Biomedical subjects

A Maekawa

Publications and source records attributed to A Maekawa.

At least 19 recordsLinked to original sources

PubMed1992

Promoting effects of 6-mercaptopurine on carcinogenesis in various organs of F344 rats.

Possible promoting effects of 6-mercaptopurine (6-MP) on carcinogenesis in various organs, including the hematopoietic system, were investigated in female F344 rats, using a 2-stage carcinogenesis model. 6-MP was given as a dietary supplement (50 ppm) for 35 weeks subsequent to wide-spectrum initiation with N-ethyl-N-nitrosourea (ENU). Various tumors were observed in the carcinogen-initiated groups. No significant influence of 6-MP on their development, including the occurrence of leukemia, was apparent. However, the incidences of some proliferative lesions in the lung, intestine and kidney were slightly higher in the ENU/6-MP group than the ENU group. Further studies may be needed on promoting effects of 6-MP, based on dose-effect relation using several 6-MP doses and/or other initiators.

Animals↗

PubMed1992

Selective mutation of codons 204 and 213 of the p53 gene in rat tumors induced by alkylating N-nitroso compounds.

Kidney and esophageal tumors induced by alkylating N-nitroso compounds in rats contain a high incidence (75-100%) of G----A transition mutations in the p53 gene. These are almost selectively (89%) located in the first base of codon 204 and the second base of 213, leading to amino acid substitutions Glu----Lys and Arg----Gln, respectively. In contrast to human neoplasms, a considerable fraction of rat kidney and esophageal tumors carries multiple p53 mutations. All nephroblastomas induced by transplacental exposure to N-nitrosoethylurea and 56% of esophageal tumors induced by N-nitrosomethylurea showed double mutations in codons 204 and 213 of exon 6. The selective targeting of p53 codons by alkylating nitrosamines may provide a basis for molecular epidemiological studies on this class of chemical carcinogens.

Acylation↗

PubMed1992

Neurochemical and histological analysis of motor dysfunction observed in rats with methylnitrosourea-induced experimental cerebellar hypoplasia.

Histological and neurochemical changes related to motor dysfunction observed in rats after neonatal treatment with nitrosoureas were examined. Neonatal rats received subcutaneous injections of methylnitrosourea (MNU: 0.125 mmol/kg, s.c.) or ethylnitrosourea (ENU: 0.25 mmol/kg, s.c.) daily at 4,5,6 and 7 days post partum, a period of cerebellar granule cell, stellate cell and basket cell formation. At 14 days and 45 days after birth, MNU-treated rats displayed a lowering in motor coordination skills measured by tests of retainment ability on a rod of 26 mm diameter, chinning-climbing ability on parallel rods or retainment ability on a rotating rod. Histological examination at 14 days after birth showed a cerebellar hypoplasia with reduced cellularity of the internal granule cell layer and a disperse disposition of Purkinje cells in the granule cell layer. Cerebellar growth and cerebellar content and concentration of DNA were remarkably reduced in the MNU-treated rat. The degree of the reduction in cerebellar content of glutamic acid paralleled the degree of the cerebellar hypoplasia at 14 and 45 days after birth. In contrast, the concentrations of gamma-aminobutyric acid, acetylcholine, 5-hydroxytryptamine and norepinephrine were significantly increased by MNU treatment. ENU treatment control did not exert any significant changes in the neurotransmitters and motor coordination. These results suggest that the motor dysfunctions observed in MNU treated rats are induced by unbalanced output activities from Purkinje cells to motor neurons.

Acetylcholine↗

PubMed1992

Toxicity to rats of methanol-fueled engine exhaust inhaled continuously for 28 days.

Fischer 344 rats were exposed to three concentrations of exhaust generated by an M85 methanol-fueled engine (methanol with 15% gasoline) without catalyst for 8 h/d, 7 d/wk for 7, 14, 21, or 28 d. Concentration- and time-dependent yellowing of the fur was prominent in all treated groups. Concentration-dependent increases in the erythrocyte count, hematocrit, hemoglobin concentration, formaldehyde in plasma, and carboxyhemoglobin in the erythrocytes, and decrease in serum alkaline phosphatase activity were seen after all exposure periods. Histopathologically, lesions were found in the nasal cavity and lungs after 7 d of exposure. Squamous metaplasia of the respiratory epithelium of level 1 (level of the posterior edge of the upper incisor teeth) lining of the nasoturbinate and/or maxilloturbinate and infiltration of neutrophils into the submucosa, and decreases of Clara cells in the terminal bronchiolus and of cilia in the bronchiolar epithelium, were observed in the high-concentration group (carbon monoxide, 94 ppm; formaldehyde, 6.9 ppm; methanol, 17.9 ppm; nitrogen oxides, 52.7 ppm; nitrogen dioxide, 10.6 ppm). The histopathological extents of several lesions increased slightly with the exposure time. Slight squamous metaplasia and hyperplasia of the respiratory epithelium at level 1 were also observed in the medium-concentration group (one in three of the high-concentration group). No histopathological changes were found in the olfactory epithelium of the nasal cavity. In the low-concentration group (one in nine of the high-concentration group), no marked histopathological changes in these organs were observed. These results may suggest that the lesions observed in the nasal cavity of rats exposed to methanol-fueled engine exhaust were mainly caused by formaldehyde, although other components in the exhaust also may have affected nasal cavity and/or lungs to less extent.

Alkaline Phosphatase↗

PubMed1992

Correlation between cataract and retinopathy due to lighting in F344 rats used in a long-term carcinogenicity study.

Correlations between light intensity of animal room lighting and both cataract and retinopathy of rats were examined, and relationships between the cataract and the retinopathy were further investigated. Seventy-nine male rats and 106 female rats surviving to the end of a 2-yr carcinogenicity study of monosodium succinate were used in this investigation. Animals were housed in polycarbonate cages, each containing 4 rats, with wire lids and hardwood chips for bedding and with a 12-h light/dark cycle. Individual groups comprising 13 cages were inserted into 3 by 5 cage hanging type racks. Light intensity was measured at the bottom (on the bedding) of individual cages. Statistically, both the incidence of cataracts and the severity of retinopathy were closely related to light intensity. The incidence of cataracts in males was significantly higher than that in females, while no sex difference was observed for the severity of retinopathy. Meanwhile, no differences in either the incidence of cataracts or the severity of retinopathy were observed between the monosodium succinate-treated and control groups and between the right and left eyes. While the occurrences of retinopathy and cataract were strongly associated, our results indicated that retinopathy occurs more frequently than cataracts, and thus the retina appeared to be more sensitive to the effects of lighting.

Animals↗

PubMed1992

Threshold dose dependence in phenobarbital promotion of rat hepatocarcinogenesis initiated by diethylnitrosamine.

The dose-response of phenobarbital (PB) promotion of hepatocarcinogenesis in rats was investigated. Male F344 rats were given 1, 4, 16, 75, 300 or 1200 p.p.m. PB solutions given ad libitum as their drinking water for 39 weeks following initiation with a single i.p. injection of diethylnitrosamine (DEN) (100 mg/kg). At week 40, the incidence of hepatic tumors was increased clearly in the DEN + PB groups given 300 p.p.m. PB or above, as compared to that in the group given DEN only. Linear dose-response curves for numbers and sizes of enzyme-altered hepatic foci (gamma-glutamyl-transpeptidase or placental glutathione S-transferase positive foci) were obtained in the dose range 16-1200 p.p.m. PB. The minimum promoting dose level of PB for enzyme-altered foci, estimated from dose-response curves by the Logit model, was calculated to be 15-23 p.p.m. Thus while dose dependence was demonstrated over a large range, a threshold was evident at low doses.

Animals↗

PubMed1992

High susceptibility of analbuminemic rats to neurogenic tumor induction by transplacental administration of N-ethyl-N-nitrosourea.

The susceptibilities of Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR) to N-ethyl-N-nitrosourea (ENU) were compared. In Experiment I, the rats were given daily subcutaneous injections of 10 mg/kg of ENU for a week from 4 weeks of age. In Experiment II, mother rats were given a single subcutaneous injection of 60 mg/kg of ENU on day 17 of pregnancy and tumor development in their offspring was examined. In Experiment I, the incidence of neurogenic tumors was slightly, but not significantly, higher in NAR than in control rats. In Experiment II, the incidence of total tumors including neurogenic tumors was significantly higher in NAR (40/43, 93.0%) than in SDR (13/61, 21.3%). NAR showed particularly high susceptibility to induction of neurogenic tumors (34/43, 79.1%) and renal tumors (15/43, 34.9%). In an attempt to elucidate the underlying mechanisms of the increased susceptibility of NAR to ENU, O6-ethylguanine, a major premutagenic ethylated DNA adduct, was quantitated in fetal brain DNA of NAR and SDR after a pulse exposure to 60 mg/kg ENU. No significant difference in the initial formation or subsequent repair of O6-ethylguanine was observed in the two strains, indicating that abnormality at some later stage(s) of chemical carcinogenesis may lead to the increased susceptibility of NAR to induction of neurogenic tumors.

Animals↗

PubMed1992

Tumor-promoting effects of both iodine deficiency and iodine excess in the rat thyroid.

Thyroid tumor-promoting effects of iodine deficiency and iodine excess were investigated in a rodent 2-stage model to estimate an optimal iodine intake range that would not effectively promote development of thyroid neoplasia. Six-week-old male F344 rats were given a single subcutaneous injection of 2,800 mg/kg body weight N-bis(2-hydroxypropyl)-nitrosamine (DHPN) or saline vehicle, maintained on Remington's iodine-deficient diet (21 +/- 2 ng/g iodide), and supplemented with various amounts of potassium iodide up to 260 mg/liter in drinking water to generate conditions ranging from severe iodine deficiency to severe iodine excess. In DHPN-treated rats, both conditions significantly increased thyroid follicular tumorigenesis. In DHPN-untreated rats, iodine deficiency produced diffuse thyroid hyperplasia, characterized by small follicles with tall epithelium and reduced colloid, together with a decrease in thyroxine (T4) and an increase in thyroid-stimulating hormone (TSH). On the other hand, iodine excess produced colloid goiter, characterized by large follicles with flat epithelium and abundant colloid admixed with normal or small-sized follicles lined by epithelium of normal height, together with normal serum T4 and slightly decreased TSH. These effects were directly proportional to the severity of iodine deficiency or extent of iodine excess and suggest that each condition has a different thyroid tumor promotion mechanism. Iodine intakes that showed the least tumor promotion were 2.6 and 9.7 micrograms/rat/day in this study. Promoting mechanisms and the problem of statistically estimating recommended daily iodine intake range are briefly discussed.

Animals↗

PubMed1992

Effects of vitamin B12-deficiency on testes tissue in rats.

The state of vitamin B12-deficiency in rats was evaluated by determination of hepatic vitamin B12-dependent enzyme activities after the animals had fed on a vitamin B12-deficient soybean protein diet for 150 days. The effect of vitamin B12-deficiency on testicular tissue was also studied by morphological observations. Growth of vitamin B12-deficient rats was retarded and marked increase in urinary methylmalonic acid was observed. Vitamin B12 contents in the organs were depressed distinctly by the deficiency, especially in testes, vitamin B12 content decreased to 2.5 ng/g. Hepatic methionine synthase and methylmalonyl-CoA mutase activities showed striking depression to 5% of the control rats and extreme vitamin B12-deficiency was confirmed. Testes weight also showed marked decrease together with their relative weight per 100 g body weight. Morphological observations of testes of vitamin B12-deficient rats revealed atrophy of the seminiferous tubules and aplasia of sperms and spermatids. The above results proved that vitamin B12-deficiency affected rat testes, and suggested that the rat could be the animal model for elucidation of the mechanism of B12 action on testicular functions.

Animals↗

PubMed1992

[Twenty-eight day repeated dose toxicity test of dihepthyl phthalate in F344 rats].

A twenty-eight day repeated oral dose toxicity test of dihepthyl phthalate (DHP) was carried out in male and female F344 rats at the dose levels of 0, 0.2, 1 and 5 g/kg/day. All rats in each group, consisting of 5 males and 5 females, received a daily intragastric administration of DHP for 28 days. Additional two groups of animals exposed to dose levels of 0 and 5 g/kg were used for investigation of subsequent recovery for 2 weeks. No animals died during the administration period. Inhibition of body weight gain was observed in both sexes of the 5 g/kg group. Blood biochemistry revealed significant increases in albumin and A/G ratio in males of the groups treated with 0.2 g/kg or more, and in albumin and total protein in females treated with 1 g/kg or more. In the 5 g/kg group, BUN, GOT, GPT, ALP and Zn was increased in males, and GOT in females. The increases in GOT, GPT and ALP were also observed in males of the 1 g/kg group. Increases in liver and kidney weights were noted in both sexes treated with 1 g/kg or more and in males of the 5 g/kg group, respectively. Testicular weight was decreased in the 5 g/kg group. On histopathological examination, swelling and necrosis of hepatocytes were found in males of the 1 and 5 g/kg groups. Males of the 5 g/kg group showed atrophy of the seminiferous tubules accompanied with loss of spermatogenesis. In the recovery group, similar changes were detected in the testis, but some of the seminiferous tubules showed slight regenerative changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Age-dependent induction of thymic lymphomas by N-propyl-N-nitrosourea in the F344/DuCrj rat.

N-Propyl-N-nitrosourea (PNU) is one of the most potent thymic-lymphomagenic agents in rats. Our previous experiments strongly suggested that leukemogenic viruses were not the cause of thymic lymphomas in rats and that target cells of PNU exist in the thymus but not in the bone marrow. On the other hand, the role of retrovirus in lymphomagenesis is undeniable in mice. Therefore, chemically induced rat thymic lymphoma provides a good model to analyse lymphomagenesis without viral implications. In the present experiment 1, we investigated the relationship between the age of animal at commencement of PNU treatment and the incidence of thymic lymphomas. Incidences of thymic lymphomas were 100, 100, 80 and 18, and average latent periods were 15.1, 18.7, 25.4 and 27.3 weeks after the start of PNU-treatment, in 5-, 10-, 20- and 40-week-old groups, respectively. In experiment 2, rats were sacrificed postnatally at 5, 10, 20, 30 and 40 weeks each, and thymus weight, number of thymocytes in the thymus, frequency of mitosis, and percentage of OX-7 (Thy 1.1), OX-8 (CD8), or W3/25 (CD4) positive cells, were examined cytologically. Thymus weight, number of cells in the thymus and mitotic index were maximum at 10 weeks old, and thereafter decreased gradually. No marked changes were observed in the ratio of each cell-surface marker positive cell. These results indicate that induction of thymic lymphomas by PNU is very closely related with the total number of mitotic cells in the thymus. Thus, chemical induction of rat thymic lymphoma reflects an age-dependent function of the thymus.

Age Factors↗

PubMed1991

Long-term toxicity/carcinogenicity study of calcium lactate in F344 rats.

The long-term toxicity/carcinogenicity of calcium lactate, a food additive, was examined in F344 rats. Calcium lactate was given ad lib. in the drinking-water at levels of 0, 2.5 or 5% to groups of 50 male and 50 female rats for two years. No clear toxic lesion was specifically caused by long-term administration of calcium lactate. No significant dose-related increase was found in the incidences of tumours in any organ or tissue. The results indicated that calcium lactate had neither toxic nor carcinogenic activity in F344 rats.

Animals↗

PubMed1991

A fact database for toxicological data at the National Institute of Hygienic Sciences, Japan.

The computerized fact database for the toxicity data of chemicals was constructed at the National Institute of Hygienic Sciences, Tokyo, Japan (biological database, BL-DB). The BL-DB stores data on mutagenicity, teratogenicity, carcinogenicity, and other toxicological tests of chemicals that appeared in the scientific literature. The BL-DB includes information about chemical identification, test system, results of the assays, and a bibliography. The system consists of five modules: data collection, data maintenance, data search, data downloading, and backup. ADABAS is used as a core database management system. Many kinds of test data are stored with the same formats; therefore, users can retrieve data of different toxicological data by the same manner. A user of the BL-DB can use about 50 kinds of commands to interact with the system, and the majority of fields are defined as search fields, thereby facilitating retrieval of target data through many ways. Currently, there are mainly data for the mutagenicity, especially on the Salmonella/microsome assay and the rodent micronucleus assay. These data can be retrieved and used for structure-activity relationship studies.

Abnormalities, Drug-Induced↗

PubMed1991

[Dose-response relationship of promotion by phenobarbital in rat two-stage hepatocarcinogenesis].

Investigation of the effect of various doses of phenobarbital (PB) in Experiment I (PB dose levels: 0, 38, 75, 150, 300 or 600 ppm) and Experiment II (PB dose levels: 0, 1, 4 or 16 ppm) given to male F344 rats (20 animals/group) in drinking water for 39 weeks after a single intraperitoneal injection of diethylnitrosamine (DEN) was performed using incidence of hepatic tumors and number or area of enzyme-altered foci as end-point lesions. There were no significant differences in the final body weight changes between DEN-initiated PB treatment (DEN+PB) and DEN-initiated (DEN) groups. Dose-dependent increases in the absolute and relative liver weights and in the incidence of hepatic carcinoma were found in the DEN+PB groups treated with 38 ppm PB or above 75 ppm PB or above, respectively. The numbers or areas of gamma-GTP or GST-P positive foci of the liver were increased in the DEN+PB groups treated with 38 ppm PB or above. Additional investigation of 7-ethoxycoumarin o-deethylase (7-ECDE) induction in Experiment III, 7 groups consisting of 3 animals/group being fed water containing PB (0, 1, 4, 16, 75, 300 or 1200 ppm) for 1 week after the initiation of DEN and a further 7 groups (5 rats/group) receiving the same drinking water without DEN treatment, revealed dose-dependent increases of 7-ECDE in the DEN+PB groups and PB groups treated with 16 ppm PB or above. The present studies indicate that the threshold for promotion by PB is 38 ppm.

Administration, Oral↗

PubMed1991

[Subchronic oral toxicity study of cyanoguanidine in F344 rats].

A 13-week subchronic oral toxicity study of cyanoguanidine was performed in male and female F344 rats by feeding of CRF1 powder diets containing 0, 1.25, 2.5, 5 and 10% cyanoguanidine to determine appropriate dose levels for a subsequent 2-year carcinogenicity study. The rats were randomly allocated to 5 groups, each consisting of 10 males and 10 females. No animals died during the administration period. Inhibition of body weight gain was more marked in both sexes of the 10% group and in females of the 5% group as compared with the control group. Mean food intake in males of the groups treated with 5% or 10% and in females of the 10% group was significantly higher than that in the control group. Serum biochemical investigation revealed a higher level of serum BUN in both sexes of the 10% group. On histopathological examination, toxic changes characterized by the occurrence of intranuclear eosinophilic inclusion bodies in the proximal tubular epithelium of the kidney were observed in both sexes of the 10% group. Similar inclusion bodies were also seen in 2 out of 10 males of the 5% group. From these results, it was concluded that a level of 10% of cyanoguanidine in the diet is unequivocally toxic. A dose level, 5% cyanoguanidine, in the diet might be appropriate as a high dose for a carcinogenicity study.

Administration, Oral↗

PubMed1991

[Twenty-eight day repeated dose toxicity test of m-nitroaniline in F344 rats].

A twenty-eight day repeated oral dose toxicity test of m-nitroaniline (m-NA) was carried out in male and female F344 rats at dose levels of 0, 15, 50 or 170 mg/kg/day. Animals of both sexes were divided into 6 groups, each consisting of 30 animals, 4 groups being used for the 28 days dosing study and the remainder for investigation of subsequent recovery. Inhibition of body weight gain, and induction of cyanosis and methemoglobinemia were observed in the highest dose groups of both sexes, but there were no animal mortalities. Testicular atrophy was evident but there was no effect on the ovaries in the same group. In addition to these findings, hemolytic anemia and increases of liver, spleen and kidney weights were also observed in both sexes in a dose-related fashion. Histologically, the highest dose group showed reduction of spermatogenesis with multinucleated giant cell formation, lipofuscin deposition mainly in the proximal renal tubules, and increases in hemosiderin deposition and extramedullary hematopoiesis in the liver. Dose-related increases in the incidence of hemosiderin deposition in the spleen, erythroid hyperplasia in the bone marrow and swelling of hepatocytes were observed in treated groups. After a 14 day recovery period, these findings were attenuated or had disappeared. Based on these results obtained under the present experimental conditions, it was concluded that m-NA induces hemolytic anemia and exerts testicular toxicity in rats and that the non-observed-effect level of m-NA is less than 15 mg/kg/day.

Administration, Oral↗

PubMed1990

Two-year carcinogenicity study of 6-mercaptopurine in F344 rats.

The carcinogenicity of 6-mercaptopurine (6-MP), an anticancer drug, was examined in F344 rats of both sexes, administered the chemical at dietary levels of 0 (control), 25 ppm or 50 ppm for 2 years. Many tumors developed in all groups including the control group, the organ distribution and histological types being similar to those reported for spontaneous lesions. In males, there was no significant increase in the incidence of any tumor in the treated groups over that in the control group. In females, however, positive trends were noted in the occurrence of C-cell tumors, pheochromocytomas, uterine adenocarcinomas and gliomas, and the incidences of C-cell tumors and pheochromocytomas in the 50 ppm group were significantly higher than the values in the respective control group. In addition, the total numbers of malignant tumors increased significantly in the female 50 ppm group. However, most of the tumors demonstrating increase are frequently observed spontaneous lesions in this strain of rats, and their incidences in the present female control group were lower than in our historical data. In addition, there were no significant differences in the incidences of preneoplastic changes and induction times for the above-listed tumors between the female control and the 50 ppm groups. These results thus indicated that while the carcinogenic potential of 6-MP can not be precluded, it can be only very weak or marginal, after continuous administration in the diet at the 50 ppm level for 2 years. The leukemogenic action of 6-MP was negative under the present experimental conditions.

Animals↗

PubMed1990

Spontaneous uterine adenocarcinomas in aged rats and their relation to endocrine imbalance.

In addition to spontaneous uterine endometrial adenocarcinomas at a high incidence (35.1%), development of endometrial hyperplasia/adenoma was also frequently detected in rats of the Donryu strain. The total yield of all observed proliferative endometrial lesions was very high (60.6%). The tumors arose commonly in the uterine horn of aged rats. Histologically, most demonstrated glandular structures, consisting of cuboidal or columnar cells with weak eosinophilic or basophilic cytoplasm and large nuclei. In about half of the animals with adenocarcinomas, metastasis to remote organs such as the lung was observed. Histological examination of the ovary and vaginal epithelium revealed ovarian cysts, atrophy of the ovary and cornification of the vaginal epithelium more frequently in rats with endometrial carcinomas than in animals without tumors. These findings indicate that adenocarcinoma development in Donryu rats is associated with endocrine imbalance [increased serum estrogen: progesterone (E2:P)ratios]. By comparative investigation of strain differences, it was confirmed that irregular estrous cycles began earlier with higher incidence in Donryu rats than in F344 rats, a low-incidence strain. Histological findings of the ovary and vaginal epithelium also suggested relatively increased estrogen levels in Donryu rats compared to F344 rats. Estimated plasma values of gonad steroids showed that the E2:P ratio in Donryu rats at 12 months of age was about five times that in F344 rats. These results therefore indicate that hormone imbalance, particularly an increased E2:P ratio, may play an important role in the spontaneous occurrence of endometrial adenocarcinoma in Donryu rats.

Adenocarcinoma↗