 1, 2-dimethylhydrazine (DMH)-induced intestinal carcinogenesis was examined in a rat model using 1, 2-dimethylhydrazine (DMH). Although the incidence or multiplicity of the small intestinal tumors of rats of Groups 2-5 which were s.c. injected DMH (20mg/kg, body weight) once 2 weeks for 10 times at the commencement of experiment and were given magnesium hydroxide (250 or 500 or 1000 or 2000ppm in diet) throughout the experiment, were not different from those of Group 1 exposed to DMH alone (Group 1), the incidence or multiplicity of the large intestinal tumors of the groups given the carcinogen and magnesium hydroxide were rather lower or smaller than that of the group given the carcinogen alone. Significant differences were obtained with the mutiplicity between Group 2 or 4 or 5 and Group 1 (P<0.02 or P<0.02 or P<0.05). These results appear to indicate an inhibitory effect of magnesium hydroxide on DMH induced large bowel carcinogenesis and are in agreement with those of our previous study in rats using methylazoxymethanol acetate. The agent could be a promising chemopreventive agent for large bowel carcinogenesis in humans together with other trace elements such as selenium or calcium.
Enhancing effects of bladder carcinogens or promoters on the early development of neoplastic or putative preneoplastic epithelial lesions in the rat bladder were investigated. The rats were given 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water for 4 weeks, and then fed test chemical during experimental weeks 5 to 9 (5 weeks) and weeks 13 to 20 (8 weeks). In addition, during weeks 10 to 12 (3 weeks), the rats were fed 3% uracil in diet. Rats in a control group were treated with BBN and uracil. The total observation period was 20 weeks. Significantly higher numbers of papillary or nodular hyperplasia in the bladder were observed in all test chemical treated-groups [3, 3'-dichlor-obenzidine, N, N-dibutylnitrosamine (DBN), N-methyl-N-nitrosourea (MNU), sodium o-phenyl-phenate (SOPP), and sodium saccharin (SS)] after BBN treatment. Incidences or numbers of papilloma were significantly increased in the groups of rats treated with DBN, MNU, SOPP or SS, and those of carcinoma were increased in the groups treated with.DBN or SOPP. These results suggest that this system might be useful for the more rapid detection of bladder carcinogens and promoters.
Histological testicular changes were investigated sequentially in WBN/Kob rats from 7 to 60 weeks of age. Severe atrophy of the seminiferous tubules was first observed in two out of five rats of 15 weeks of age. The severely atrophied tubules initially appeared in patches among the normal tubules and gradually spread throughout the testis. The testicular degeneration was progressive with advancing age, about 90% of all tubules in the testis being severely atrophied after 40 weeks of age. This degeneration was characterized by disappearance of germinal cells, a reduction in tubular diameters with thickening of the basement membrane, and slight Leydig cell hyperplasia. The number of BrdU positive germinal cells declined with advancing age. In electron microscopic examinations using a lanthanum tracer, the blood-testis barrier consisting of tight junctions between Sertoli cells was not disrupted in severely atrophied tubules. It was concluded that the testicular degeneration in WBN/Kob rats occurred from young age and there was no relationship between these lesions and diabetes.
Two testicular tumors classified as so-called gonadal stromal tumor were found in 113-week-old F344 and 103-week-old Slc : Wistar rats. In Case 1 observed in an F344 rat, the cut surface of the testis showed a yellow or yellow-brownish lobular structure. A nodule, surrounded by cells of interstitial cell tumor, demonstrated glandular structure in most areas. The glands were composed of cuboidal cells with eosinophilic cytoplasm and round to oval nuclei with one or two prominent nucleoli. In the marginal area between this lesion and interstitial cell tumor, glandular structure was obscure. In some areas, vacuolated cells with abundant cytoplasm were partially intermingled. In Case 2 in a Wistar rat, a tumor occupied the greater part of the right testis and compressed the surrounding tissue. Histologically, tortuous tubular structures without distinct lumina were formed by elongated or spindle cells in a palisade arrangement on a delicate fibrovascular stroma. Electron microscopically, the tumor cells had a nucleus with irregular invagination. From these findings, it may be considered that Case 1 was a gonadal stromal tumor, although the cell origin was not specified, and that Case 2 was a Sertoli cell tumor.
Histopathological and electron microscopical studies were made on epithelial cells of the prostate gland in spontaneously hypertensive rats (SHR) and compared with those of Wistar-Kyoto rats (WKY). The prostate gland tissue of SHR showed a developmental retardation at 5 weeks of age. At and after 18 weeks of age (terminal experimental age was 31 weeks), and glands were small in size with tall columnar epithelial cells, frequently protruding into the glandular lumens and scant secretory substance. On the other hand, the prostate of WKY had large-sized glands with small columnar or cuboidal epithelial cells and with abundant secretory substance. Electron-microscopically, the cytoplasm of glandular epithelial cells of SHR had well-developed rough endoplasmic reticulum (RER), but Golgi apparatus was small in size and undeveloped. In addition, there were fewer condensed vacuoles and secretory granules. From these findings, it was considered that transfer of secretory materials from RER to Golgi apparatus was congenitally disturbed and the secretory cycle was inhibited in the epithelium of the prostate gland of SHR.