Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of environmental estrogenic compounds, soy isoflavone mixture (SI), genistein (GEN), and nonylphenol (NP), and the possible goitrogen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), on thyroid carcinogenesis were investigated in ovariectomized (OVX) female rats. Five-week-old OVX F344 rats were given a single subcutaneous injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN; 2400 mg / kg, body weight) or vehicle alone. Starting 1 week later, GEN (250 or 25 ppm in diet), SI (400 ppm in diet), NP (250 or 25 ppm in diet), MX (30 ppm, in drinking water), sulfadimethoxine (SDM), a known thyroid tumor-promoter (1000 ppm in drinking water), or beta-estradiol 3-benzoate (EB), a synthetic estrogen (0.5 mg in cholesterol pellet, s.c.) were administered for 12 weeks. SDM and EB were included as positive controls. At sacrifice the major organs including the thyroid, pituitary, liver, kidney, uterus, vagina, brain and pancreas were collected and histopathological observation was performed. Thyroid weights were significantly increased (P < 0. 001) only in the SDM treatment group and pituitary weights were elevated with SDM (P < 0.05) and EB (P < 0.001). Kidney and uterus weights were also significantly increased (P < 0.05) by EB. Histopathologically, proliferative lesions of the thyroid were only observed in the SDM treatment group and of the pituitary in the SDM or EB treatment groups. Renal tubule lesions, uterine squamous metaplasia, vaginal keratinization and telangiectasia of pancreatic islets were also observed with EB. There were no organ weight changes or histopathological lesions in the major organs, including the thyroid, in the GEN, SI, MX or NP treatment groups. Our results thus indicated a lack of modifying effects on thyroid carcinogenesis in female OVX rats, in agreement with our previous finding in males.
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PMID:Lack of modification by environmental estrogenic compounds of thyroid carcinogenesis in ovariectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). 1105 Apr 65

Thyroid hormone (T(3)) exerts its many biological activities through interaction with specific nuclear receptors (TRs) that function as ligand-dependent transcription factors at genes that contain a thyroid hormone response element (TRE). Mutant TRs have been detected in human hepatocellular carcinoma cell lines and tissue, but their contribution to carcinogenesis has remained unclear. The interaction of four such mutant TRs (J7-TRalpha1, J7-TRbeta1, H-TRalpha1, and L-TRalpha1) with transcriptional coregulators has now been investigated. With the exception of J7-TRalpha1, which in the absence of T(3) exhibited transcriptional silencing activity with a TRE-reporter gene construct in transfected cells, the mutant TRs had little effect (compared with that of wild-type receptors) on transcriptional activity of the reporter gene in the absence or presence of T(3), of the transcriptional corepressors SMRT, NCoR or of the transcriptional coactivator SRC. Electrophoretic mobility-shift assays revealed that, in the presence of T(3), the J7-TRss1 mutant did not interact with SRC, whereas J7-TRalpha1 and H-TRalpha1 exhibited reduced abilities to associate with this coactivator and L-TRalpha1 showed an ability to interact with SRC similar to that of wild-type TRalpha1. The dominant negative activity of the mutant TRs in transfected cells appeared inversely related to the ability of the receptors to interact with SRC. Whereas J7-TRss1, H-TRalpha1, and L-TRalpha1 did not interact with SMRT, and NCoR. J7-TRalpha1 bind to corepressors but failed to dissociate from them in the presence of T(3). These aberrant interactions between the mutant TRs and transcriptional coregulators may contribute to the highly variable clinical characteristics of human hepatocellular carcinoma.
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PMID:Impaired interaction of mutant thyroid hormone receptors associated with human hepatocellular carcinoma with transcriptional coregulators. 1115 36

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.
Thyroid 2001 Feb
PMID:Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. 1128 83

Thyroid tumorigenesis proceeds through the progressive accumulation of alterations in genes involved in the regulation of cell proliferation and differentiation accompanying the acquisition of phenotypic, biological and clinical characteristics of increasing malignancy and dedifferentiation. The molecular alterations specific to thyrocyte carcinogenesis are examined. Ras mutations seem to represent an early occurrence in thyroid tumorigenesis being common to both benign and malignant follicular tumors; they would represent the early mutational events able to enhance the cell proliferation. Subsequent alterations in several genes will probably result in the determination of a follicular or papillary phenotype. In particular, mutational events activating ret, met and trk thyrokinase receptors direct the tumor growth and development towards the papillary type. Progression towards a follicular phenotype would instead occur in two stages: first there is the loss of function of genes on chromosome 11q13 which may direct the tumor cell towards the phenotype of follicular adenoma, second, there is the inactivation of the probable suppressor oncogene on chromosome 3p which might be fundamental in the transition from adenoma to follicular carcinoma. Undifferentiated or anaplastic tumors are characterized by the presence of p53 gene mutations.
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PMID:Molecular biology of thyroid neoplasms. 1137 May 34

Thyroid hormone (T(3)) regulates proliferation and differentiation of cells, via its nuclear receptors (TRs). These processes have been shown to be abnormally regulated during carcinogenesis. We have previously found aberrant expression of TRalpha and TRbeta mRNAs in renal clear cell carcinoma (RCCC), suggesting possible involvement of TRs in the carcinogenesis of RCCC. To understand the molecular actions of TRs in RCCC, cDNAs for TRbeta1 and TRalpha1 were cloned from 22 RCCC tissues and 20 surrounding normal tissues. Mutations were found in seven TRbeta1 and three TRalpha1 cDNAs. Two TRbeta1 cDNAs had a single mutation, while five TRbeta1 and three TRalpha1 had two or three mutations. Most of the mutations were localized in the hormone-binding domain. Using the TRs prepared by in vitro transcription/translation, we found that these mutations led to a loss of T(3) binding activity and/or impairment in binding to thyroid hormone response elements (TREs). Furthermore, nuclear extracts from RCCC tissues also exhibited impairment in binding to TREs. These results indicate that the normal functions of TRs in RCCC tissues were impaired. Together with the aberrant expression patterns, these mutated TRs could contribute to the carcinogenesis of RCCC.
Carcinogenesis 2002 Jan
PMID:Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma. 1175 20

In order to improve the sensitivity of our previously established thyroid carcinogenesis model and to clarify whether endocrine disrupting chemicals with weak estrogenic activity have any modifying effects on the development of thyroid proliferative lesions, 6-week-old female castrated F344 rats were first given a single subcutaneous injection of 2000 mg/kg body weight of N-bis(2-hydroxypropyl)nitrosamine. From 1 week later, they received diets with: no supplement (basal diet (BD) group); cholesterol pellets containing 0.5 mg 17 beta-estradiol 3-benzoate (EB); or diet admixed with 1000 ppm methoxychlor (MXC) or 10,000 ppm bisphenol A (BPA) for 20 weeks. Furthermore, additional groups were administered 200 ppm sulfadimethoxine (SDM) in the drinking water simultaneously with the BD, EB, MXC or BPA treatments. Thyroid follicular cell hyperplasias, adenomas and/or carcinomas were induced only in the EB+SDM group, the incidences of non-malignant lesions being significantly increased, as compared with the BD+SDM group values. Furthermore, the serum level of thyroid stimulating hormone (TSH) was significantly increased in this group. No significant variation in quantitative values for thyroid proliferative lesions or TSH levels were observed in the other treated groups. The results of the present study convincingly indicate that EB, with strong estrogenic activity, but not MXC and BPA, with weak estrogenic activities, exerts promoting effects on thyroid carcinogenesis in rats. The present modified rat two-stage thyroid carcinogenesis model appears to have advantages over our previous model for screening purposes.
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PMID:Improvement of a two-stage carcinogenesis model to detect modifying effects of endocrine disrupting chemicals on thyroid carcinogenesis in rats. 1184 35

Man has utilized a wide variety of pesticides to combat the crop pests and vectors of human diseases. However, in this process, he has overlooked the darker side of these noxious chemicals, the concentrations of which have reached the environment and pose serious threats, such as mutagenesis, teratogenesis, carcinogenesis and endocrine dysfunction in various components of the ecosystem. The present study was planned to assess the burden of organochlorine pesticides and their influence on thyroid function in women. The study included a total of 123 women from Jaipur City who visited the Thyroid clinic in SMS Medical College and Hospital. One hundred women showed normal thyroid hormone levels while the remaining 23 women had depleted T4 and high TSH levels. The qualitative and quantitative estimation of organochlorine pesticides was carried out by gas chromatography. Out of the analyzed pesticides, the concentration of p,p'-DDT and its metabolites was higher in all the subjects, but dieldrin was found to be significantly high in the hypothyroid women. The correlation analysis for dieldrin and depleted T4 levels in hypothyroid women elicited an inverse relationship between them.
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PMID:Burden of organochlorine pesticides in blood and its effect on thyroid hormones in women. 1218 88

The molecular genetic basis of thyroid carcinogenesis is not well understood. Most of the existing models of thyroid cancer only rarely show metastases, and this has limited progress in the understanding of the molecular events in thyroid cancer invasion and metastasis. We have recently generated a mutant mouse by introducing a dominant negative mutant thyroid hormone nuclear receptor gene, TRbetaPV, into the TRbeta gene locus. In this TRbetaPV mouse, the regulation of the thyroid-pituitary axis is disrupted, leading to a mouse with high levels of circulating thyroid-stimulating hormone and extensive hyperplasia of follicular epithelium within the thyroid. As TRbeta(PV/PV) mice, but not TRbeta(PV/+) mice, aged, metastatic thyroid carcinoma developed. Histologic evaluation of thyroids of 5-14-month-old mice showed capsular invasion (91%), vascular invasion (74%), anaplasia (35%), and metastasis to the lung and heart (30%). Previous models of thyroid cancer have focused on genes that control initial carcinogenesis, but this model provides an unusual opportunity to study the alterations in gene regulation that occur with clinically relevant changes during progression and metastasis in a predictable fashion.
Thyroid 2002 Nov
PMID:Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. 1249 73

HC Yellow 4 is used in semipermanent hair dyes. Toxicology and carcinogenesis studies were conducted by administering HC Yellow 4 (greater than 93% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-Day Studies: Groups of five rats of each sex were given 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm and groups of five mice of each sex were given 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm HC Yellow 4 in feed for 14 days. All animals survived to the end of the studies. Final mean body weights of male rats that received 20,000 ppm or more, female rats that received 10,000 ppm or more, and female mice that received 20,000 ppm were significantly lower than those of the controls. The mean body weights of exposed and control groups of male mice were similar. No chemical-related decrease in feed consumption was observed. No chemical-related clinical findings or changes in absolute or relative organ weights occurred in rats or mice. No gross or microscopic changes were related to HC Yellow 4 administration in rats or mice. 13-Week Studies: Groups of 10 rats of each sex were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm and groups of 10 mice of each sex were fed diets containing 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm HC Yellow 4 for 13 weeks. All rats survived to study termination. Chemical-related deaths occurred at the two highest dose levels in male and female mice. Final mean body weights of male rats that received 10,000 ppm or greater, female rats that received 20,000 or 40,000 ppm, and mice that received 10,000 ppm or greater were significantly lower than those of the controls. There were no biologically significant changes in absolute or relative organ weights. Mineralization of the renal papilla occurred in all male rats in the 40,000 ppm group. Thyroid pigmentation occurred in rats receiving 40,000 ppm and in mice at all dose levels. Uterine atrophy occurred in female rats in the 20,000 and 40,000 ppm groups and female mice in the 40,000 and 80,000 ppm groups. Lymphoid depletion and atrophy of the spleen occurred in male mice that received 40,000 or 80,000 ppm and female mice that received 80,000 ppm. Atrophy of the thymus occurred in male and female mice that received 40,000 or 80,000 ppm. 2-Year Studies: Groups of 70 male rats were fed diets containing 0, 2,500, or 5,000 ppm and groups of 70 female rats and 70 mice of each sex were fed diets containing 0, 5,000, or 10,000 ppm HC Yellow 4 for up to 2 years. Interim evaluations were performed on 10 rats and 10 mice from each dose group at 6 and 15 months. No biologically significant changes in absolute or relative organ weight or hematology or clinical chemistry values were found in these rats or mice. No compound-related lesions were seen in exposed rats. In exposed mice, pigmentation of the thyroid gland was observed at the 6-month interim evaluations; pigmentation and hyperplasia of the thyroid gland were seen at the 15-month interim evaluations. Body Weight, Survival, and Feed Consumption in the 2-Year Studies: The mean body weight of female rats that received 10,000 ppm was significantly lower than that of the controls. The mean body weights of mice receiving 10,000 ppm were 20% to 30% lower than those of the controls during the second year of the studies. The survival of exposed rats and mice was similar to that of the controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Pituitary gland pars distalis adenomas were marginally increased in exposed male rats (0 ppm, 17/45; 2,500 ppm, 20/49; 5,000 ppm, 28/49), and there was a concomitant dose-related increase in the incidence of hyperplasia (8/45, 13/49, 18/49). There was no increase in the incidence of pituitary gland adenomas or carcinomas in female rats (34/49, 35/48, 30/49). In mice, no neoplasms were considered related to chemical administration. However, a dose-related incr, a dose-related increased incidence of thyroid gland pigmentation and follicular cell hyperplasia occurred in both sexes of mice. Genetic Toxicology: HC Yellow 4 was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous metabolic activation (S9); the response in strain TA1535 without S9 was equivocal. HC Yellow 4 induced sister chromatid exchanges in Chinese hamster ovary cells in the absence but not the presence of S9 activation; no induction of chromosomal aberrations occurred in Chinese hamster ovary cells, with or without S9. HC Yellow 4 induced sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster when administered by injection; results of a reciprocal translocation test in D. melanogaster were negative. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of HC Yellow 4 in male F344/N rats based on the increased incidence of pituitary gland adenomas and hyperplasia. The male rats may have been able to tolerate a slightly higher dose of the chemical. There was no evidence of carcinogenic activity of HC Yellow 4 in female F344/N rats given 5,000 or 10,000 ppm. There was no evidence of carcinogenic activity of HC Yellow 4 in male or female B6C3F1 mice given 5,000 or 10,000 ppm. There was a chemical-related increase in the incidence of thyroid gland pigmentation and follicular cell hyperplasia in mice. Synonym: N,O-di(2-hydroxyethyl)-2-amino-5-nitrophenol
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PMID:NTP Toxicology and Carcinogenesis Studies of HC Yellow 4 (CAS No. 59820-43-8) in F344 Rats and B6C3F1 Mice (Feed Studies). 1261 92

Tris(2-chloroethyl) phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams, and synthetic fibers, was studied as part of the National Toxicology Program's class study of trisalkyl phosphate flame retardants. Toxicology and carcinogenesis studies were conducted by administering TRCP (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 16 weeks, or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 16-Day Studies: There were no chemical-related deaths, differences in final mean body weight, or histopathological lesions in rats receiving 22 to 350 mg/kg TRCP or in mice receiving 44 to 700 mg/kg TRCP for 12 doses over 16 days. Serum cholinesterase activity in female rats receiving 175 or 350 mg/kg TRCP was reduced slightly (80% of control levels), but enzyme activity in dosed male rats and in mice was similar to that in controls. 16-Week Studies: Rats received 22 to 350 mg/kg TRCP for 16 weeks (female) or 18 weeks (male). Several male and female rats in the 175 or 350 mg/kg dose groups died from chemical toxicity. Final mean body weights of female rats receiving 350 mg/kg were 20% greater than those of controls; final mean body weights of the remaining groups of dosed female rats and dosed male rats were similar. Chemical-related neuronal necrosis occurred in the hippocampus and thalamus of female rats and, to a lesser extent, of male rats. Serum cholinesterase activity was reduced in females receiving 175 or 350 mg/kg TRCP. There were no chemical-related deaths, differences in final mean body weight, or differences in cholinesterase activity in mice receiving 44 to 700 mg/kg TRCP for 16 weeks. Tubule epithelial cells with enlarged nuclei (cytomegaly and karyomegaly) were observed in the kidneys of high-dose (700 mg/kg) male and female mice. 2-Year Studies: The 2-year studies in rats were conducted by administering 0, 44, or 88 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 9 or 10 rats of each dose group were evaluated at 66 weeks. The survival of high-dose male and female rats was reduced relative to that of controls. Final mean body weights of surviving rats were similar to those of controls. The principal chemical-related effects occurred in the kidney and brain of dosed rats. Focal hyperplasia of the renal tubule epithelium and renal tubule adenomas were markedly increased in male rats receiving 88 mg/kg TRCP and, to a lesser extent, in female rats (renal tubule hyperplasia, male rats: 0/50; 2/50; 24/50; female rats: 0/50; 3/50; 16/50; renal tubule adenoma, male rats: 1/50; 5/50; 24/50; female rats: 0/50; 2/50; 5/50). Renal tubule carcinomas occurred in one control and one high-dose male rat. Degenerative lesions consisting of gliosis, mineralization, hemorrhage, and/or hemosiderin accumulation occurred in the cerebrum and brain stem of more than 50% of female rats receiving 44 or 88 mg/kg TRCP; similar lesions were seen in only a few dosed males. Slightly increased incidences of thyroid gland follicular cell neoplasms (male rats: 5/50; 14/50; 13/50; female rats: 14/50; 16/50; 20/50) occurred in dosed males and females, but it is uncertain whether these were related to chemical administration. The 2-year studies in mice were conducted by administering 0, 175, or 350 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 8 to 10 mice of each sex per dose group were evaluated at 66 weeks. There were no significant differences in survival between dosed and control groups of either sex, and final mean body weights of mice were similar among all groups. The principal chemical-related effects occurred in the kidney, in which nuclear enlargement (karyomegaly) of tubule epithelial cells was present in approximately 80% of high-dose mice. In the original diagnosis, renal tubule adenomas were seen in one control male, one high-dose male, and one low-dose female. A carcinoma was also seen in one high-dose male. In a s seen in one high-dose male. In a subsequent examination of step sections of all the mouse kidneys, adenomas were found in one low-dose male and two high-dose males. The incidences of renal tubule neoplasms in the original and step sections combined were 1/50, 1/50, and 4/50 for males. Female mice receiving TRCP demonstrated a marginally increased incidence of neoplasms (primarily adenomas) of the harderian gland (3/50; 8/50; 7/50); in addition, three harderian gland neoplasms occurred in high-dose female mice evaluated after 66 weeks. Genetic Toxicology: TRCP was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9), and it tested negative for the induction of chromosomal aberrations in Chinese hamster ovary (CHO) cells. TRCP produced an equivocal response in the presence of S9 for the induction of sister chromatid exchanges (SCE) in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving tris(2-chloroethyl)phosphate as shown by increased incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally increased incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice as shown by a marginally increased incidence of harderian gland adenomas. Renal tubule cell hyperplasia in male and female rats and gliosis, hemorrhage, pigmentation (hemosiderin accumulation), and mineralization in the brains of female rats were associated with the administration of tris(2-chloroethyl) phosphate. Karyomegaly of renal tubule epithelial cells in male and female mice was also chemical related. Synonyms: 2-chloroethanol phosphate (3:1); tris(b-chloroethyl) phosphate Trade Names: Fyrol CEF; Disflamoll TCA; NIAX flame retardant
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PMID:NTP Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate (CAS No. 115-96-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1263 68


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