thiourea and diisopropanolnitrosamine

In our previous investigation, which focused on two-stage carcinogenicity in the thyroid, rats were administered N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by thiourea (TU) over an experimental period of 19 weeks. Simultaneous treatment with a high level of vitamin A (VA) enhanced the induction of proliferative lesions that originated from the thyroidal follicular epithelium. To examine whether hormone synthesis in the thyroid could be inhibited by simultaneous treatment with a large amount of VA and TU, all of the rats were initially given a single subcutaneous injection of 2,800 mg DHPN/kg followed by a supply of 0% TU + 0% VA (DHPN only, control group), 0.2% TU in their drinking water (DHPN/TU group), 0.1% VA in their diet (DHPN/VA group), or 0.2% TU + 0.1% VA (DHPN/TU + VA group) during an experimental period of 4 weeks. Results obtained indicate that the iodine uptake and organification, namely iodination of tyrosine residue in thyroglobulin, of the thyroid, were significantly decreased in the DHPN/TU group compared to the DHPN control group. The variation in these values was attributable to the inhibitory effect of TU upon thyroid hormone synthesis. Results obtained from the DHPN/TU + VA and DHPN/TU groups were comparable. Therefore, the possibility that modification of hormone synthesis contributes to the enhancing effect of simultaneous treatment with a large amount of VA on thyroidal tumor induction by TU is considered to be very minimal.

Topics: Adenoma; Animals; Body Weight; Bromodeoxyuridine; Carcinogens; Drug Synergism; Hyperplasia; Iodine; Liver; Nitrosamines; Organ Size; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Gland; Thyroid Hormones; Thyroid Neoplasms; Vitamin A

In order to examine modifying effects of simultaneous treatment with large amounts of vitamin A (VA) and thiourea (TU) on the thyroid tumorigenesis in rats, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection), and starting 1 week later received diet containing 0.1% VA (VA group), drinking water containing 0.2% TU (TU group), 0.2% TU + 0.1% VA (TU + VA group) or tap water/basal diet (control group) for 19 weeks. Serum T3 and T4 in the TU and TU + VA groups were significantly decreased as compared to the control group, while serum TSH levels were remarkably increased. The ratios of T3 and T4 decrease and TSH increase in the TU + VA group were remarkably more pronounced than in the TU group. Thyroid neoplastic lesions were only induced in the TU and TU + VA groups. The multiplicity of intracapsular follicular cell proliferative foci in the TU + VA group was significantly increased as compared to the TU group value. Cell proliferation of hypertrophic and subcapsular follicular cells, as well as in hyperplasias, and neoplasias with adenomatous growth pattern was significantly higher in the combined treatment case than after TU alone. In the liver, centrilobular hypertrophy of hepatocytes was seen in the TU and TU + VA groups, this being especially marked in the latter group. In the combined group case the affected cells were strongly positive for GST-P antibody binding. The results of the present study suggest that cell proliferation of thyroid follicular cell proliferative lesions in rats is enhanced by strong TSH stimulation with simultaneous treatment of TU and large amounts of VA.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Cell Division; Drug Synergism; Male; Nitrosamines; Rats; Rats, Inbred F344; Reference Values; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine; Vitamin A

To examine changes in serum TSH and determine whether the sustained excess is necessary for the development and/or progression of thyroid tumors, male F344 rats were administered drinking water containing thiourea (TU), at 0.1 or 0.05%, or sulfadimethoxine (SM), at 0.025 or 0.0125%, for one week in Experiment I. All of the treated animals showed decreased serum levels of T3 and T4 and an increased TSH. In Experiment II, male rats were given a s.c. injection of N-bis(2-hydroxypropyl) nitrosamine (DHPN:1500 mg/kg BW) and, starting one week later, received drinking water containing the same doses of TU or SM as in Experiment I for the following 20 weeks. Thyroid follicular proliferative lesions were induced in most rats treated with TU and SM. However, these treated animals did not demonstrate any consistent alterations in serum T3, T4 and TSH levels, except for the high dose TU group. The present studies thus suggest that thyroid tumors can grow even under conditions of fluctuating serum TSH levels during the progression phase, although TSH stimulation might be an absolute requirement in the early phase of tumor development.

Topics: Animals; Antithyroid Agents; Male; Nitrosamines; Rats; Rats, Inbred F344; Sulfadimethoxine; Thiourea; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine

Time course changes in serum TSH and quantitative data for thyroid proliferative lesions in male F344 rats administered N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2000 mg/kg body weight, single s.c. injection) followed by 0.1% thiourea (TU), were assessed at weeks 1, 2, 4, 8, 12 and 16 of treatment. The serum T4 level in the TU group was markedly decreased at week 1 and remained significantly lowered throughout the experiment. Serum TSH levels, in contrast, were elevated up to a peak at around week 4 with a return to the normal range at week 12. Thyroid weights in the TU group were increased significantly in a treatment period-dependent manner. Histopathologically, marked hypertrophy of thyroid follicular cells occurred at the early stage of TU treatment. Proliferative lesions, such as hyperplasia and adenomas, occurred from weeks 2 and 4, respectively, and increased with the later treatment period. The cell proliferative activity of follicular cells, assessed by BrdU incorporation, was high until week 2, but then returned to normal. The initially appearing hyperplasias and adenomas were characterized by marked proliferation but this also greatly decreased at later stages when TSH was no longer elevated. The results of our study thus suggest that a high serum TSH level plays an important role in the early phase of thyroid tumorigenesis and 8 weeks treatment with test substances is sufficient for detection of thyroid tumor promoter potential in two-stage thyroid carcinogenesis models.

Topics: Adenoma; Animals; Body Weight; Carcinogens; Cell Division; Drug Administration Schedule; Hyperplasia; Male; Nitrosamines; Organ Size; Pituitary Gland; Rats; Rats, Inbred F344; Thiourea; Thyroid Diseases; Thyroid Gland; Thyrotropin; Time Factors

To evaluate the effects of phenobarbital (PB) and thiourea (TU), alone or in combination, on proliferative lesions of the liver, thyroid and lung, male F344 rats initiated with 2000 mg/kg body weight N-bis(2-hydroxypropyl) nitrosamine (DHPN) were given diet and/or drinking water containing 0% PB/TU (group 1), 1000 ppm PB (group 2), 0.1% TU (group 3) and 500 ppm PB and 0.05% TU (group 4), from weeks 2 to 20 for 19 weeks. Group 4 showed remarkable increases in the number of hepatocellular altered foci per animal, the values being superior to the averages of groups 2 and 3. The number of thyroid proliferative lesions per animal was highest in group 3 and lowest in group 2. Lung proliferative lesions were induced in all groups, but no modifying influence on their development was evident in the combined group. The present results indicate that combined administration of PB and TU exerts synergistic enhancing effects on hepatocarcinogenesis.

Topics: Animals; Cell Division; Drug Synergism; Liver; Liver Neoplasms, Experimental; Lung; Male; Nitrosamines; Phenobarbital; Precancerous Conditions; Rats; Rats, Inbred F344; Thiourea; Thyroid Gland

To evaluate the mechanism of the promoting effect of goitrogens on thyroid tumorigenesis, well-known goitrogens having different pharmacologic action, i.e., thiourea, phenobarbital sodium (PB), potassium thiocyanate (KSCN), and 3,4,5,6-tetrachloro-2',4',5',7'-tetraiodo-fluorescein sodium salt (Rose Bengal B, FD&C Red No. 105) (FR105) were administered to the DHPN-initiated and non-initiated F344 male rats in the drinking water for 25 weeks. Remington's iodine deficient diet (I-def) was fed as a positive control. These goitrogens showed significant tumor promoting effect or promoting tendency on the rat thyroids. According to the changes in thyroid morphology and thyroid-related hormone titers observed in the present study, we proposed to classify goitrogens at least into 2 groups, i.e., iodine deficiency-type promoters and the iodine excess-type promoters. The former contains goitrogens inducing TSH-stimulated diffuse goiter composed of uniform follicles with activated tall follicular epithelial cells, such as thiourea, KSCN and PB, and the latter contains goitrogens inducing colloid goiter composed of a mixture of colloid-rich follicles with flat follicular cells and normal-looking follicles with cuboidal follicular cells, such as FR105. This classification may be useful for the risk assessment of goitrogens.

Topics: Animals; Antithyroid Agents; Body Weight; Carcinogens; Male; Nitrosamines; Organ Size; Phenobarbital; Rats; Rats, Inbred F344; Rose Bengal; Thiocyanates; Thiourea; Thyroid Gland; Thyroid Hormones; Thyrotropin