Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have provided evidence recently for a defect in DNA topoisomerase II in ataxia--telangiectasia (A-T) lymphoblastoid cells. This study was initiated to investigate in greater detail the nature of this defect. Southern hybridization analysis was carried out on DNA from control and A-T Epstein--Barr virus-transformed lymphoblastoid cells. The pattern of digestion, using several restriction enzymes, was the same in both cell types. Expression of topoisomerase II mRNA occurred to the same extent and there was no difference in the size of mRNA between the cell types. Western blot analysis revealed that the same amount of a major band of topoisomerase II protein was present in A-T and control cells but there was evidence for a reduced amount of a lower-molecular-weight form in A-T only. Extraction and purification did not lead to alteration in size of the enzyme or in amount recovered.
Carcinogenesis 1989 Jul
PMID:Study of DNA topoisomerase II in ataxia-telangiectasia cells. 247 31

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.
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PMID:Recombinational DNA repair and human disease. 1242 31

NTP Toxicology and Carcinogenesis studies of a-methylbenzyl alcohol (greater than 99% pure), a cosmetic ingredient and food flavoring agent, were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. a-Methylbenzyl alcohol was nominated for study by the National Cancer Institute because of the potential for widespread human exposure. Sixteen-Day and Thirteen-Week Studies: The doses used in the 16-day studies for rats and mice ranged between 125 and 2,000 mg/kg. Six of 10 rats and all mice dosed at 2,000 mg/kg died. In addition, because 7/9 mice dosed at 1,000 mg/kg died, the doses selected for the 13-week studies for mice (47-750 mg/kg) were half those used for rats (93-1,500 mg/kg). In the 13-week studies, deaths of 1/10 male and 3/10 female rats dosed at 1,500 mg/kg were compound related; none of the mice died. Body weight gain was reduced in rats at 1,500 mg/kg; there were no significant histopathologic lesions in either rats or mice. The only compound-related effects were ataxia, labored breathing, and lethargy for up to 30 minutes after dosing in rats and mice given the two highest doses and increases in liver weight to body weight ratios for male rats given the three highest doses and for female rats at all doses. Based on the pattern of mortality and the effects on body weight gain in the short-term studies, doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats and 50 mice of each sex. Two-Year Studies: Significant reduction in body weight gain commenced at weeks 20-30 in high dose male and female rats, and body weights were 20%-30% below those of vehicle controls at study termination. In the low dose groups, body weight reduction occurred only in male rats during the last 10 weeks of the study. After 80 weeks, 60% of the high dose rats and 80%-100% of the low dose and vehicle control rats were alive; thereafter, the number of deaths in the chemically exposed groups increased sharply so that, at the end of 2 years, final survival for vehicle control, low dose, and high dose rats was 35/50; 8/50; and 1/50 for males and 34/50, 25/50, and 11/50 for females. There were a large number of gavage accidents in these studies (1, 9, and 8 for male rats and 1, 4, and 14 for female rats), but these accidents did not contribute to the increase in mortality after week 80, as all but 4 of these occurred earlier. Mortality in the last quarter of the study was thought to be due to the effects of cumulative toxicity of a-methylbenzyl alcohol on a renal excretory system already compromised by aging. Renal nephropathy that commonly occurs during aging was found in all groups of rats, but the severity was greater in male rats dosed with a-methylbenzyl alcohol. In addition, a collection of nonneoplastic lesions (parathyroid hyperplasia, calcification of the heart and glandular stomach, and fibrous osteodystrophy of bone) was found in the dosed male rats; these lesions were probably secondary to mineral imbalance arising from renal dysfunction. Since survival was poor in low and high dose male and high dose female rats, the sensitivity of the study for detecting a carcinogenic effect in these groups was reduced. Despite this limitation, there were dose-related increases in the incidences of renal tubular cell adenomas or adenocarcinomas (combined) in male rats (vehicle control, 0/50; low dose, 2/50; high dose, 5/50). In addition, transitional cell papillomas of the urinary bladder were observed in one high dose male and two high dose female rats. In mice, a reduction in body weight gain was apparent in the high dose groups of males and females. Final survival rates in mice were similar among groups (male: 39/49; 40/50; 28/50; female: 41/50; 41/50; 38/50). No neoplastic or nonneoplastic lesions were attributed to a-methylbenzyl lesions were attributed to a-methylbenzyl alcohol administration in mice of either sex. Genetic Toxicology: a-Methylbenzyl alcohol was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation. a-Methylbenzyl alcohol produced a positive response without activation in the mouse L5178Y/TK+/- lymphoma assay for induction of trifluorothymidine resistance; it was not tested with activation. In cytogenetic tests with CHO cells, a-methylbenzyl alcohol induced chromosomal aberrations in the presence, but not the absence, of metabolic activation; no induction of sister chromatid exchanges was observed in CHO cells after exposure to a-methylbenzyl alcohol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activityof a-methylbenzyl alcohol for male F344/N rats, as shown by increased incidences of renal tubular cell adenomas and adenomas or adenocarcinomas (combined). There was no evidence of carcinogenic activity for female F344/N rats administered 375 or 750 mg/kg. Renal toxicity characterized by severe nephropathy and related secondary lesions was observed in the dosed rats, and excessive mortality occurred during the last quarter of the studies. Poor survival reduced the sensitivity of the studies for detecting the presence of a carcinogenic response both in chemically exposed groups of male rats and in the high dose group of female rats. There was no evidence of carcinogenic activity of a-methylbenzyl alcohol for male or female B6C3F1 mice administered 375 or 750 mg/kg for 2 years. Synonyms: styrallyl alcohol; styralyl alcohol; a-methylbenzenemethanol; phenylmethylcarbinol; 1-phenethyl alcohol
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PMID:NTP Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol (CAS No. 98-85-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 35

Hexachloroethane is used in organic synthesis as a retarding agent in fermentation, as a camphor substitute in nitrocellulose, in pyrotechnics and smoke devices, in explosives, and as a solvent. In previous long-term gavage studies with B6C3F1 mice and Osbourne-Mendel rats (78 weeks of exposure followed by 12-34 weeks of observation), hexachloroethane caused increased incidences of hepatocellular carcinomas in mice. However, survival of low and high dose rats was reduced compared with that of vehicle controls, and the effects on rats were inconclusive. Therefore, additional toxicology and carcinogenesis studies were conducted in F344/N rats by administering hexachloroethane (approximately 99% pure) in corn oil by gavage to groups of males and females for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Urinalysis was performed in conjunction with the 13-week studies. Sixteen-Day Studies: In the 16-day studies (dose range, 187-3,000 mg/kg), all rats that received 1,500 or 3,000 mg/kg and 1/5 males and 2/5 females that received 750 mg/kg died before the end of the studies. Final mean body weights of rats that received 750 mg/kg were 25% lower than that of vehicle controls for males and 37% lower for females. Compound-related clinical signs seen at 750 mg/kg or more included dyspnea, ataxia, prostration, and excessive lacrimation. Other compound-related effects included hyaline droplet formation in the tubular epithelial cells in all dosed males and tubular cell regeneration and granular casts in the tubules at the corticomedullary junction in the kidney in males receiving 187 and 375 mg/kg. Thirteen-Week Studies: In the 13-week studies (dose range, 47-750 mg/kg), 5/10 male rats and 2/10 female rats that received 750 mg/kg died before the end of the studies. The final mean body weight of male rats that received 750 mg/kg was 19% lower than that of vehicle controls. Compound-related clinical signs for both sexes included hyperactivity at doses of 94 mg/kg or higher and convulsions at doses of 375 or 750 mg/kg. The relative weights of liver, heart, and kidney were increased for exposed males and females. Kidney lesions were seen in all dosed male groups, and the severity increased with dose. Papillary necrosis and tubular cell necrosis and degeneration in the kidney and hemorrhagic necrosis in the urinary bladder were observed in the five male rats that received 750 mg/kg and died before the end of the studies; at all lower doses, hyaline droplets, tubular regeneration, and granular casts were present in the kidney. No chemical-related kidney lesions were observed in females. Foci of hepatocellular necrosis were observed in several male and female rats at doses of 188 mg/kg or higher. Dose selection for the 2-year studies was based primarily on the lesions of the kidney in males and of the liver in females. Studies were conducted by administering hexachloroethane in corn oil by gavage at 0, 10, or 20 mg/kg body weight, 5 days per week, to groups of 50 male rats. Groups of 50 female rats were administered 0, 80, or 160 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were slightly (5%-9%) lower than those of vehicle controls toward the end of the studies. No significant differences in survival were observed between any groups of rats (male: vehicle control, 31/50; 10 mg/kg, 29/50; 20 mg/kg, 26/50; female: vehicle control, 32/50; 80 mg/kg, 27/50; 160 mg/kg, 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Incidences of kidney mineralization (vehicle control, 2/50; low dose, 15/50; high dose, 32/50) and hyperplasia of the pelvic transitional epithelium (0/50; 7/50; 7/50) were increased in dosed male rats. Renal tubule hyperplasia was observed at an increased incidence in high dose male rats (2/50; 4/50; 11/50). These lesions have been described as characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generateted with an accumulation of liver-generated a2μ-globulin in the cytoplasm of tubular epithelial cells. The severity of nephropathy was increased in high dose male rats (moderate vs. mild), and the incidences and severity of nephropathy were increased in dosed females (22/50; 42/50; 45/50). The incidences of adenomas (1/50; 2/50; 4/50), carcinomas (0/50; 0/50; 3/50), and adenomas or carcinomas (combined) (1/50; 2/50; 7/50) of the renal tubule were also increased in the high dose male group. One of the carcinomas in the high dose group metastasized to the lung. No compound-related neoplasms were observed in females. The incidence of pheochromocytomas of the adrenal gland in low dose male rats was significantly greater than that in vehicle controls (15/50; 28/50; 21/49), and the incidences for both dosed groups were greater than the mean historical control incidence (28% ± 11%). Genetic Toxicology: Hexachloroethane was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation. In CHO cells, hexachloroethane did not induce chromosomal aberrations with or with out metabolic activation but did produce sister chromatid exchanges in the presence of exogenous metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of hexachloroethane have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of hexachloroethane for male F344/N rats, based on the increased incidences of renal neoplasms. The marginally increased incidences of pheochromocytomas of the adrenal gland may have been related to hexachloroethane administration to male rats. There was no evidence of carcinogenic activity of hexachloroethane for female F344/N rats administered 80 or 160 mg/kg by gavage for 103 weeks. The severity of nephropathy and incidences of linear mineralization of the renal papillae and hyperplasia of the transitional epithelium of the renal pelvis were increased in dosed male rats. The incidences and severity of nephropathy were increased in dosed female rats. Synonyms: carbon hexachloride; ethane hexachloride; hexachlorethane; hexachloroethylene; 1,1,1,2,2,2-hexachloroethane; perchloroethane Trade Names: Avlothane; Distokal; Distopan; Distopin; Egitol; Falkitol; Fasciolin; Mottenhexe; Phenohep
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PMID:Toxicology and Carcinogenesis Studies of Hexachloroethane (CAS No. 67-72-1) in F344/N Rats (Gavage Studies). 1269 80

N-Methylolacrylamide is a cross-linking agent used in adhesives, binders for paper, crease-resistant textiles, resins, latex film, and sizing agents. Toxicology and carcinogenesis studies were conducted by administering N-methylolacrylamide (98% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells; an in vivo bone marrow micronucleus test was performed with B6C3F1 mice. Neurobehavioral assays were performed during the 13-week studies. Sixteen-Day Studies: The doses of N-methylolacrylamide used ranged from 25 to 400 mg/kg. All rats that received 400 mg/kg died within 4 days, and 3/5 male rats that received 200 mg/kg also died before the end of the studies. Compound-related clinical signs seen with 200 mg/kg included ataxia, muscle tremors, and hyperirritability. Ataxia after dosing was observed from day 7 to the end of the studies for rats that received 100 mg/kg. The final mean body weight of male rats that received 100 or 200 mg/kg was 10% or 27% lower than that of the vehicle controls. The final mean body weight of female rats that received 200 mg/kg was 20% lower than that of the vehicle controls. Compound-related lesions in rats included hyperplasia of the bronchiolar and tracheal epithelium, dysplasia of the nasal and tracheal epithelium, centrilobular hepatocellular necrosis, lymphoid depletion of the spleen, and myelin degeneration of the lumbar ventral spinal nerve. All 5 male and 4/5 female mice that received 400 mg/kg N-methylolacrylamide died on the second day of the 16-day studies. The surviving female mouse in the 400 mg/kg group and the male and female mice in the 200 mg/kg groups were ataxic after they were dosed, starting on day 2. Weight changes were inconsistent among dose groups. Bronchial epithelial hyperplasia (mild) appeared to be dose related in males and females. Sinusoidal congestion of the liver and vacuolar degeneration of myocardial fibers were seen in males and females given 400 mg/kg. Thirteen-Week Studies: The doses of N-methylolacrylamide used ranged from 12.5 to 200 mg/kg. All rats that received 100 or 200 mg/kg died before the end of the studies. Rats that received 100 or 200 mg/kg had hind limb ataxia, which progressed to hind limb paralysis. Rats that received 50 mg/kg had hind limb ataxia beginning at week 8, which progressed to hind limb paresis by week 11. The final mean body weight of rats that received 25 or 50 mg/kg was 8% or 16% lower than that of the vehicle controls for males and 6% or 10% lower for females. In neurobehavioral assessments, decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and at doses as low as 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly increased for male and female rats that received 50 mg/kg. Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses. Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders at gross examination. All mice that received 200 mg/kg N-methylolacrylamide died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. A decreased relative testis weight was observed for mice that received 12.5 mg/kg or more. The relative kidney weights for male mice receiving 50 or 100 mg/kg were greater than that for vehicle controls. Neurobehavioral studies indicated decreased forelimb grip strength in male and female mice at doses as low as 25 mg/kg. An exaggerated startle response was seen for female mice given 100 mg/kg. A reduction in rotarod performance was seen for male and female mice receiving 100 mg/kg and for male mice receiving 25 mg/kg. Hepatocellular necrosis anmale mice receiving 25 mg/kg. Hepatocellular necrosis and thymic lymphocytic necrosis were compound-related effects in mice given 200 mg/kg N-methylolacrylamide. Hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were present in 3/10 female mice given 200 mg/kg, and cytoplasmic vacuolization of the adrenal cortex was seen with lower doses. Based on the results of these short-term studies, 2-year studies were conducted by administering 0, 6, or 12 mg/kg N-methylolacrylamide in water by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. Groups of 50 mice of each sex were administered 0, 25, or 50 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were within 6% of those of vehicle controls throughout most of the studies. Mean body weights of dosed mice were as much as 25% greater than those of vehicle controls for females and as much as 13% greater for males. The survival of female rats given 25 mg/kg per day was lower than that of vehicle controls after day 550, but survival of female rats given 50 mg/kg per day was not different from that of vehicle controls (vehicle control, 35/50; low dose, 22/50; high dose, 33/50). No differences in survival were observed between any other groups of rats or mice of either sex (male rats: 28/50; 22/50; 27/50; male mice: 30/50; 20/50; 21/50; female mice: 41/50; 35/50; 33/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In rats, no biologically important nonneoplastic or neoplastic lesions were attributed to administration of N-methylolacrylamide. Higher doses might have increased the sensitivity of the studies to determine the presence or absence of a carcinogenic response. In mice, the incidences of adenomas of the Harderian gland were increased in males given either dose of N-methylolacrylamide and in females given the top dose (male: vehicle control, 1/48; low dose, 14/49; high dose, 29/50; female: 5/47; 8/45; 20/48). The incidences of carcinomas of the Harderian gland were not significantly increased by N-methylolacrylamide administration (male: 1/48; 0/49; 2/50; female: 0/47; 3/45; 2/48). The incidences of hepatocellular adenomas were increased in male and female mice given 50 mg/kg N-methylolacrylamide (male: 8/50; 4/50; 19/50; female: 3/50; 4/50; 17/49). The incidences of hepatocellular carcinomas were also marginally increased in dosed male mice (male: 6/50; 13/50; 12/50; female: 3/50; 3/50; 2/49). Hepatocellular adenomas and carcinomas (combined) occurred with positive trends, and the incidences in male and female mice receiving 50 mg/kg were increased compared with those in the vehicle controls (male: 12/50; 17/50; 26/50; female: 6/50; 7/50; 17/49). Chronic inflammation and alveolar epithelial hyperplasia of the lung were observed at increased incidences in mice given N-methylolacrylamide. Sentinel mice were seropositive for Sendai virus at 18 months. The incidences of alveolar/bronchiolar adenomas (3/49; 6/50; 11/50) and carcinomas (2/49; 4/50; 10/50) were increased in male mice given 50 mg/kg. Alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a positive trend in male mice (5/49; 10/50; 18/50). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was increased in female mice given the top dose of 50 mg/kg (6/50; 8/50; 13/49). Ovarian atrophy was observed at increased incidences in female mice receiving N-methylolacrylamide (3/50; 39/45; 38/47). The incidences of benign granulosa cell tumors were also increased in the dosed groups (0/50; 5/45; 5/47). The incidence of adenomas of the pars distalis in high dose female mice was significantly lower than that in vehicle controls (13/49; 5/14; 4/43). Genetic Toxicology: N-Methylolacrylamide was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without exogenous metabolic activation. N-Methylolacrylamide induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells with and without metabolic activation. No increase in micronucleated polychromatic erythrocytes (PCEs) was observed in the bone marrow of B6C3F1 mice after intraperitoneal injection of N-methylolacrylamide. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg per day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. In rats, because no biologically important toxic effects were attributed to N-methylolacrylamide administration, somewhat higher doses could have been used to increase the sensitivity of these studies for determining the presence or absence of a carcinogenic response. In female mice, ovarian atrophy was compound related. Synonyms: N-(hydroxymethyl)acrylamide; N-(hydroxymethyl)-2-propenamide; N-methanolacrylamide; monomethylolacrylamide
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PMID:NTP Toxicology and Carcinogenesis Studies of N-Methylolacrylamide (CAS No. 924-42-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1270 32

Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular casts, and mineralization. Arsenic levels in urine, blood, kidney, and liver of dosed rats increased (140%-300%) with time on study and were proportional to the dietary concentrations of roxarsone. No compound-related hematologic or clinical chemical effects were observed in rats. In the first 13-week studies, final mean body weights of mice that received 800 ppm were 11%-18% lower than those of controls. Deaths occurred in males and females receiving 400 and 800 ppm. No compound-related gross or histopathologic lesions were observed. In the second 13-week studies in mice, no compound-related hematologic or clinical chemical effects were observed. At the end of the studies, arsenic concentrations in dosed mice ranged from 0.45 to 0.99 ug/g of liver and from 0.85 to 2.98 ug/g of kidney. No arsenic was detected in the liver or kidney of control mice. Because of kidney lesions, lower body weight gain, and increased mortality in rats and lower body weight gain and increased mortality in mice in the short-term studies, dietary concentrations of roxarsone selected for the 2-year studies were 0, 50, or 100 ppm for rats and 0, 100, or 200 ppm for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of controls. No significant differences in survival were observed between any groups of rats of either sex, although survival in males was lower than usual (final survival--male: control, 24/50; low dose, 18/50; high dose, 18/50; female: 27/50; 35/50; 32/50). The average feed consumption by high dose rats was 95% that of controls for males and 88% for females. The average amount of roxarsone consumed per day was approximately 2 mg/kg for low dose rats and 4 mg/kg for high dose rats. Mean body weights of high dose male mice were generally 5%-8% higher than those of the controls, whereas those of female mice were generally 6%-15% lower than those of the controls. The survival of the control group of male mice was lower than that of the low dose group after month 22; survival for females was low (final survir than that of the low dose group after month 22; survival for females was low (final survival--male: 27/50; 40/50; 33/50; female: 14/50; 18/50; 17/50). The low survival in females was due in part to utero-ovarian infection, with more than 50% of the animals in each dose group having suppurative inflammation at this site. The average daily feed consumption by dosed mice was 105%-110% that by the controls. The average amount of roxarsone consumed per day was approximately 21 or 43 mg/kg for low dose or high dose male mice and 27 or 54 mg/kg for low dose or high dose female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Although the incidence of adenomas of the exocrine pancreas in high dose male rats was not statistically greater than that in the controls (control, 1/50; low dose, 1/50; high dose, 5/50), it was greater than that seen in any historical control group of male F344/N rats. The historical rate is 1/437 (0.2%) for the study laboratory and 5/1,871 (0.3%) throughout the Program. The incidences of hyperplasia were 2/50; 0/50; 3/50. No hyperplasia oradenomas were observed in the exocrine pancreas of female rats. Clitoral gland adenomas in female rats occurred with a marginally positive trend (1/44; 3/47; 6/48; P=0.049). One carcinoma was also observed in each of the groups. The incidences of adenomas or of adenomas or carcinomas (combined) in the dosed groups were not significantly different from those in the controls. This marginal effect was not considered to be related to roxarsone administration. No chemical-related increases in neoplastic or nonneoplastic lesions occurred in male or female mice. Lymphomas in female mice occurred with a negative trend; the incidences in the dosed groups were lower than that in the controls (13/50; 2/50; 3/50; P≤0.01). Genetic Toxicology: Roxarsone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Roxarsone induced trifluorothymidine (Tft) resistance in mouse lymphoma L5178Y cells in the absence of metabolic activation; it was not tested with activation. Exposure of adult male Drosophila melanogaster to roxarsone by injection or by feeding did not cause an increase in sex--linked recessive lethal mutations. Audit: The data, documents, and pathology materials from the 2-year studies of roxarsone have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally increased incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 years. Synonyms: 4-hydroxy-3-nitrophenylarsonic acid; 4-hydroxy-3-nitrobenzenearsonic acid; 2-nitro-1-hydroxybenzene-4-arsonic acid; nitrophenolarsonic acid; 3-nitro-4-hydroxybenzenearsonic acid; 3-nitro-4-hydroxyphenylarsonic acid Trade Names: Ristat; Ren-O-sal; 3-nitro; 3-nitro-10; 3-nitro-20; 3-nitro-50; 3-nitro-80
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PMID:NTP Toxicology and Carcinogenesis Studies of Roxarsone (CAS No. 121-19-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1272 87

H4(D10S170) gene has been identified upon its frequent rearrangement with RET in papillary thyroid tumours (RET/PTC1). The kinase ataxia telangectasia mutated (ATM) phosphorylates a limited number of downstream protein targets in response to DNA damage. We investigated the potential role of H4(D10S170) in DNA damage signaling pathways. We found that in cells treated with etoposide or ionizing radiation (IR), H4(D10S170) underwent ATM-mediated phosphorylation at Thr 434, stabilizing nuclear H4. In ataxia telangectasia cells (A-T), endogenous H4(D10S170) was localized to cytoplasm and was excluded from the nucleus. Moreover, H4(D10S170) was not phosphorylated in ATM-deficient lymphoblasts after ionizing irradiation. Inhibition of ATM kinase interfered with H4(D10S170) apoptotic activity, and expression of H4 with threonine 434 mutated in Alanine, H4(T434A), protected the cells from genotoxic stress-induced apoptosis. Most importantly, after exposure to IR we found that silencing of H4(D10S170) in mammalian cells increased cell survival, as shown by clonogenic assay, allows for DNA synthesis as evaluated by bromodeoxyuridine incorporation and permits cells to progress into mitosis as demonstrated by phosphorylation on Histone H3. Our results suggest that H4(D10S170) is involved in cellular response to DNA damage ATM-mediated, and that the impairment of H4(D10S170) gene function might have a role in thyroid carcinogenesis.
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PMID:Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage. 1742 Jul 23

The process of skin aging in humans is complex and is induced by multiple factors, including genetic and various environmental ones. In particular, the superposition of environmental factors, such as UV irradiation on skin, results in massive wound-like morphological alterations mainly of the dermis. In sun-protected areas the most pronounced changes occur within the epidermis and affect mostly the basal cell layer. As a result, while sun-protected aged skin appears thin, finely wrinkled, and dry, photoaged skin is characterized by deep wrinkles, laxity, and roughness. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways in the generation of aged skin. Recent data obtained by expression-profiling studies and studies of progeroid syndromes (e.g., Hutchinson-Gilford progeria, Werner syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, ataxia teleangiectasia, and Down syndrome) illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, ubiquitin-induced proteolysis, and cellular metabolism. One of the major factors that has been proposed to play an exquisite role in the initiation of aging is the physiological hormone decline occurring with age. However, hormones at age-specific levels may not only regulate age-associated mechanisms but also regulate tumor-suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies in dealing with the various diseases accompanying aging, including cancer.
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PMID:Molecular mechanisms of skin aging: state of the art. 1805 53

Inorganic arsenic increases urinary bladder transitional cell carcinoma in humans. In F344 rats, dimethylarsinic acid (DMA[V]) increases transitional cell carcinoma. Arsenic-induced inhibition of DNA repair has been reported in cultured cell lines and in lymphocytes of arsenic-exposed humans, but it has not been studied in urinary bladder. Should inhibition of DNA damage repair in transitional epithelium occur, it may contribute to carcinogenesis or cocarcinogenesis. We investigated morphology and expression of DNA repair genes in F344 rat transitional cells following up to 100 ppm DMA(V) in drinking water for four weeks. Mitochondria were very sensitive to DMA(V), and swollen mitochondria appeared to be the main source of vacuoles in the transitional epithelium. Real-time reverse transcriptase polymerase chain reaction (Real-Time RT PCR) showed the mRNA levels of tested DNA repair genes, ataxia telangectasia mutant (ATM), X-ray repair cross-complementing group 1 (XRCC1), excision repair cross-complementing group 3/xeroderma pigmentosum B (ERCC3/XPB), and DNA polymerase beta (Polbeta), were not altered by DMA(V). These data suggested that either DMA(V) does not affect DNA repair in the bladder or DMA(V) affects DNA repair without affecting baseline mRNA levels of repair genes. The possibility remains that DMA(V) may lower damage-induced increases in repair gene expression or cause post-translational modification of repair enzymes.
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PMID:Dimethylarsinic acid in drinking water changed the morphology of urinary bladder but not the expression of DNA repair genes of bladder transitional epithelium in F344 rats. 1938 86

Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity). It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation therapy, all these phenomena should be taken into account.
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PMID:Biological complexities in radiation carcinogenesis and cancer radiotherapy: impact of new biological paradigms. 2470 45


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