thiourea and Hyperplasia

Male Wistar rats were divided into two groups. Rats of group 1 were fed basal powdered diet containing 610 ppm 2,4- diaminoanisole sulfate (DAAS), 46 ppm 4,4'-thiodianiline (TDA) and 200 ppm N,N'-diethylthiourea (DETU) for 52 weeks (DTD treatment). Rats of group 2 were maintained on basal diet throughout the experiment as controls. At 52 weeks all surviving rats were sacrificed and subjected to an autopsy. Thyroid, lungs, stomach, liver, spleen, kidneys, testes and all gross lesions suspected of being a tumor were removed. After DTD treatment, the incidence of thyroid hyperplasia and papillary thyroid carcinoma was 59% (10/17) and 65% (11/17), respectively. Hepatocellular adenoma was induced in 2 of 17 rats (12%). Papillary thyroid carcinoma metastasis was found in the lung of 1 rat. No neoplastic tumors were found in kidney, spleen, stomach and testis tissue.

Topics: Adenoma, Liver Cell; Aniline Compounds; Animals; Carcinogens; Carcinoma, Papillary; Drug Synergism; Hyperplasia; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Phenylenediamines; Rats; Rats, Inbred F344; Rats, Wistar; Species Specificity; Thiourea; Thyroid Gland; Thyroid Neoplasms

The rodenticide alpha-naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a small, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mechanism by which rats develop resistance by a prior, small dose exposure has yet to be determined. Growth factor induced-pulmonary hyperplasia has been demonstrated to attenuate ANTU-induced lung leak. We hypothesized that a small dose of ANTU protects against a large dose through pulmonary cell hyperplasia induced by the protective dose. Furthermore, we hypothesized that this hyperplasia is associated with altered transcription of growth factors. Male Sprague-Dawley rats (175-225 g) were treated with a low dose of ANTU (5 mg ANTU/kg; ANTU(L)) 24 h before challenge with a 100% lethal dose of ANTU (70 mg ANTU/kg; ANTU(H)) resulting in 100% protection against the lethal effect of ANTU(H). ANTU(L) protection against ANTU(H) lasted for 5 days, slowly phased out, all being lost by day 20. Injury was assessed by estimating pulmonary vascular permeability and through histopathological examination. ANTU(H) alone resulted in an increase in pulmonary edema leading to animal death. However, injury was prevented if the rats were first treated with ANTU(L). There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU(L) treated rats as measured by [3H]-thymidine and bromodeoxyuridine incorporation. Treatment with the antimitotic agent colchicine abolished ANTU(L)-induced resistance to ANTU(H). ANTU resistant rats were also resistant to the lethal effect of paraquat. Paraquat is not taken up by pneumocytes if they are undergoing hyperplasia. ANTU(L) administration resulted in an up regulation of gene transcription for keratinocyte growth factor, transforming growth factor-beta, keratinocyte growth factor receptor and epidermal growth factor receptor as determined through reverse transcription-polymerase chain reaction. A significant increase in transforming growth factor-alpha was not observed. These findings collectively suggest that ANTU(L)-induced pulmonary cell hyperplasia underlies resistance to ANTU(H). Furthermore, the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions.

Topics: Animals; Capillary Permeability; Cell Nucleus; Colchicine; Drug Resistance; Herbicides; Hyperplasia; Lung Diseases; Male; Mitosis; Paraquat; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Rodenticides; Thiourea; Thymidine; Time Factors

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

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

Previous studies have shown that agents such as indomethacin and hydrocortisone act to reduce the level of epidermal hyperplasia produced by various chemical, but little information is available about the effects of such anti-inflammatory agents on the induction of hyperplasia in oral mucosa. Hamster cheek-pouch epithelium and ear epidermis were treated with indomethacin, metiamide and acetylsalicylic acid prior to treatment with turpentine, podophyllin or TPA. The levels of hyperplasia induced were monitored by rates of epithelial glycolysis, protein synthesis and mitosis. The response of the metabolic assays to epinephrine was also examined. Alone, turpentine, podophyllin and TPA each caused a 3-5 fold increase in the metabolic assays and loss of the normal tissue response to epinephrine. Tissues pretreated with indomethacin showed significant reductions in the levels of hyperplasia produced and they retained a normal response to epinephrine. No reduction in hyperplasia was observed following pretreatment with acetylsalicylic acid, an alternative inhibitor or prostaglandin synthesis or with metiamide, a histamine blocker. The results indicate that the production of epithelial hyperplasia by turpentine, podophyllin and TPA can be inhibited by indomethacin.

Topics: Animals; Aspirin; Cricetinae; Ear, External; Epidermis; Hyperplasia; Indomethacin; Mesocricetus; Metiamide; Mouth Mucosa; Podophyllin; Tetradecanoylphorbol Acetate; Thiourea; Turpentine

Topics: Animals; Blood Cell Count; Body Weight; Carcinogens; Female; Hemoglobinometry; Hyperplasia; Iodine; Iodine Radioisotopes; Male; Organ Size; Rats; Thiourea; Thyroid Gland; Thyroid Neoplasms; Time Factors

Topics: Animals; Connective Tissue; Cysts; Epithelial Cells; Epithelium; Fishes; Gonads; Hyperemia; Hyperplasia; Hypertrophy; Injections, Intraperitoneal; Iodine Isotopes; Pituitary Gland; Temperature; Thiourea; Thyroid Diseases; Thyroid Gland

Topics: Humans; Hyperplasia; Liver Diseases; Thiouracil; Thiourea; Thyroid Gland

Topics: Animals; Fibrous Dysplasia of Bone; Hyperplasia; Osteitis; Parathyroid Diseases; Parathyroid Glands; Rats; Thiouracil; Thiourea

Topics: Animals; Hyperplasia; Rats; Thiouracil; Thiourea; Thyroid Diseases

Topics: Goiter; Hyperplasia; Methylthiouracil; Pharmaceutical Preparations; Thiouracil; Thiourea; Thyroid Gland