[Clinical evaluation of Periograf ceramic implants in periodontal bone defects].
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Adult↗
Biomedical subjects
M Ohshima
Publications and source records attributed to M Ohshima.
Dietary iodine deficiency as a tumor promoter and carcinogen in male F344/NCr rats.
Groups of 6-wk-old male F344/NCr rats received a single i.v. injection of either vehicle or N-nitrosomethylurea (Cas: 684-93-5) (MNU) at a dose of 41.2 mg/kg body weight. Two wk later, groups of rats were placed on iodine-deficient, iodine-adequate, or commercial (Wayne Lab Blox) diets, or one of these diets and without previous MNU injection. Animals were sacrificed at either 52 or 77 wk, or when they became moribund. Carcinogen-treated rats on the iodine-deficient diet for up to 52 wk had significantly increased thyroid gland weights and increased incidences of both thyroid follicular cell carcinoma (90%) and diffuse pituitary thyrotroph hyperplasia (90%) at 52 wk. The majority of the follicular carcinomas were transplantable and invasive into the mammary fat pad of weanling F344/NCr rats. No other tumors induced by MNU were affected by the iodine-deficient diets. Rats fed the iodine-deficient diet without MNU injection had a 40% incidence of thyroid follicular adenomas at 52 wk and 60% at 77 wk, and a 10% incidence of follicular carcinomas at 77 wk. Thus this experiment provided evidence that the iodine-deficient diet is a potent promoter of thyroid tumors initiated by MNU and carcinogenic by itself. In addition, pituitary tumors were found in 29 of the 58 rats treated with the carcinogen alone, compared to only 3 of the 20 rats in the control groups. The vast majority of these pituitary tumors contained prolactin that was demonstrable by the avidin:biotin:peroxidase complex immunocytochemical technique.
Animals↗
Protective effects of zinc acetate toward the toxicity of nickelous acetate in rats.
Zinc pretreatment is known to ameliorate the acute and chronic effects of the toxic heavy metal, cadmium. However, the ability of zinc to decrease the toxicity of other metals has not been widely investigated. Therefore, this study was designed to determine the effects of zinc pretreatment on the acute toxicity of nickel. Male Fischer rats received either nickel alone (i.p.), zinc alone (s.c.), zinc plus nickel, or saline (i.p. and s.c.; controls). In the lethality studies, the dose of nickel was 115 mumol nickel/kg (as nickel acetate) while for all other studies the dose was 95 mumol nickel/kg. Zinc was given in multiple doses of 300 mumol zinc/kg (as zinc acetate) at -24, 0 and +24 h relative to nickel (total zinc dose 900 mumol/kg) for lethality studies or -24 and 0 h for studies 24 h and under in duration (total dose 600 mumol/kg). Zinc pretreatment significantly increased the 14-day survival of nickel-related rats. Zinc did not, however, prevent the reduction in weight gain over 2 weeks seen with nickel treatment. Histopathologically, at 120 h following nickel exposure, kidneys in the group receiving nickel alone generally showed moderate nephropathy (multifocal proximal tubule degeneration with necrosis) while in the zinc plus nickel group the nephropathy was generally mild. Zinc pretreatment had no apparent effect on the pharmacokinetics of nickel over 24 h as assessed by urinary excretion, blood levels or organ distribution. Zinc pretreatment also did not alter the subcellular distribution of renal nickel 6 h after nickel exposure. Enhanced synthesis of metallothionein did not appear to play a critical role in the reduction of nickel toxicity, since renal concentrations of this metal-binding protein, although elevated compared to control, were not different in rats receiving zinc and nickel or zinc alone. Zinc pretreatment did, however, have marked effect on nickel-induced hyperglycemia, reducing both the duration and severity of elevated blood glucose levels. Results of this study show that zinc can prevent some of the toxic effects of nickel and that the mechanism of this action does not appear to involve either metallothionein or alterations in the pharmacokinetics of nickel.
Acetates↗
Evidence for lack of promotion of the growth of the common naturally occurring basophilic focal hepatocellular proliferative lesions in aged F344/NCr rats by phenobarbital.
Aged female F344/NCr rats were exposed to phenobarbital (PB), 500 p.p.m. in the drinking water, from 26 months of age, for periods of 4, 8 or 9-27 weeks. In groups of control and PB-exposed rats sacrificed at these time periods the number and volume of basophilic and eosinophilic focal hepatocellular proliferative lesions (FHPL), including altered foci and adenomas in hematoxylin- and eosin-stained sections and FHPL identified histochemically by their content of gamma-glutamyl transpeptidase (GGT), were determined using computerized image analysis. Tritiated thymidine [3H]TdR was injected prior to sacrifice to determine labeling indices (LI) of normal hepatocytes and hepatocytes in FHPL. Rats receiving PB had significantly increased numbers and volumes of eosinophilic and GGT-positive FHPL while the numbers and volumes of the common basophilic FHPL seen in controls were not affected by PB exposure. The LI of all FHPL were higher than that of normal hepatocytes, but PB exposure did not affect the LI of basophilic FHPL. An uncommon GGT-positive FHPL found in control rats was detected in zone 1 of the hepatic acinus, a similar location of the GGT-positive eosinophilic FHPL seen in PB-exposed rats, while the common basophilic FHPL was observed in zones 1-3. These findings suggest that PB does not promote the growth or development of the common naturally occurring basophilic FHPL but either promotes the uncommon GGT-positive FHPL or induces new FHPL de novo.
Adenoma↗
Fetal mouse susceptibility to transplacental lung and liver carcinogenesis by 3-methylcholanthrene: positive correlation with responsiveness to inducers of aromatic hydrocarbon metabolism.
The role of metabolic activation of carcinogens in fetal tissue as a determinant of sensitivity in transplacental carcinogenesis was investigated in a pharmacogenetic experiment utilizing backcrosses of C57BL/6 (AhbAhb, responsive to induction of aromatic hydrocarbon metabolism) and DBA/2 (AhdAhd, non-responsive) mice. Responsive (C57BL/6 X DBA/2)F1 and non-responsive DBA mothers, all carrying both responsive (AhbAhd) and non-responsive (AhdAhd) fetuses, were given i.p. doses of the carcinogen 3-methylcholanthrene (MC) ranging from 5 to 175 mg/kg on gestation day 17. At 10 months of age the metabolic phenotype of each offspring was determined, and correlated with number of lung and liver tumors. Both male and female AhbAhd (responsive) offspring in most dose groups presented a consistent two- to three-fold higher incidence of lung tumors than did non-responsive AhdAhd littermates. The difference held for offspring of both (C57BL/6 X DBA)F1 and DBA mothers and it was of statistical significance for one or both sexes at most dosage levels. Hepatocellular tumors were also significantly more frequent in responsive male AhbAhd progeny of (C57BL/6 X DBA/2)F1 mothers than in non-responsive AhdAhd littermates. Progeny of the DBA mothers exhibited significantly more liver and lung tumors than did those of the (C57BL/6 X DBA/2)F1 mothers receiving the same dose. These results suggest that in this model system both maternal and fetal genotype for responsiveness to induction of aromatic hydrocarbon metabolism are important factors modulating fetal carcinogenic risk.
Animals↗
[Immunogenicity and safety of hepatitis B virus vaccine (HEPTAVAX-B)].
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Adult↗
Different responses to phenobarbital promotion in the development of gamma-glutamyltranspeptidase-positive foci in the liver of rats initiated with diethylnitrosamine, N-hydroxy-2-acetyl-aminofluorene and aflatoxin B1.
The promoting activities of phenobarbital (PB) on the development of gamma-glutamyl-transpeptidase-positive (gamma-GT+) foci in rat liver with three different initiating agents were compared in a short-term system (8 weeks). Male F344 rats were initiated by a single application of 200 mg/kg of diethylnitrosamine (DEN), 30 mg/kg of N-hydroxy-2-acetylaminofluorene (N-OH-AAF), 1.0 or 0.5 mg/kg of aflatoxin B1 (AFB1) or the vehicles alone. Two weeks after the initiation, animals were placed on a 0.05% PB diet for 6 weeks. Partial hepatectomy was performed at the end of the third week of the experiment. As a positive control, some animals were fed diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) after the initiation. The number and area of gamma-GT+ foci in the liver were quantified. All three initiators showed a summation effect with 3'-Me-DAB on the appearance of gamma-GT+ foci. Promotion by PB, however, was observed only in DEN-initiated rats and not in N-OH-AAF- or AFB1-initiated rats. It is apparent from the present experimental data that the promoting potential of PB on liver carcinogenesis depends on the initiating agent.
Aflatoxin B1↗
Preventive and enhancing effects of retinoids on the development of naturally occurring tumors of skin, prostate gland, and endocrine pancreas in aged male ACI/segHapBR rats.
The effects of dietary retinoids on the development of naturally occurring tumors in retired breeder male ACI/segHapBR rats were investigated. Groups of rats (21-25 mo of age, an age when early neoplasms first appear and tumor incidences are generally low) were fed diets containing 1 of 3 retinoids--all-trans-N-4-(4-hydroxyphenyl)retinamide (4-HPR), 783 mg/kg diet; all-trans-N-(4-pivaloyloxyphenyl)retinamide (4-PPR), 951 mg/kg; or all-trans-4-N-(2-hydroxyethyl)retinamide (2-HER), 687 mg/kg--or control diet for up to 54 weeks (average, 33 wk). Rats were maintained until less than 20% remained and the experiment was terminated. Contributing causes of death were determined, and a complete necropsy was performed for each rat. There was no difference between the retinoid-treated rats and control rats in the average age at death (30-31 mo) or in the average experimental survival time (29-35 wk), in the proportions of tumor-bearing rats (95.6-100%), or in the average number of organs with tumor per rat (2.1-2.5). The incidences of pancreatic islet cell adenoma and skin tumors were significantly different between control and some retinoid-treated groups. 4-PPR and 2-HER significantly enhanced pancreatic islet cell adenoma yields (P less than .025 and 0.05, respectively) whereas 4-HPR significantly inhibited epithelial and connective tissue skin tumor yields (P less than .025). Incidences of skin and prostate tumors were lower than in controls, but not significantly, in rats receiving 4-PPR and 2-HER. Most of the islet cell adenomas were shown, by avidin-biotin-peroxidase complex immunocytochemistry, to be insulinomas. 4-HPR would seem to be the most effective retinoid in the group, inasmuch as it prevented skin tumor development, may have slightly decreased the incidence of prostate tumors, and did not enhance islet cell tumor incidence.
Adenoma, Islet Cell↗
Comparative tumor-promoting activities of phenobarbital, amobarbital, barbital sodium, and barbituric acid on livers and other organs of male F344/NCr rats following initiation with N-nitrosodiethylamine.
Tumor-promoting abilities of four barbiturates, phenobarbital [(PB) CAS: 50-06-6], amobarbital [(AB) CAS: 57-43-2], barbital sodium [(BB) CAS: 144-02-5], and barbituric acid [(BA) CAS: 67-52-7], on the development of neoplasms in livers and other organs of rats following initiation with N-nitrosodiethylamine [(DENA) CAS: 55-18-5] were compared. Four-week-old F344/NCr male rats were given a single ip injection of 75 mg DENA/kg body weight. Beginning 2 weeks later, they were given either tap water (group 1) or drinking water containing 500 ppm of PB (group 2), the sodium salt of BB (group 3), AB (group 4), or BA (group 5) for the remaining experimental period. Control groups (groups 6-10) received an ip injection of saline alone and 2 weeks later were given either tap water or drinking water containing barbiturates as listed above. Animals were sacrificed at either 52 weeks or 78 weeks. None of the barbiturates altered the growth and survival of animals. PB and BB increased liver weights and significantly enhanced the development of hepatocellular foci and hepatocellular adenomas at 52 weeks and hepatocellular foci, hepatocellular adenomas, and trabecular carcinomas at 78 weeks in DENA-treated rats. No such enhancing effects were observed with AB or BA. PB or BB did not significantly enhance the incidence of nonhepatic tumors at 52 weeks. However, at 78 weeks BB significantly enhanced the development of renal tubular adenomas and carcinomas, while PB enhanced the development of thyroid follicular cell neoplasms in DENA-treated rats. These results clearly showed that barbiturates exhibited structure-promoting activity relationships and that their promoting abilities were not restricted to liver alone. Substitution of both hydrogen atoms at the C-5 position of the pyrimidine ring by alkyl or aryl groups appears to be essential but not sufficient for tumor-promoting activity of barbiturates.
Amobarbital↗
N-Nitroso-N-methylurea initiation in multiple tissues for organ-specific tumor promotion in rats by phenobarbital.
Effects of phenobarbital [(PB) CAS: 50-06-6], a systemic tumor promoter, on carcinogenesis initiated by the broad-spectrum carcinogen N-nitroso-N-methylurea [(NMU) CAS: 684-93-5] were investigated in F344/NCr rats. Single and divided doses of NMU were evaluated for this purpose in 4-week-old rats of both sexes. Rats received iv injections of either 0.2 mmol NMU/kg (body wt) once or 0.05 mmol NMU/kg (body wt) for 4 weeks (1 injection/wk), followed by or concurrently with PB (0.05% in drinking water) that was continued until the termination of the experiment. Half the rats were killed at 52 weeks and survivors at 80 weeks. At 52 weeks, PB given subsequent to NMU or concurrently with divided doses of NMU significantly enhanced the incidence of thyroid follicular tumors only in male rats. This sex difference in thyroid tumorigenesis was somewhat less pronounced in animals killed at 80 weeks. Only 1 liver cell adenoma occurred in males and none in females given NMU alone. PB given concurrently with divided doses of NMU enhanced the yield of hepatocellular foci/cm2 but had no significant effect on hepatic tumor development. Subsequent exposure to PB, however, significantly promoted hepatocarcinogenesis in rats of both sexes given NMU in divided doses; 50% of males and 40% of females given NMU (0.05 mmol/kg, administered four times) followed by PB had hepatocellular adenomas and carcinomas by 80 weeks. PB did not affect the incidence of any other kind of neoplasms seen in NMU-initiated or control rats. These lesions included squamous cell neoplasms of the skin, oropharynx, and forestomach; nonsquamous epithelial tumors of mammary gland, pituitary body, intestinal mucosa, and urinary bladder; tumors of the central and peripheral nervous system; and mesenchymal tumors of the kidney. A sequence of multiple low doses of NMU appeared to be a convenient and useful systemic, multitissue, tumor-initiation regimen for systematic investigation of organ-specific tumor promotion in rats.
Animals↗
Immunocytochemical and morphological evidence for the origin of N-nitrosomethylurea-induced and naturally occurring primary lung tumors in F344/NCr rats.
Naturally occurring and N-nitrosomethylurea-induced lung tumors were studied in male F344/NCr rats by sequential histological, electron microscopic, and immunohistochemical methods. Rats were given one injection at 6 weeks of age of N-nitrosomethylurea at a dosage level of 41.2 mg/kg body weight i.v. Groups of rats were sacrificed at 20, 33, and 52 weeks, while some were sacrificed while moribund. Nine lung tumors from aged F344/NCr male rats were also studied. For determining localization of pulmonary antigens, sections of lungs were stained by the avidin-biotin-peroxidase complex immunocytochemical technique using antibodies to rat surfactant apoprotein or rat Clara cell antigen. At 20 weeks, in rats receiving N-nitrosomethylurea, focal alveolar type II cell hyperplasia, adenoma in focal alveolar type II cell hyperplasia, and adenoma were found in 15 (100%), 1 (7%), and 2 (13%) of 15 rats, respectively. At 33 weeks, there were 19 rats (95%) with focal alveolar type II cell hyperplasias, 10 rats (50%) with adenoma in focal alveolar type II cell hyperplasia, and 2 rats (10%) with adenomas in 20 rats. In 53 rats allowed to live up to 52 weeks, there were 10 (19%) adenomas and 3 (6%) carcinomas, as well as 49 (92%) rats with focal hyperplasia and 31 (58%) with adenomas in focal type II cell hyperplasia. Rat surfactant apoprotein was found in the cytoplasm of normal alveolar type II cells and the majority of cells in focal alveolar type II cell hyperplasias, adenomas in hyperplastic lesions, adenomas, and carcinomas. The ultrastructure of these lesions supported immunocytochemical findings with evidence of lamellar bodies. All nine naturally occurring lung tumors studied contained rat surfactant apoprotein. Rat Clara cell antigen was found, however, only focally within one adenoma induced by N-nitrosomethylurea and one adenoma in a hyperplastic lesion, and also focally in three neoplasms which occurred naturally. This study provided morphological, immunohistochemical, and ultrastructural evidence that the vast majority of N-nitrosomethylurea-induced and naturally occurring pulmonary neoplasms of F344 rats are alveolar type II cell adenomas and carcinomas and that a portion of these tumors arise within focal alveolar type II cell hyperplasias.
Animals↗
Comparative histogenesis and pathology of naturally-occurring human and experimentally induced large bowel cancer in the rat.
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Adenocarcinoma↗
Oncocytoma of the ovary: light and electron microscopic study.
An oncocytoma of the right ovary in a 22-year-old Japanese woman was examined by light and electron microscopy. The tumor was composed of oxyphilic cells with a granular cytoplasm. Electron microscopic studies revealed mitochondrial hyperplasia, a characteristic feature of the oncocyte . This may be the first report of an oncocytoma in the ovary.
Adenoma↗
Di(2-ethylhexyl)phthalate but not phenobarbital promotes N-nitrosodiethylamine-initiated hepatocellular proliferative lesions after short-term exposure in male B6C3F1 mice.
The differential effects of short- or long-term exposure to the liver tumor promoters di(2-ethylhexyl)phthalate (DEHP) or phenobarbital (PB) were studied in male B6C3F1 mice. Mice were injected intraperitoneally (i.p.) at 4 weeks of age with N-nitrosodiethylamine (DEN) at a dosage of 80 mg/kg. At 5 weeks of age, the mice were fed diets containing PB or DEHP for periods of from 1 to 168 days and killed at 168 or 252 days. When DEHP was fed at a dietary level of 3000 ppm for 28, 84, or 168 days, or PB was fed in the water at 500 ppm for 168 days, there were significantly increased incidences of mice with focal hepatocellular proliferative lesions (FHPL) as compared with those in mice receiving DEN alone. There was no significant promotion of FHPL when DEHP was fed for 1 or 7 days or when PB was fed for 1, 7, 28, or 84 days. Thus, DEHP was an effective promoter after only 28, 84, or 168 days exposure whereas PB required 168 days of continuous exposure for a promotive effect to be evident.
Animals↗
Inhibition by phenobarbital and lack of effect of amobarbital on the development of liver tumors induced by N-nitrosodiethylamine in juvenile B6C3F1 mice.
The effects of phenobarbital (PB) and amobarbital (AB) on the rate of development of hepatocarcinogenesis induced by N-nitrosodiethylamine (DEN) were studied in mice. Groups of 40 B6C3F1 male mice were injected i.p. at 15 days of age with 5 micrograms DEN/g body wt. Beginning at 4 weeks of age, DEN treated groups were given either normal drinking water or water containing either 0.05% PB or AB for up to 36 weeks. DEN alone induced multiple focal hepatic lesions including hepatocellular foci, hepatocellular adenomas and trabecular carcinomas. Subsequent exposure to PB had a suppressing effect on DEN-induced hepatocarcinogenesis. Hepatocellular foci in PB-exposed mice were significantly smaller in size (area) and fewer in number throughout the study. Also, PB treatment either prolonged the latency period or significantly slowed the rate at which hepatocellular tumors developed in these mice. No such effects were seen in AB-exposed mice; AB neither inhibited nor promoted the development of focal hepatic lesions in DEN-pretreated mice. Possible mechanisms responsible for the inhibition of DEN-induced hepatocarcinogenesis include the feminizing effects of perinatal administration of PB.
Adenocarcinoma↗
Three-dimensional observations by scanning electron microscopy on the blood supply and organization of vasculature during hepatocarcinogenesis in rats.
Three-dimensional vascular changes in rats during hepatocarcinogenesis were studied by stereoscopic and scanning electron microscopic observation of vascular casts of sinusoids by injecting resin from hepatic artery (red color) and portal vein (blue color). Neoplastic lesions were synchronously induced by injection of diethylnitrosamine (DENA) followed by feeding of 2-acetylaminofluorene (2-AAF) plus partial hepatectomy, then periodically killed for examination. At 6 weeks after DENA injection sinusoids of hyperplastic foci (HF) were filled with blue resin similar to surrounding tissue, then at 8 weeks some HF and hyperplastic nodules (HN) took up red resin leaving surrounding sinusoids blue. At 12 to 18 weeks, red HN became more discrete with obvious compression of surroundings but decreased their number whereas blue HN were not. Red HN had incomplete anastomosing sinusoids giving a coral-like appearance. Spongy or cystic areas contained little or no resin, suggesting ischemic condition. Hepatocellular carcinomas (HCC) at 40 weeks took exclusively arterial red resin forming irregularly shaped anastomosing sinusoids. These findings indicate that acquisition of arterial blood supply by HF may relate to their further development to persistent HN and HCC.
2-Acetylaminofluorene↗
Promotion of 2-(ethylnitrosamino)ethanol-induced renal carcinogenesis in rats by nephrotoxic compounds: positive responses with folic acid, basic lead acetate, and N-(3,5-dichlorophenyl)succinimide but not with 2,3-dibromo-1-propanol phosphate.
The promoting effects of nephrotoxic chemicals, folic acid (FA), N-(3,5-dichlorophenyl)succinimide (NDPS), 2,3-dibromo-1-propanol phosphate (Tris-BP), and basic lead acetate (LAB), on 2-(ethylnitrosamino)ethanol (EHEN)-induced renal carcinogenesis were examined in F344 rats. The rats were treated with 0.1% EHEN in their drinking water for 1 week and then given one of the nephrotoxic chemicals for 35 weeks. FA was injected sc once a week at a dose of 300 mg/kg for the first 8 weeks and thereafter at 100 mg/kg. NDPS, Tris-BP, and LAB were mixed in the diet at concentrations of 0.5, 0.01, and 0.1%, respectively. At week 3 the right kidney was removed to enhance renal neoplasia. Renal cell tumor incidence was significantly increased by both FA and LAB and was slightly increased by NDPS, whereas Tris-BP had no effect. The data show that FA, LAB, and NDPS are promoters of EHEN-induced renal carcinogenesis.
Animals↗
A sequential study of methapyrilene hydrochloride-induced liver carcinogenesis in male F344 rats.
Methapyrilene hydrochloride [2-[2-(dimethylamino)-ethyl)-2-thenylamino)pyridine monohydrochloride (CAS: 135-23-9)]-induced hepatocarcinogenesis was studied in male F344/NCr rats by sequential histologic, histochemical, and biologic methods. Methapyrilene hydrochloride was administered in the feed to rats at a concentration of 1,000 ppm for periods up to 89 weeks. Groups of rats were killed after 5, 10, 15, 29, 40, or 73 weeks of ingesting the carcinogen. Another group was allowed to live out their life-span. Hepatocellular eosinophilic foci and adenomas were seen after 10 and 15 weeks, respectively. Basophilic foci and adenomas were found after 29 and 40 weeks, respectively. Hepatocellular carcinomas developed in 5 of 10 rats at week 40, in 3 of 5 rats at week 73, and in 19 of 19 rats that lived out their life-span. Carcinomas arose within adenomas or as small in situ carcinomas. The histologic types included trabecular, adenocarcinoma, mixed, and solid poorly differentiated hepatocellular carcinomas. Eleven of the mixed and solid poorly differentiated carcinomas metastasized to the lung. Solid poorly differentiated hepatocellular carcinomas grew upon transplantation to the mammary fat pad of weanling F344 rats. Cholangiocarcinomas were found in 7 of 19 rats only in the life-span group. Mucous cholangiofibrosis was seen in all rats after 15 weeks. With the use of Regaud's mitochondrial stain, an increased cellular density of mitochondria was seen in some hepatocytes of peripheral and central lobular areas and in some hepatocellular carcinoma cells, but not in cells in many of the adenomas and foci. Cellular alpha-fetoprotein was found by immunoperoxidase staining in portions of hepatocellular carcinomas, but not in foci, adenomas, and nonneoplastic areas. The majority of hepatocytes in foci, adenomas, and hepatocellular carcinomas contained gamma-glutamyl transpeptidase. The findings suggest that multiple pathways may be followed in the development of methapyrilene-induced liver cancer that are similar to those found in rats exposed to many other hepatic carcinogens.
Aminopyridines↗