UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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The homeobox (HOX) was originally described as a conserved DNA motif of about 180 base pairs. The protein domain encoded by the homeobox, the homeodomain, is thus about 60 amino acids long. The homeodomain is a DNA-binding domain, and many homeobox genes have now been shown to bind to DNA and regulate the transcription of other genes. Thus homeodomain proteins are basically transcription factors, most of which play a role in development. The homeobox genes seem to represent another class of oncofetal antigens involved in both normal development and carcinogenesis, as well as tumor progression. The expression pattern of three homeobox gene products (HOX-B3, HOX-B4, and HOX-C6) was examined immunocytochemically in human thymuses of different ages and developmental stages (prenatal: 16 weeks and postnatal: 3 years, 5 years, and 21 years) employing an indirect alkaline phosphatase conjugated antigen detection technique on formalin-fixed, paraffin-embedded tissue sections. The immunoreactivity was located in the thymic RE cellular network (cortical and medullar), showing different intensity (+3 to +4 or 50% to 90% and over 90% in the prenatal thymic tissue and +2 to +3 or 50% to 90% during the three different postnatal stages). Intense expression was identified in the thymic medulla, including very strong immunoreactivity in the immigrating, committed hematopoietic stem cells (HSCs) present within the interlobular connective tissue (ICT). Strong presence of the HOX-B3 and HOX-B4 proteins was detected in the thymic Hassall's bodies (HBs), suggesting an intensive functional activity of the RE cells present within these unique formations within the thymic medulla. The precise role of these and other HOX gene products in the various steps of intrathymic T lymphopoieis should be elucidated through further basic molecular biological research.
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PMID:Immunocytochemical detection of the homeobox B3, B4, and C6 gene products within the human thymic cellular microenvironment. 1090 75

The homeobox was originally described as a conserved DNA motif of about 180 base pairs. The protein domain encoded by the homeobox, the homeodomain, is thus about 60 amino acids long. The homeodomain is a DNA-binding domain, and many homeobox genes have now been shown to bind to DNA and regulate the transcription of other genes. Thus homeodomain proteins are basically transcription factors, most of which play a role in development. The homeobox genes seem to represent another class of oncofetal antigens involved in both normal development and carcinogenesis, as well as tumor progression. It has been shown that HOX-B3 and HOX-B4 are preferentially expressed in primitive CD34+, lineage-committed hematopoietic stem cells (HSCs) in human bone marrow. HOX-B3 overexpression in HSCs causes defective lymphoid development and progressive myeloproliferation, while HOX-B4 leads to selective expansion of HSCs without altering their differentiation. The HOX-C6 gene product leads to cell differentiation in neuroblastomas, while also being associated with the neoplastically transformed mammary cell phenotype and progression in primary cutaneous lymphomas. The expression pattern of these three homeobox gene products (HOX-B3, HOX-B4, and HOX-C6) was examined immunocytochemically in childhood MEDs/PNETs employing an indirect alkaline phosphatase conjugated technique on formalin-fixed, paraffin-embedded tissue sections. Strong staining intensity (A, B) of HOX-B3 and HOX-B4 was registered in all MEDs/PNETs, with immunoreactivity in between 50% and 90% (+3), but usually over 90% (+4) of the tumor cells. HOX-C6 was detected at medium intensity (mostly B) in 50% to 90% (+3) of the MED/PNET cells. This report is the first to describe the expression of these three homeobox gene products in MEDs/PNETs, and provides further evidence for the role of these proteins in the progression of human malignancies. The value of these genes and proteins in the early diagnosis and possible treatment of various human neoplasms, including childhood brain tumors, should be assessed in further immunocytochemical and molecular biological experiments.
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PMID:Immunocytochemical detection of the homeobox B3, B4, and C6 gene products in childhood medulloblastomas/primitive neuroectodermal tumors. 1092 6

Tamoxifen-DNA adducts detected in the liver of mice treated with tamoxifen have not yet been identified. In the present study a new type of tamoxifen-DNA adduct, four stereoisomers of alpha-(N:(2)-deoxyguanosinyl)tamoxifen N:-oxide 3'-monophosphate (dG(3'P)-N:(2)-TAM N:-oxide) were prepared as standard DNA adducts by reacting 2'-deoxyguanosine 3'-monophosphate with trans-alpha-acetoxytamoxifen N:-oxide in addition to four stereoisomers of alpha-(N:(2)-deoxyguano- sinyl)tamoxifen 3'-monophosphate (dG(3'P)-N:(2)-TAM) that was reported previously. Liquid chromatography-electrospray ionization-mass spectrometry of the reaction products gave the most abundant ion at m/z 731 ([M - H](-)), which corresponded to dG(3'P)-N:(2)-TAM N:-oxide. The modified products digested by alkaline phosphatase corresponded to the isomers of dG-N:(2)-TAM N:-oxide whose structures were identified previously by mass spectrometry and nuclear magnetic resonance. Using these standard markers, we analyzed the hepatic DNA adducts of female DBA/2 mice treated with tamoxifen at a dosage of 120 mg/kg/day for 7 days by (32)P-post-labeling coupled with an HPLC/radioactive detector. Mixtures of eight isomers of dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N-oxide were separated into six peaks, since each of the cis epimers were not separated under the present HPLC conditions. Nine adducts were detected in all liver samples of mice. An epimer of trans-dG(3'P)-N:(2)-TAM was detected as the principal DNA adduct at a level of 29.0 adducts/10(8) nucleotides, which accounted for 53.3% of the total tamoxifen-DNA adducts. Lesser amounts of cis-dG(3'P)-N:(2)-TAM (2.8%) were also observed. An epimer of the trans-dG(3'P)-N:(2)-TAM N:-oxide (3.9 adducts/10(8) nucleotides) was detected as the third biggest adduct (7.2% of the total). The cis-dG(3'P)-N:(2)-TAM N:-oxide (0.4 adducts/10(8) nucleotides) accounted for 0.7% of the total. Thus, dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N:-oxide were identified in tamoxifen-treated mouse liver.
Carcinogenesis 2000 Sep
PMID:Identification of hepatic tamoxifen-DNA adducts in mice: alpha-(N(2)-deoxyguanosinyl)tamoxifen and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide. 1096 6

Accumulation of intracellular beta-catenin, as a result of inactivation of the adenomatous polyposis coli (APC) gene or by mutation of the beta-catenin gene (CTNNB1) itself, is involved in a wide range of human cancers. By means of fluorescent differential display using a murine fibroblast cell line (L-MT), which expresses an activated form of beta-catenin that accumulates in the cells, we found that expression of murine monocyte chemotactic protein-3 (mMCP-3) was suppressed by activated beta-catenin. Inversely, expression of MCP-3 in human colon cancer cells was induced by depletion of beta-catenin after adenovirus-mediated transfer of wild-type APC genes into the cells. A reporter-gene assay indicated that the accumulation of beta-catenin in the nucleus suppressed activity of the MCP-3 promoter through a putative T-cell factor/lymphocyte enhancer factor (Tcf/LEF)-binding site, ATCAAAG; but when the promoter sequence contained a two-base substitution in the binding site, it failed to suppress reporter-gene (luciferase) activity. An electrophoretic mobility-shift assay using the putative Tcf/LEF-binding sequence revealed interaction of the candidate sequence with the beta-catenin complex. Furthermore, induction of MCP-3 cDNA into HT-29 colon cancer cells increased expression of two markers of differentiation: alkaline phosphatase and carcinoembryonic antigen. Our results implied that activation of beta-catenin through the Tcf/LEF signaling pathway may participate in colonic carcinogenesis by inhibiting MCP-3-induced differentiation of colorectal epithelial cells.
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PMID:Down-regulation of monocyte chemotactic protein-3 by activated beta-catenin. 1111 53

Administration of tamoxifen (TAM) has been shown to induce hepatocellular carcinogenesis and TAM-DNA adduct formation in rat liver. Here we present TAM-DNA adduct localization and semi-quantitation in hepatic tissue of rats by immunohistochemical staining followed by image analysis. We have also used a quantitative immunoassay to provide a validation for the immunohistochemical values. Rats were fed diets containing 0, 5, 50, 150 or 500 p.p.m. TAM for 45 weeks. Serial sections of paraffin-embedded liver were stained for TAM-DNA adducts using a polyclonal TAM-DNA antiserum. Subsequently, visualization of TAM-DNA adducts was performed by peroxidase-conjugated secondary antibody-mediated signal amplification using biotinyl tyramide followed by streptavidin-alkaline phosphatase and fast red. Semi-quantitation of nuclear color intensity was achieved with an Automated Cellular Imaging System (ACIS), with a detection limit of 1 TAM-DNA adduct per 10(7) nt for these experiments. In parenchymal cells of liver sections from TAM-exposed animals a dose-dependent increase in nuclear staining was observed by ACIS and the TAM-DNA adduct levels determined by ACIS were validated in liver DNA by quantitative chemiluminescence immunoassay (CIA). Comparison of semi-quantitative values determined by ACIS with quantitative values determined by CIA showed a strong correlation (r = 0.924) between the two methods. At 45 weeks of TAM exposure the liver cytoplasm contained placental glutathione S-transferase (GST-p)-positive foci, as indicated by new fuchsin staining. Staining of serial sections revealed a relative lack of TAM-DNA adducts within these enzyme-altered foci. In addition, some GST-p foci contained islands of cells that did not stain for GST-p but were positive for TAM-DNA adduct formation. This study validates the use of ACIS for TAM-DNA adduct formation and demonstrates that steady-state TAM-DNA adduct levels observed in livers of rats chronically fed TAM for several months increase in relation to dose. In addition, unlike the normal surrounding liver, preneoplastic GST-p-positive foci have virtually no TAM-DNA adducts.
Carcinogenesis 2001 Oct
PMID:Immunohistochemical localization and semi-quantitation of hepatic tamoxifen-DNA adducts in rats exposed orally to tamoxifen. 1157 11

3,3'-Diindolylmethane (DIM), a major in vivo product of indole-3-carbinol (I3C), is a promising anticancer agent derived from vegetables of the Brassica genus including broccoli, Brussels sprouts and cabbage. We report here that DIM has a potent cytostatic effect in cultured human Ishikawa endometrial cancer cells. A combination of northern blot and quantitative PCR analyses revealed that DIM induced the level of TGF-alpha transcripts by approximately 4-fold within 24 h of indole treatment. DIM also induced a 4-fold increase in the activity of the estrogen response marker, alkaline phosphatase (AP). Co-treatment of cells with the estrogen receptor (ER) antagonist ICI, or with the inhibitor of PKA-mediated activation of the ER, H89, ablated the DIM induction of both TGF-alpha expression and AP activity. Furthermore, DIM increased the maximum stimulatory effect of estrogen on TGF-alpha expression. Co-treatment with the protein synthesis inhibitor, cycloheximide, abolished the inductive effects of DIM, indicating differences in the mechanistic requirements of DIM and estrogen. DIM treatment also stimulated levels of secreted TGF-alpha protein by >10-fold. The ectopic addition of TGF-alpha inhibited the growth of Ishikawa cells, whereas incubation with a TGF-alpha antibody partially reversed the growth inhibitory effects of DIM. Taken together, these results extend our previous findings of the ligand independent estrogen receptor agonist activity of DIM, and uncover an essential role for the stimulation in TGF-alpha expression and the TGF-alpha activated signal transduction pathway in the potent cytostatic effects of DIM in endometrial cancer cells.
Carcinogenesis 2001 Nov
PMID:Cytostatic effects of 3,3'-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. 1169 43

Respirable quartz has been classified as a human lung carcinogen (IARC, 1997). However, the mechanisms involved in quartz-induced carcinogenesis remain unclear. The aim of the present study was to investigate acute DNA damage in epithelial lung cells from rats exposed to quartz. Since surface reactivity is considered to play a crucial role in the toxicity of quartz, the effect of surface modifying agents polyvinylpyridine-N-oxide (PVNO) and aluminium lactate (AL) was evaluated. Therefore, rats were instilled with quartz (DQ12, 2 mg/rat) or quartz treated with PVNO or AL. After 3 days animals were killed and brochoalveolar lavage (BAL) was performed to evaluate inflammatory cell influx. BAL-fluid levels of lactate dehydrogenase (LDH), alkaline phosphatase (AP) and total protein were used as lung damage markers. Neutrophil activation was assessed by myeloperoxidase (MPO) measurement, and total antioxidant capacity of the BAL-fluid was determined using the TEAC (trolox equivalent antioxidant capacity) assay. Lung epithelial cells were isolated and DNA strand breakage was determined by single cell gel electrophoresis (comet assay). DNA damage was significantly increased in epithelial cells from rats instilled with DQ12, whereas no enhanced DNA strand breakage was observed when quartz was treated with PVNO or AL. Total protein, LDH and TEAC were increased in rats treated with native quartz, and this was inhibited by both coatings. A significant correlation between neutrophil numbers and MPO levels was observed, indicating neutrophil activation. Inhibition of DNA damage by both coatings was paralleled by a reduction of neutrophil influx as well as MPO activity. In this study we provide evidence that modification of the particle surface prevents DNA strand breakage in epithelial lung cells from quartz-exposed rats. Furthermore, the present data show the feasibility of our in vivo model to evaluate the role of inflammation, antioxidant status, and cytotoxicity in particle-induced DNA damage.
Carcinogenesis 2002 Jul
PMID:DNA damage in lung epithelial cells isolated from rats exposed to quartz: role of surface reactivity and neutrophilic inflammation. 1211 67

Splenic macrophages are highly efficient in trapping and concentrating foreign substances carried in the blood and also the major sites where antibodies are synthesised and from where they are released into the circulation. Lead and Arsenic as environmental agents are considered to be high priority toxic substances largely due to their carcinogenic potentials in humans. However, these heavy metals as carcinogens remain an enigma because while they are definitely active in humans, carcinogenesis in the rodent model has never been convincingly demonstrated. Although macrophages are predominantly recruited to the site of inflammation during inflammatory distress as well as in immune response, nothing is known about the interaction of lead and arsenic with macrophages and their possible role in immunotoxicologic effect. In the present study it is reported that in vivo lead acetate treatment (10 mg/kg body wt) inhibits the cell adhesion property and alters the cell morphology in the splenic macrophages. Results show that there is a significant decrease in alkaline phosphatase release in lead treated macrophages (6.7 +/- 0.88 IU/100 mL) with respect to control (14.17 +/- 0.18). In vivo exposure of sodium arsenite (0.5 mg/kg body wt) also decreases phagocytic activity for ingestion and digestion of exogenous antigens, such as whole microorganism, as evident from the phagocytic index, 11555.55 +/- 62.86 (in control) to 5555.5 +/- 1571.33 in arsenic treated cells. Arsenic exposed cells release 8.15 +/- 0.05 microM nitric oxide, whereas control cells release 10.95 +/- 0.15 microM of nitric oxide, which is also identical following LPS stimulation. Results show that the functional integrity of the target cell is also decreased after arsenic exposure as obtained from the percentage of DNA fragmentation. A greater percentage of DNA fragmentation upon arsenic treatment (43.1 +/- 0.05%) with respect to control (14.9 +/- 0.34%) indicates that arsenic induces apoptosis. In immune cells which are rapidly proliferating and differentiating, inhibition of these heavy metal induced functions may result in similar degree of toxicity and lead to diseased state.
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PMID:Effect of lead and arsenic on murine macrophage response. 1237 52

4,4'-Thiobis(6- t -butyl- m -cresol) (TBBC) is used in the rubber and plastics industries as an antioxidant. TBBC is also used as a stabilizer in polyethylene and polyolefin packaging materials for foodstuffs. Toxicology and carcinogenesis studies were conducted by administering TBBC (99% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 15-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 2,500, 5,000, 10,000 or 25,000 ppm TBBC for 15 days. Rats given to 1,000, 2,500, 5,000, or 10,000 ppm received approximate doses of 95, 235, 335, or 365 mg TBBC per kilogram body weight per day (males) or 85, 220, 325, or 270 mg/kg per day (females). Approximate doses for rats receiving 25,000 ppm could not be calculated due to early deaths. All 25,000 ppm rats and three male and four female 10,000 ppm rats died. Surviving rats in the 10,000 ppm groups had a significant weight loss and the final mean body weights of 5,000 and 10,000 ppm male and female rats were significantly lower than those of the controls. Male and female rats exposed to 5,000, 10,000, or 25,000 ppm TBBC consumed markedly less feed than the controls. Diarrhea occurred in 5,000, 10,000, and 25,000 ppm males and females. The principal lesions attributed to the administration of TBBC were renal papillary and tubule necroses which occurred in 10,000 ppm rats. Focal necrosis or erosions of the glandular stomach also occurred in some 10,000 ppm rats. Changes observed in the thymus and spleen were attributed to debilitation or stress; bone marrow depletion was attributed to nutrient deficiency accompanying weight loss. 15-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 1,000, 2,500, 5,000, 10,000, or 25,000 ppm TBBC for 15 days. Mice given 1,000, 2,500, or 5,000 ppm received approximate doses of 285, 585, or 475 mg TBBC per kilogram body weight per day (males) or 360, 950, or 1,030 mg/kg per day (females). Approximate doses for mice given 10,000 or 25,000 ppm could not be calculated due to early deaths. All 10,000 and 25,000 ppm mice died, as did eight males and eight females given 5,000 ppm. A significant weight loss occurred in surviving 5,000 ppm males and females and the final mean body weights of 2,500 ppm females and 5,000 ppm males and females were significantly lower than those of the controls. Feed consumption by mice given 5,000, 10,000, or 25,000 ppm was markedly reduced. Diarrhea occurred in all 25,000 ppm mice and in most male and female mice given 5,000 or 10,000 ppm. Renal tubule necrosis occurred in eight males and three females in the 5,000 ppm groups. Lymphocytic depletion of Iymphoid tissues in many 5,000 ppm males and females was attributed to debilitation and stress or to nutrient deficiency accompanying weight loss. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 250, 500, 1,000, 2,500, or 5,000 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 60, 165, or 315 mg TBBC per kilogram body weight per day (males) or 15, 35, 70, 170, or 325 mg/kg per day (females). All rats survived to the end of the study. The final mean body weight of 5,000 ppm males was 40% lower than that of the controls; the final mean body weight of 5,000 ppm females was 27% lower than that of the controls. Feed consumption by male and female rats exposed to 5,000 ppm TBBC was markedly lower than that by the controls throughout the study. The absolute and relative liver weights of 5,000 ppm females were significantly greater than those of the controls. Serum alkaline phosphatase (ALP) levels were significantly higher in 2,500 and 5,000 ppm males and slightly higher in 5,000 ppm females. Serum alanine aminotransferase levels were significantly higher in 2,500 and 5,000 ppm males and females. Hematocrit and hemoglobin concentrations and mean erythroions and mean erythrocyte volume (MCV) values were significantly lower in 1,000, 2,500, and 5,000 ppm males than in controls; MCV values were also significantly lower in 5,000 ppm females. A dose-related significant increase in forelimb and hindlimb grip strength was observed in exposed male and female rats. Histopathologic findings in the liver of 2,500 and 5,000 ppm males and females included hypertrophy of Kupffer cells, bile duct hyperplasia, and individual cell necrosis of hepatocytes; centrilobular hepatocyte hypertrophy also occurred in males and females exposed to 5,000 ppm TBBC. Macrophages were increased in size and number in the mesenteric Iymph nodes of males and females exposed to 5,000 ppm, and to a lesser extent in 2,500 ppm male and female rats. Pigmentation and degeneration of the renal cortical tubule epithelial cells was also present in males and females in the 2,500 and 5,000 ppm groups; cortical tubule necrosis occurred in 5,000 ppm males and females. 13-WEEK STUDY IN MICE: Groups of up to 10 male and 10 female B6C3F1 mice were fed diets containing 0, 100, 250, 500, 1,000, or 2,500 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 65, 145, or 345 mg TBBC per kilogram body weight per day (males) or 10, 35, 60, 165, or 340 mg/kg per day (females). All mice survived to the end of the study. The final mean body weights of 2,500 ppm males and of 500,1,000, or 2,500 ppm females were significantly lower than those of the controls. Feed consumption by 2,500 ppm males averaged 24&percnt; lower than that by controls through week 3 and was similar to that by controls for the remainder of the study. Feed consumption by females receiving 2,500 ppm averaged 27&percnt; less than that by the controls during most of the study. The absolute and relative liver weights of males and females exposed to 2,500 ppm TBBC were slightly but significantly greater than those of the controls. Males exposed to 500, 1,000, or 2,500 ppm and females exposed to 2,500 ppm had significantly increased absolute and relative spleen weights. No clinical findings in mice were considered chemical related. Hematocrit concentrations and erythrocyte counts of males receiving 1,000 or 2,500 ppm were significantly less than those of the controls; hemoglobin concentration in males receiving 2,500 ppm was significantly less and mean erythrocyte volume was significantly less in males receiving 2,500 ppm. Females in the 1,000 and 2,500 ppm groups had significantly decreased hematocrit concentrations and erythrocyte counts; 2,500 ppm females also had significantly decreased hemoglobin concentrations and mean erythrocyte volumes. Kupffer cell hypertrophy, bile duct hyperplasia, and an increase in size and number of macrophages in mesenteric Iymph nodes were present in 2,500 ppm male and female mice. 2-YEAR STUDY IN RATS: Doses selected for the 2-year study of TBBC were based on the lower body weights and liver and kidney toxicity observed at 5,000 ppm in the 13-week study. Groups of 115 male and 75 female F344/N rats were fed diets containing 0, 500, 1,000, or 2,500 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in a daily ingestion of TBBC of approximately 20, 40, or 100 mg/kg body weight for males and 20, 45, or 120 mg/kg body weight for females. Hematology, clinical chemistry, and urinalysis evaluations were performed on 15 male and 15 female rats from each group at 3, 9, and 15 months. Also at 15 months, an additional 10 male and 10 female rats from each group were evaluated for histopathology, hematology, and clinical chemistry. Forty male rats per group were evaluated for neurotoxic effects. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates and mean body weights of exposed male and female rats were generally similar to those of the controls. The mean body weights of 2,500 ppm male rats were slightly lower than those of the controls throughout the study. At week 65, the mean body weight of 2,500 ppm females was 14&percnt; lower than that of the controls, but the final mean body weight of this group was 6&percnt; lower than that of the control group. Feed consumption, behavior, and general health and appearance of exposed male and female rats were similar to those of the controls. Hematology and Clinical Chemistry: Results of the hematology evaluation were not uniformly consistent at 3, 9, and 15 months in one set of rats, nor were they consistent between the two sets of rats evaluated at 15 months. Slight but significant decreases in hematocrit levels, hemoglobin concentrations, and erythrocyte counts were observed in the 1,000 and 2,500 ppm groups in one set of males at 15 months. Similar significant decreases in hematocrit level and hemoglobin concentration occurred in 2,500 ppm females at 9 months. Mean erythrocyte hemoglobin and mean erythrocyte hemoglobin concentration of 2,500 ppm females were also significantly lower than those of controls at 9 months and in both sets of female rats evaluated at 15 months. Platelet counts of 2,500 ppm male and female rats were slightly but significantly higher than those of controls at 3 and 9 months. Platelet counts were also slightly but significantly increased in 2,500 ppm males of one set evaluated at 15 months, and in 2,500 ppm females of the second set evaluated at 15 months. Serum activities of alkaline phosphatase, alanine aminotransferase, and sorbitol dehydrogenase in 2,500 ppm males were significantly greater than those in the controls at 3, 9, and 15 months. Alkaline phosphatase activities in both sets of 1,000 ppm males evaluated at 15 months were also significantly greater than those of controls. Serum activities of alanine aminotransferase and sorbitol dehydrogenase in 2,500 ppm females were also significantly greater than those in controls at 3, 9, and 15 months. Neurotoxicity Findings: There were no significant inhibitory effects of TBBC on motor nerve excitability or conduction, neuromuscular transmission, or muscle contractility. There were no microscopic lesions in the sciatic nerve, quadriceps muscle, or teased nerve preparations of sciatic nerve that could be attributed to TBBC administration. Pathology Findings: At the 15-month interim evaluation, the absolute and relative liver weights of 2,500 ppm female rats were significantly greater than those of controls; at 15 months and at the end of the study, the incidences of Kupffer cell hypertrophy, hepatocyte cytoplasmic vacuolization, and mixed cell foci were also significantly increased. At the end of the study, the incidence of hepatocellular fatty change was significantly increased in 2,500 ppm females. The incidence of Kupffer cell hypertrophy was significantly increased in 2,500 ppm males at 15 months and at 2 years; the incidence of cytoplasmic vacuolization was significantly increased in all exposed males at 15 months but only moderately increased in 1,000 and 2,500 ppm males at 2 years; the incidence of basophilic foci was significantly increased in 2,500 ppm males at 15 months and the incidence of mixed cell foci was significantly increased in 1,000 and 2,500 ppm male rats at 2 years. The incidences of hepatocellular adenoma or carcinoma (combined) in exposed male rats were not significantly greater than that in the controls (0 ppm, 1/50; 500 ppm, 3/50; 1,000 ppm, 3/50; 2,500 ppm, 5/49), were within the historical control range, and were not considered chemical related. The severity of nephropathy was significantly increased in 2,500 ppm female rats. There was a significant negative trend in the incidence of mammary gland fibroadenoma, adenoma, or carcinoma (combined) in female rats (32/50, 24/50, 11/50, 16/50), and the incidences of fibroadenoma in 1,000 and 2,500 ppm females were significantly less than that of the controls. 2-YEAR STUDY IN MICE: Because of the reduction in body weights, the increase in liver and spleen weights, and the accompanying histopathologic changes in the liver of 2,500 ppm male and female mice in the 13-week study, the doses selected for the 2-year study were 250, 500, and 1,000 ppm. Groups of 80 male and 80 female mice were fed diets containing 0, 250, 500, or 1,000 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in the daily ingestion of approximately 30, 60, or 145 mg TBBC/kg body weight for males and 45, 110, or 255 mg TBBC/kg body weight for females. Nine or 10 animals from each exposure group were evaluated at 3, 9, and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed male and female mice were similar to those of the controls. The final mean body weights of male and female mice exposed to 1,000 ppm were 8&percnt; and 18&percnt; lower than those of the controls, respectively. The final mean body weights of females exposed to 250 or 500 ppm were 8&percnt; to 9&percnt; lower than that of the controls. Feed consumption by exposed males was similar to that by controls, and there were no clinical findings attributed to TBBC administration. Hematology and Clinical Chemistry: Hematocrit level, hemoglobin concentration, and erythrocyte count in 1,000 ppm male mice were significantly lower than those in controls at the 15-month interim evaluation. Serum alkaline phosphatase activities in 1,000 ppm males were slightly but significantly greater than those in controls at 3 and 9 months, as was the serum alkaline phosphatase activity in 1,000 ppm females at 9 months. Serum levels of total bilirubin in all exposed groups of males were significantly greater than those in controls at 9 and 15 months. Pathology Findings: In the liver of male mice, negative trends in the incidences of fatty change, clear cell foci, and adenoma or carcinoma combined occurred at the end of the 2-year study. There were no compound-related increased incidences of neoplasms or nonneoplastic lesions in mice receiving TBBC for 2 years. A negative trend in the incidence of fatty change in the liver of male mice also occurred at 15 months. GENETIC TOXICOLOGY: 4,4'-Thiobis(6- t -butyl- m -cresol) was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Sister chromatid exchanges were induced in cultured Chinese hamster ovary cells treated with TBBC, with and without S9, but no increases in chromosomal aberrations were noted in cultured Chinese hamster ovary cells after treatment with TBBC. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of 4,4'-thiobis(6- t -butyl- m -cresol) in male or female F344/N rats administered 500, 1,000, or 2,500 ppm or in male or female B6C3F1, mice administered 250, 500, or 1,000 ppm. Nonneoplastic lesions associated with exposure to TBBC included: Kupffer cell hypertrophy, cytoplasmic vacuolization, and mixed cell foci in the liver of male and female rats, fatty change in the liver of female, rats, and an increase in the severity of nephropathy in the kidney of female rats. In addition, decreased incidences of fibroadenoma, adenoma, or carcinoma (combined) were observed in the mammary gland of female rats. Decreases also occurred in the incidences of fatty change, clear cell foci, and adenoma or carcinoma (combined) in the liver of male mice. Synonyms: 4,4'-Thiobis(6- t -butyl-3-cresol); bis(3- t -butyl-4-hydroxy-6-methylphenyl)sulfide
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PMID:NTP Toxicology and Carcinogenesis Studies of 4,4'-Thiobis(6- t -butyl- m -cresol) (CAS No. 96-69-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 28

The effect of sodium selenite (Se) was investigated against two-stage rat liver carcinogenesis initiated by a single intraperitoneal injection of N-nitrosodiethylamine (DEN, 200 mg kg(-1) i.p.) followed by promotion with phenobarbital (PB, 0.05%) in a basal diet. Se (4 p.p.m.) was administered per os daily throughout the entire experiment, before the initiation, or during the promotion stage. The plasma, liver (hepatoma and surrounding tissue) and kidney tissue were investigated biochemically for lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and 5'-nucleotidase. These enzyme activities were increased (p < 0.001) in plasma of hepatoma-bearing rats compared with normal control rats. The elevation of these enzyme activities in plasma was indicative of the persistent deteriorating effect of DEN in cancer-bearing animals. Aminotransferase levels were decreased in hepatoma and surrounding liver tissue, whereas lactate dehydrogenase, alkaline phosphatase and 5'-nucleotidase were increased in the cancer condition. These enzyme activities were reversed to near normal control values in animals treated with Se. It is apparent that the beneficial effect of Se is primarily exerted on the initiation phase and secondarily during the promotion stage of DEN-initiated rat liver carcinogenesis. The analysis of marker enzyme activities taken together with our previous findings clearly indicates the antitumour efficacy of sodium selenite on DEN-induced hepatoma animals.
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PMID:Sodium selenite modulates tumour marker indices in N-nitrosodiethylamine-initiated and phenobarbital-promoted rat liver carcinogenesis. 1273 4

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