Kyoko Furuta

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 Remingtons 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 cpithelium 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 μg/rat/day in this study. Promoting mechanisms and the problem of statistically estimating recommended daily iodine intake range are briefly discussed.

Organ-specific carcinogenicity of N-methyl-N-nitrosourea in F344 and ACI/N rats

SummaryMale and female F344 rats were continuously administered N-methyl-N-nitrosourea (MNU) in their drinking water at concentrations of 200 or 100 ppm, and both sexes of ACI/N rats were given MNU at a concentration of 200 ppm. By the 42nd week of the experiment, high incidences of brain/spinal cord tumors were observed in both strains of rats. Histologically, many of them were astrocytomas or anaplastic astrocytomas. In addition, malignant neurinomas were also detected in the spinal nerve roots and trigeminal nerves, although their incidences were rather low. There was no difference in the type and incidence of these neurogenic tumors between the two strains of rats. Tumors of the tongue and esophagus were mainly observed in the high-dose group of F344 rats and those of the glandular stomach were observed in the low-dose group of F344 rats. In ACI/N rats, tumors of the heart and renal pelvis were detected. The organ-specific carcinogenicity of MNU in these two strains of rats was compared with that of MNU in Donryu rats. It was demonstrated that organ specificity of MNU given orally was influenced not only by the strain of rats but also by the dose level.

The rat urinary bladder as a new target of heterocyclic amine carcinogenicity: tumor induction by 3-amino-1-methyl-5H-pyrido[4,3-b]indole acetate.

In order to examine the carcinogenicity of 3‐amino‐l‐methyl‐5H‐pyrido[4,3‐β]indole acetate (Trp‐P‐2), 30 male and 30 female F344 rats were maintained on diet containing 0, 30, or 100 ppm Trp‐P‐2 for 112 weeks. The overall mean chemical intakes in the 100 ppm and 30 ppm groups were 3.84 and 1.14 mg/kg/day in males, and 4.57 and 1.34 ing/kg/day in females, respectively. Females of the 100 ppm group showed increased mortality in the late period of the study. In the 100 ppm group, significant increases in the incidences of neoplastic lesions were found in the liver, urinary bladder and mammary gland in males, and in the mammary gland, hematopoietic system and clitoral gland in females. Histologically, tumors induced by Trp‐P‐2 were hepatocellular adenomas, transitional cell tumors (papillomas and carcinomas) of the urinary bladder, fibroadenomas/fibromas of the mammary gland, malignant lymphomas and clitoral gland tumors (adenomas and adenocarcinomas). These results indicate multi‐target carcinogenicity of Trp‐P‐2 in F344 rats and provide evidence that the urinary bladder is also a target for heterocyclic amine action.

Glandular Changes Associated with the Spontaneous Interstitial Cell Tumor of the Rat Testes

Testes of untreated F344 and Wistar rats in the control groups of carcinogenicity studies were histologically examined, and the histopathological characteristics and histogenesis of glandular changes in these testes were studied. In 266 testes of 2-year-old F344 rats, 263 had interstitial cell tumors (ICTs) (98.9%) and 39 had glandular changes (14.7%). These glandular changes were also found in 1 out of 38 1-year-old F344 rat testes (2.6%), and 3 in 154 2-year-old Wistar rat testes (1.9%). The changes were observed exclusively in the interstitial cell tumors (ICTs). These glandular changes showed variation in size, shape and number. They were composed of tubules or cysts lined by a layer of cuboidal or columnar epithelial cells, which had terminal bars, occasionally PAS-and alcian blue-positive brush borders, and rarely, alcian blue-positive cytoplasmic vacuoles. Serial sections revealed that the changes were not connected with the rete testes, but with the degenerative seminiferous tubules involved in the ICTs lined by a layer of flat endothelial-like cells. The findings suggest that the lesions constitute metaplastic changes of the Sertoli cells.

Malignant fibrous histiocytomas induced in rats by polymers

SummaryFive polymeric materials (3 polyvinyl chlorides, 1 polyhydroxyethyl methacrylate, and 1 dimethyl polysiloxane) were implanted into subcutaneous (SC) tissues of rats. Subcutaneous tumors developed in all experimental groups. The incidences of the tumors differed however, although the experimental conditions were the same for all these materials. This result indicates that chemical characteristics of the materials may influence the incidence of SC tumors. From the histological and electron-microscopic findings many of these tumors were diagnosed as malignant fibrous histiocytomas.

Induction of Sertoli cell tumors in the rat ovary by N-alkyl-N-nitrosoureas.

SummaryRelatively high incidences of Sertoli cell tumors of the ovary were induced in Donryu rats given a 400 ppm N-ethyl-N-nitrosourea solution as drinking water for 4 weeks or a single dose of 200 mg/kg N-propyl-N-nitrosourea by stomach tube. Typical Sertoli cell tumors were composed of solid areas showing tubular formation. Tubules were lined by tall, columnar cells having abundant, faintly eosinophilic, often vacuolated cytoplasm, and basally oriented round nuclei. In some cases, Sertoli cell tumors were found to be mixed with granulosa cell tumors.

Carcinogenicity of N-alkyl-N-(acetoxymethyl)nitrosamines after subcutaneous injections in F-344 rats

SummaryAs model compounds for metabolically activated N,N-dialkylnitrosamines, five N-alkyl-N-(acetoxymethyl)nitrosamines were synthesized and their carcinogenicy was testet in F-344 rats of both sexes. Compounds used in this study are N-methyl-(MAMN), N-ethyl-(EAMN), N-propyl-(PAMN), N-butyl-(BAMN), and N-isobutyl-N-(acetoxymethyl)nitrosamines (i-BAMN). All chemicals were dissolved in olive oil and rats received 10 weekly subcutaneous injections of these chemicals (10×5 mg MAMN or equimolar amounts of other chemicals) at the interscapular region. Subcutaneous tumors were detected in many rats of all groups treated with the chemicals, although no tumor was detected in the control group. Lung and/or thyroid tumors were also observed in many rats in the experimental groups. The incidence of subcutaneous tumors was highest in EAMN, followed in order by MAMN, PAMN, BAMN, and i-BAMN. On the contrary, the incidence of lung and thyroid tumors was highest in MAMN and decreased as the length of the alkyl chain of the chemicals increased. Histologically, almost all subcutaneous tumors were malignant fibrous histiocytomas. The results indicate that the chemicals possess systemic as well as local carcinogenicity in F-344 rats. The potent carcinogenic effects at the injection site of the α-acetoxy nitrosamines, coupled with their direct mutagenic activity reported previously, support the notion that these derivatives are useful as models for the ultimate form in the metabolic activation of N,N-dialkylnitrosamines.

Induction of tumors in the small intestine and mammary gland of female Donryu rats by continuous oral administration of N-carboxymethyl-N-nitrosourea

SummaryThe carcinogenicity of N-carboxymethyl-N-nitrosourea (CMNU), a naturally occurring N-nitroso compound, was tested in female Donryu rats. Four groups of female Donryu rats were given 400, 200, 100, or 0 ppm of CMNU solution continuously as drinking water. The incidence of tumors was highest and the mean survival time shortest in the 400 ppm group. A dose-effect relationship was observed in the tumor incidence and the mean survival time and the incidences of tumors in all experimental groups were significantly different from those in the control group. In the 400 ppm group, tumors were detected most frequently in the small intestine, followed by the mammary gland. In contrast, most tumors were observed in the mammary gland in the other two experimental groups, although dose-dependent induction of tumors of the small intestine was also detected in these two groups. The organ specificity of CMNU is compared with that of other N-alkyl-N-nitrosourea derivatives.

Induction of digestive-tract tumors in F344 rats by continuous oral administration of N-butyl-N-nitrosourea.

SummaryMale and female F344/DuCrj rats were administered N-butyl-N-nitrosourea at a concentration of 400 ppm in their drinking water. By the 50th week of the experiment, the cumulative incidence of upperdigestive-tract tumors was as high as 35/39 (90%) and 34/39 (87%) in male and female rats, respectively. Among these, esophageal and forestomach tumors occurred most frequently. Except one female rat with fibroma, upper-digestive-tract neoplasms were of the epithelial type—papilloma, squamous-cell carcinoma or adenocarcinoma. In female rats, vaginal tumors were induced in 16 (41%) animals. Ear-duct tumors and hematopoietic neoplasms were also induced in both sexes of rats, with incidence of less than 21%.

Effect of Nocardia rubra cell wall skeleton and/or cyclophosphamide on leukemogenesis induced by N-ethyl-N-nitrosourea in Donryu rats

SummaryThe effect of Nocardia rubra cell wall skeleton (N-CWS) and/or cyclophosphamide (CP) on chemical carcinogenesis was examined in female Donryu rats exposed to N-ethyl-N-nitrosourea (ENU) in the drinking water for 6 weeks. Five administrations of N-CWS following ENU treatment caused a slight prolongation of the average survival of rats but did not reduce the incidence of leukemia. CP given on two occasions after ENU treatment caused a moderate prolongation of average survival period and a moderate reduction of the incidence of leukemia, but significant differences from ENU-treated control group values were not observed after statistical analysis. Combined treatment with N-CWS and CP after ENU treatment caused prolongation of the average survival period of rats and a statistically significant reduction in the incidence of leukemia. The present experiment indicates that combined treatment with N-CWS and CP effectively reduces induction of leukemia by ENU in rats, although other types of tumors were not affected.