Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We searched iron-deficient inducible cDNA, using subtraction cloning and mRNA from desferrioxamine-treated mouse macrophage Raw264.7 cells. We identified a pleomorphic adenoma gene like 2 (PLAGL2), one of PLAG superfamily proteins exhibiting antiproliferative properties on tumor cells. Mouse PLAGL2 consists of 496 amino acids with seven C2H2 zinc-fingers. PLAGL2 mRNA was induced in RAW264.7 cells, mouse erythroleukemia cells and Balb/c 3T3 cells when they were treated with desferrioxamine. Hypoxia also increased PLAGL2 mRNA. Expression of PLAGL2 in COS-7 cells led to nuclear localization. PLAGL2 had potential binding ability to GC-rich oligonucleotide and activated transcription of a gene with the binding sequence in transient reporter assay, a finding consistent with a case seen in a PLAGL2 homolog, ZAC-1. Transient co-transfection of PLAGL2 or ZAC1 cDNA and a reporter containing a lactate dehydrogenase A (LDHA) promoter carrying the hypoxia inducible factor-1 responsive element led to an increase in the basal transcription in Balb/c 3T3 and HepG2 cells. Activation in transcription from the LDHA promoter increased by desferrioxamine treatment or hypoxia was further enhanced when PLAGL2 was expressed. We propose that PLAGL2 is involved in the cell cycle arrest and apoptosis of tumor cells by regulating iron depletion- or hypoxia-inducible gene expression.
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PMID:Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines. 1149 94

High intake of fat and a low intake of foods rich in antioxidants and fibre are suggested to be associated with risk of colorectal adenomas. Inconsistency may, however, be due to dietary assessment problems or differences in the identification of cases and controls. We have compared 87 adenoma cases aged 50-76 years with 35 healthy controls and 35 'hospital' controls. All the controls were matched for sex and age (+/-5 years) and proven to be free of polyps. Current habitual diet was measured by a 5-day dietary record by weighing. Regarding the intakes of vegetable fat, protein, cholesterol, vitamin A, total vitamin D, edible fats, coffee and fish and fish products, the outcomes of the analysis depended upon the source of controls. However, an increased adenoma risk compared with either set of controls related to a low consumption of vegetables, cereals, iron, vitamin C and fibre and a high intake of total fat was found. This is suggestive of substantial differences, since bias due to abdominal symptoms, the dietary records or an inappropriate choice of controls, would have affected the estimations. The findings give further strength to the role of these dietary factors in the formation of precancerous lesions in the large intestine.
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PMID:Current diet and colorectal adenomas: a case-control study including different sets of traditionally chosen control groups. 1171 54

The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.
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PMID:Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. 1239 28

In recent years, the concept of chromophobe renal cell carcinoma (RCC) has been established. Chromophobe RCCs account for about 4-6% of all renal tumors. Macroscopically, the cut surface of the tumor is generally grey-beige in color. Histologically, there are two variants (typical and eosinophilic). In the typical variant, large tumor cells with architecture of a compact tubulo-cystic pattern proliferate. The cytoplasm is abundant and shows a fine reticular translucent pattern. The cell border is thick, prominent and eosinophilic. In the eosinophilic variant, tumor cells are smaller and markedly eosinophilic, and a perinuclear halo is often seen. Histochemically, the tumor cells generally show a diffuse and strong reaction for Hale's colloidal iron staining. Ultrastructurally, tumor cells contain many cytoplasmic microvesicles (150-300 nm). In chromosomal analysis, a low chromosome number is characteristic of chromophobe RCCs, due to the frequent occurrence of a combined loss of chromosomes 1, 2, 6, 10, 13, 17, and 21. In differential diagnosis, histological distinction from oncocytomas, which share a common phenotype (intercalated cells of the collecting duct system), is most important. In this diagnostic setting, recent studies have given rise to several problems. Firstly, some cases of coexistent chromophobe RCC and oncocytoma (so-called renal oncocytosis) or cases of oncocytoma with metastasis have recently been reported. Secondly, the existence of chromophobe adenoma, which is the benign counterpart of chromophobe RCC, and an oncocytic variant of chromophobe RCC has recently been suggested. Therefore, further studies are needed to elucidate the relationship between chromophobe RCCs and oncocytomas, to confirm whether chromophobe adenoma actually exists or not, and to identify the key gene that causes chromophobe RCCs.
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PMID:Review of chromophobe renal cell carcinoma with focus on clinical and pathobiological aspects. 1250 96

Manganese is the 12th most abundant element in the earth's crust. The base metal does not occur naturally, but is a component of more than 100 minerals, including sulfides, oxides, carbonates, silicates, phosphates, and borates. In addition to occurring in foods and drinking water, manganese occurs in the atmosphere from dust, volcanic activity, forest fires, and industrial emissions. Manganese (II) sulfate monohydrate was chosen for study because of its stability, solubility, and availability. Toxicology and carcinogenesis studies were conducted by administering manganese (II) sulfate monohydrate (97% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, germ cells of Drosophila melanogaster, and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female rats received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. All rats survived to the end of the study. Male rats exposed to 50,000 ppm had a mean body weight gain 57% lower and a final mean body weight 13% lower than those of the controls. The mean body weight gain of 50,000 ppm females was 20% lower and the final mean body weight was 7% lower than those of the controls. During the second week, 50,000 ppm males and females exhibited diarrhea. 14-DAY STUDY IN MICE: Groups of five male and five female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. One female mouse in the 25,000 ppm group died on day 1 of unknown causes; all other mice survived to the end of the study. Differences in body weights between exposed and control mice could not be attributed to chemical administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received diets containing 0, 1,600, 3,130, 6,250, 12,500, or 25,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1,700 mg/kg body weight in males and 115 to 2,000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3,130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6,250,12,500, or 25,000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25,000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6,250, 12,500, and 25,000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6,250,12,500, and 25,000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent hematocrit and erythrocyte count in the 6,250,12,500, and 25,000 ppm groups. No clinical or histopathologic findings in rats were chemical related. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7,400 mg/kg body weight in males and 390 to 6,900 mg/kg body weight in females. No deaths were chemical related. The mean body weight gains of exposed male mice and of 50,000 ppm female mice were significantly lower than those of controls. The absolute and relative liver weights of 50,000 ppm males were significantly lower than those of controls. The percent hematocrit and hemoglobin concentration of males and females exposed to 50,000 ppm were lower than those of the controls, and the mean erythrocyte volumes were significantly lower than those of the controls. The total leukocyte counts of males in the 25,eukocyte counts of males in the 25,000 and 50,000 ppm groups were significantly lower than that of the controls. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Epithelial hyperplasia and hyperkeratosis of the forestomach occurred in three 50,000 ppm males. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were fed diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. Based on average daily feed consumption, these doses resulted in the daily ingestion of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg (females). Eight to 10 rats from each group were evaluated at 9 and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 15,000 ppm male rats in the 2-year study was significantly lower than that of the control group. The deaths of males in the control and exposure groups were attributed to a variety of spontaneous neoplastic and nonneoplastic lesions; however, the greater number of deaths in the 15,000 ppm group resulted from increased incidences of advanced renal disease related to ingestion of manganese (II) sulfate monohydrate. The decreased survival of the 15,000 ppm males did not occur until approximately week 93 of the study; before week 93, survival was similar in all groups. Survival of exposed females was similar to that of the controls. The mean body weight of 15,000 ppm male rats was within 5% of the control group until week 89, by week 104, the mean body weight of 15,000 ppm males was 10% lower than that of the control group. The mean body weights of 1,500 and 5,000 ppm male rats and all exposed female groups were similar to those of the controls throughout the study. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No differences in hematology and clinical chemistry parameters attributable to the ingestion of manganese (II) sulfate monohydrate occurred between exposed and control groups. At both the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of 5,000 and 15,000 ppm male and female rats, with an accompanying depression of hepatic iron. Pathology Findings: The ingestion of diets containing 15,000 ppm manganese (II) sulfate monohydrate was associated with a marginal increase in the average severity of nephropathy in male rats (0 ppm, 2.9; 1,500 ppm, 3.0; 5,000 ppm, 3.0; 15,000 ppm, 3.2). The increased severity of nephropathy in the 15,000 ppm male rats was accompanied by significantly increased incidences of mineralization of the blood vessels (4/52, 10/51, 6/51,17/52) and glandular stomach (8/52,13/51, 9/51, 23/52), parathyroid gland hyperplasia (14/51, 14/46, 12/49, 23/50), and fibrous osteodystrophy of the femur (12/52,14/51,12/51, 24/52). These lesions are manifestations of renal failure, uremia, and secondary hyperparathyroidism. The increased incidence of advanced renal disease caused reduced survival of the high-dose male rats. No increase in the incidence of neoplasms in male or female rats was attributed to the ingestion of diets containing manganese (II) sulfate monohydrate. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. These levels resulted in an average daily ingestion of 160, 540, or 1,800 mg/kg body weight (males) or 200, 700, or 2,250 mg/kg (females). Nine or 10 mice from each group were evaluated at the 9-month and 15-month interim evaluations. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival rates of exposed male and female mice in the 2-year study were similar to those of the control groups. The mean body weights of exposed male mice were similar to that of the control group. Compared to controls, female mice had exposure related lower mean body weights after week 37, and the final mean body weights for the 1,500, 5,000, and 15,000 ppm groups were 6%, 9%, and 13% lower than that of the control group. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to the administration of manganese (II) sulfate monohydrate. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No chemical-related differences between exposed and control groups occurred in hematology or clinical chemistry parameters. At the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of the 5,000 and 15,000 ppm groups. Hepatic iron levels were significantly lower in exposed females at the 9-month interim evaluation and in 5,000 and 15,000 males and all exposed females at the 15-month interim evaluation. Pathology Findings: Incidences of thyroid follicular dilatation and hyperplasia were significantly greater in 15,000 ppm male and female mice than in controls. Follicular cell adenomas occurred in one 15,000 ppm male at the 15-month interim evaluation and in three 15,000 ppm males at the end of the study but not in the lower exposure groups or the control group. Follicular cell adenomas also occurred in two control, one 1,500, and five 15,000 ppm female mice at the end of the study. It is uncertain if the slightly increased incidence of follicular cell adenoma is related to the ingestion of manganese (II) sulfate monohydrate. The incidences of focal hyperplasia of the forestomach epithelium were significantly greater in the 15,000 ppm male and exposed female groups. The hyperplasia was associated with ulcers and inflammation in some mice, particularly males. GENETIC TOXICOLOGY: Manganese (II) sulfate monohydrate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9), and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. Tests for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells treated without S9 were positive; with S9, only the sister chromatid exchange test with manganese (11) sulfate monohydrate was positive. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male or female F344/N rats receiving 1,500, 5,000, or 15,000 ppm. There was equivocal evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male and female B6C3F1 mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia. The ingestion of diets containing manganese (II) sulfate monohydrate was associated with an increased severity of nephropathy in male rats, focal squamous hyperplasia of the forestomach in male and female mice, and ulcers and inflammation of the forestomach in male mice. These studies were not designed to assess any neurotoxicity that might have been expected with chronic exposure to sufficiently high doses of manganese. Synonyms: Manganese sulfate; manganous sulfate; sulfuric acid. manganese2+ salt (1:1), monohydrate
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PMID:NTP Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate (CAS No. 10034-96-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 3

C.I. Pigment Red 3, a yellowish red solid, is widely used for coloring paints, inks, plastics, and rubber, and in textile printing. It is used in a wide range of consumer items such as wallpaper, typewriter ribbons, carbon paper, and art materials. Toxicology and carcinogenicity studies were conducted by feeding groups of F344/N rats and B6C3F1 mice of each sex diets containing C.I. Pigment Red 3 (97% pure) for 2 weeks, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 2-Week Studies: Groups of five rats and five mice of each sex were given feed containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 3 for 2 weeks. No chemical-related deaths occurred in rats or mice. Final mean body weights of exposed rats and male mice were lower than controls; female mice that received 6,000 and 50,000 ppm had significantly increased final mean body weights compared to that of the controls. The feed consumption of treated rats and mice was slightly greater than that of the controls, suggesting that C.I. Pigment Red 3 had no adverse effects on the feed palatability. Dose-related decreases in erythrocyte counts and hematocrit values and an increase in reticulocyte counts were observed in rats. Changes in these parameters were observed in mice, but there were no clear, dose-related trends. 13-Week Studies: Groups of ten rats and ten mice of each sex were given feed containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 3 for 13 weeks. No chemical-related deaths were observed in rats or mice. The final mean body weights of exposed female rats were significantly lower than that of the controls; the final mean body weights of exposed male rats and exposed mice were similar to controls. There were significant increases in relative liver and kidney weights of exposed male rats. Increases in the relative liver weights in mice did not occur with a dose-related trend and thus they were not considered related to chemical administration. Sites for the toxicity of C.I. Pigment Red 3 were the bone marrow, kidney, liver, and spleen in rats. Lesions observed in rats included bone marrow hyperplasia, congestion and hematopoietic cell proliferation of the spleen, and iron-positive pigmentation of the spleen, kidney, and liver. Sites for the toxicity of C.I. Pigment Red 3 in mice were the liver, kidney, and spleen in males and the liver and spleen in females. Lesions noted among mice in the spleen were hematopoietic cell proliferation and iron-positive pigmentation. In the liver, there was hematopoietic cell proliferation in male and female mice. Cytomegaly occurred in the renal tubule epithelium of the male mouse kidney. 2-Year Studies: Doses selected for the 2-year feed studies were 0, 6,000, 12,500, and 25,000 ppm for rats and 0, 12,500, 25,000, and 50,000 ppm for mice. The dose selection for rats was based on body weight changes observed for females that received 50,000 ppm; the dose selection for mice was based on the lack of body weight depression or death at the doses tested during the 13-week studies. Concentrations higher than 50,000 ppm in the feed were not used because higher levels might have adversely affected the nutritional value of the diet during the 2-year studies. Body Weight, Feed Consumption, Clinical Findings, and Survival in the 2-Year Studies: Final mean body weights for male rats that received 25,000 ppm, female rats that received 12,500 and 25,000 ppm, and male and female mice that received 50,000 ppm were more than 10% lower than those of the controls. Feed consumption of exposed rats and mice was similar to that of the controls. No clinical findings indicative of toxicity were observed in rats or mice. The survival of low-dose male rats was greater than that of the controls (0 ppm, 28/50; 6,000 ppm, 40/50; 12,500 ppm, 28/50; 25,000 ppm, 20/50). Survival of exposed female rats and exposed male mice was similar to the controls; the survival of high-dose female mice was significantly decreased compared to thcompared to that of the controls (39/50, 37/50, 31/50, 25/50). The reduced survival in this dose group may have been due to the increased incidence of ovarian abscesses. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Benign adrenal pheochromocytomas were significantly increased in the 12,500 and 25,000 ppm groups of male rats compared to the controls (22/50, 29/50, 35/50, 34/50). However, malignant neoplasms were not increased in incidence (6/50, 7/50, 10/50, 4/50). The incidence of adrenal pheochromocytomas in dosed groups exceeded the range for NTP historical controls for feed studies (22%-48%), and the increased incidence of this neoplasm was attributed to C.I. Pigment Red 3 administration. Squamous cell papillomas of the skin occurred with a positive trend in male rats (0/50, 4/50, 2/50, 6/50), and the incidence in the high-dose group was significantly greater than that of the controls. A poorly differentiated squamous cell carcinoma (diagnosed as carcinoma) was observed in a control male. The historical control rate for squamous cell papillomas in NTP feed studies is low (16/800 or 2%, range 0%-4%), and the higher incidence of this tumor in male rats may have been caused by the administration of C.I. Pigment Red 3. Hepatocellular adenomas occurred with a positive trend in female rats, with a significantly greater incidence in the high-dose group than in the control group (0/50, 0/50, 1/50, 10/50). This neoplasm has occurred in only one historical control group in NTP feed studies (3/800, range 0%-6%), and the increase in hepatocellular adenomas in female rats was attributed to chemical administration. Chemical-related nonneoplastic lesions observed in the livers of male and female rats included eosinophilic or mixed type foci of cellular alteration. Foci were often accompanied by angiectasis and cystic degeneration in males and by granulomas and cholesterol pigmentation in females. Chronic nephropathy occurred with increased severity in exposed male and female rats. The lesions were more severe in males than in females. Other lesions considered secondary to renal disease included parathyroid gland hyperplasia, fibrous osteodystrophy of the bone, and mineralization of various organs (stomach, intestine, heart, and blood vessels). The increased incidence of hyperplasia of the transitional epithelium of the renal papilla observed in treated rats was considered to be part of the chronic nephropathy. Zymbal's gland carcinoma incidences were marginally increased in the mid- and high-dose male rats (0/50, 0/50, 2/50, 3/50). The incidence in the high-dose group was outside the NTP historical control range (0%-4%), and the Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. Mononuclear cell leukemias, mammary gland fibroadenomas, and preputial gland/clitoral gland adenomas occurred at lower incidences in exposed male and female rats. The decrease in mononuclear cell leukemia was attributed to the direct effect of C.I. Pigment Red 3 or its metabolites on the mechanism responsible for inducing leukemias in aging rats, while the decreased incidence of mammary gland fibroadenomas might be attributed to decreased body weights in female rats. The cause of the decreased incidences of preputial and clitoral gland tumors is unknown. Tubule adenomas of the renal cortex occurred at a significantly higher incidence in high-dose male mice than in controls (0 ppm, 0/50; 12,500 ppm, 0/50; 25,000 ppm, 0/50; 50,000 ppm, 6/50). Because this tumor occurred only in exposed males and was outside the range for NTP historical controls in feed studies (0%-2%), renal cortical tubule adenomas in male mice were considered to be related to the administration of C.I. Pigment Red 3. Follicular cell adenoma of the thyroid gland occurred with a positive trend in male mice (0/50, 0/49, 1/50, 5/50). Theincidence in the high-dose group was significantly greater than that in the controls. This chemical-related effect is supported by the increased incidence of follicular cell hyperplasia. Because the incidence of this tumor exceeded the range of the historical controls from NTP feed studies (0%-4%), the increase of follicular cell adenoma was attributed to chemical administration. Female mice receiving C.I. Pigment Red 3 had a significant increase in follicular cell hyperplasia but showed no increase in tumor incidence at this site. Focal renal tubule hyperplasia and cystic hyperplasia occurred in exposed male mice but not in the controls. Cytomegaly (karyomegaly) of the renal tubule epithelium was seen in all treated male mice. The severity of the accompanying chronic nephropathy was increased in both male and female mice. Genetic Toxicology: C.I. Pigment Red 3 was mutagenic in Salmonella typhimurium strains TA100 and TA98 in the presence of exogenous metabolic activation (S9); no increases in gene mutation were observed in strains TA1535 and TA1537, with or without S9. C.I. Pigment Red 3 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in either the presence or the absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of benign pheochromocytomas of the adrenal gland. The marginal increase in the incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as indicated by the increased incidence of hepatocellular adenomas. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as exhibited by the increased incidences of tubule adenomas of the renal cortex and follicular cell adenomas of the thyroid gland. There was no evidence of carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received 12,500, 25,000, or 50,000 ppm. The incidences of mononuclear cell leukemia and preputial gland tumors in male rats and mononuclear cell leukemia, mammary gland fibroadenoma, and clitoral gland tumors in female rats were lower in the exposed groups. The incidences of liver foci were markedly increased in exposed male and female rats. The severity of chronic nephropathy was increased in male rats and to a lesser extent in female rats given C.I. Pigment Red 3. An increase in the severity of nephropathy was observed in male and female mice; cytomegaly (karyomegaly) of renal tubule epithelium was observed in male mice. Thyroid follicular cell hyperplasia occurred with an increased incidence in male and female mice receiving C.I. Pigment Red 3. Synonyms: 2-Naphthalenol, 1-((4-methyl-2-nitrophenyl)azo)-; Calcotone Toluidine Red YP; Fast Red A; Pigment Scarlet R; Recolite Fast Red RBL; Sengale Light Red B
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PMID:Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 (CAS No. 2425-85-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1262 23

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P&lt;0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG
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PMID:NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). 1275 Jul 52

We report 3 unusual cases of liver cell adenomas with some uncommon features, corresponding to 3 women aged 45, 37, and 41 years, respectively. The diagnosis was incidental in 2 cases, and the third presented with abdominal pain. Radiologic findings were consistent with liver-cell adenoma, but gross examination failed to reveal the lesion until 24 hours of formalin fixation in 2 cases. Histopathological examination showed a striking deposition of iron pigment. In fact, Pearl's stain was the best way to visualize the limits of the neoplasm, which were irregular (pseudo-infiltrative). There was no evidence of other architectural or cytologic features suggesting an alternative diagnosis, particularly liver-cell carcinoma. Follow-up ranged from 9 months to 6 years and all patients are free of disease.
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PMID:Liver-cell adenomas with heavy iron deposition. 1530 36

Heme oxygenase (HO) breaks down the pro-oxidant heme into carbon monoxide, iron and the antioxidant biliverdin. The isoform HO-1 plays an effective role to counteract oxidative damage and to control inflammation. Prolonged cellular damage due to chronic inflammation is one of the reasons leading to the development of tumours. The aim of this work was to investigate HO-1 expression and localization along the different stages of chemically induced hepatocarcinogenesis (HCC) and the occurring morphological changes. To provoke sustained oxidative stress and chronic inflammation, CF1 mice received dietary p-dimethylaminoazobenzene (DAB, 0.5%, w/w) during a whole period of 14 months. HO-1 expression increased along the experimental trial in morphologically normal hepatocytes in DAB-treated animals. HO-1 expression diminished in altered hepatic foci (AHF) and oval cells and early preneoplastic lesions. Otherwise, marked HO-1 overexpression was detected in Kupffer cells and macrophages surrounding necrotic and nodular areas. Adenomas showed decreased HO-1 immunostaining. In hepatocellular carcinomas, an inverse relationship was found between the immunohistochemical expression of HO-1 and the degree of tumour differentiation, being negative in poorly differentiated tumours. In our experimental model, down modulation of HO-1 expression correlated with malignancy progression. Thus, our data point to activation of HO-1 as a potential therapeutic tool.
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PMID:Immunohistochemical analysis of heme oxygenase-1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis. 1531 26

Iron has been suggested to be a risk factor for colorectal neoplasia. Some individuals who are heterozygous for mutations in the hemochromatosis gene (HFE) have higher than average serologic measures of iron. We therefore investigated whether heterozygosity for HFE mutations was related to risk of advanced distal adenoma and whether the relationship was affected by dietary iron intake. In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 679 persons with advanced distal adenoma and 697 control persons were genotyped for the two major HFE mutations (C282Y and H63D), one HFE polymorphism (IVS2+4), and one polymorphism (G142S) in the transferrin receptor gene (TFRC). HFE haplotypes were also created to examine the effect of haplotype on risk. Food frequency questionnaire data were used to estimate daily iron intake. There was no relationship between any HFE genotype or haplotype and advanced adenoma. Stratification of HFE genotype by TFRC genotype did not change the results. In addition, there was no relationship between dietary iron intake and risk of adenoma or between HFE genotype and risk of adenoma, stratified by iron intake. These results do not support a relationship between HFE heterozygosity and risk of advanced distal adenoma.
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PMID:Hemochromatosis gene mutations and distal adenomatous colorectal polyps. 1566 90


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