Fundamental and applied toxicology : official journal of the Society of Toxicology最新文献_第9页

Determination of N7- and O6-methylguanine in rat liver DNA after oral exposure to hydrazine by use of immunochemical and electrochemical detection methods. 免疫化学和电化学检测法测定口服联氨暴露大鼠肝脏DNA中N7-和o6 -甲基鸟嘌呤的含量。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/TOXSCI/35.1.131

J. V. Delft, M. Steenwinkel, A. J. D. Groot, A. A. Zeeland, G. Eberle-Adamkiewicz, M. F. Rajewsky, Jürgen Thomale, R. A. Baan

{"title":"Determination of N7- and O6-methylguanine in rat liver DNA after oral exposure to hydrazine by use of immunochemical and electrochemical detection methods.","authors":"J. V. Delft, M. Steenwinkel, A. J. D. Groot, A. A. Zeeland, G. Eberle-Adamkiewicz, M. F. Rajewsky, Jürgen Thomale, R. A. Baan","doi":"10.1093/TOXSCI/35.1.131","DOIUrl":"https://doi.org/10.1093/TOXSCI/35.1.131","url":null,"abstract":"Hydrazine belongs to a group of compounds for which there is evidence that the in vivo genotoxic effects become manifest only upon exposure to toxic dose levels. The present study was performed to investigate whether this phenomenon is also reflected in the pattern of DNA methylation. The induction of N7- and O6-methylguanine (MeGua) was studied in liver DNA of rats, 16 hr after treatment with various doses of hydrazine. After DNA isolation, the presence of N7-MeGua in DNA was assessed with an immunochemical method and with a physicochemical technique (HPLC with electrochemical detection). Application of these two methods resulted in almost identical patterns of dose-dependent induction of guanine N7-methylation in rats dosed orally with 0.1 to 10 mg hydrazine per kilogram of body weight, increasing from 1.1-1.3 to 39-45 N7-MeGua per 10(6) nucleotides. At lower dosages a constant adduct level was observed, equivalent to that in untreated rats (background level). The O6-MeGua level was analyzed by a combination of HPLC separation and competitive radioimmunoassay. A background level was observed for untreated rats and no increase was visible up to the 0.2 mg/kg dose group. After hydrazine doses from 0.2 to 10 mg/kg, O6-MeGua increased from 0.29 to 134 per 10(9) nucleotides. These data show that even at dosages below the maximum tolerated dose (0.6 mg/kg/day), for which carcinogenic effects have not been described, DNA adducts are formed. A comparison is made of the data obtained in this study with models that describe the mechanism of hydrazine-induced DNA methylation.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"31 1","pages":"131-7"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81860098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

A comparison of the acute behavioral effects of inhaled amyl, ethyl, and butyl acetate in mice. 吸入乙酸戊酯、乙酸乙酯和乙酸丁酯对小鼠急性行为影响的比较。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/35.2.189

S. Bowen, R. Balster

{"title":"A comparison of the acute behavioral effects of inhaled amyl, ethyl, and butyl acetate in mice.","authors":"S. Bowen, R. Balster","doi":"10.1093/toxsci/35.2.189","DOIUrl":"https://doi.org/10.1093/toxsci/35.2.189","url":null,"abstract":"The acute neurobehavioral effects of three acetates (amyl, ethyl, and n-butyl acetate) were investigated after 20-min inhalation exposures in mice using locomotor activity and a functional observational battery (FOB). Ethyl and n-butyl acetate produced significant decreases in locomotor activity at the highest concentrations examined, while amyl acetate was without effect. Minimally effective concentrations for activity-decreasing effects were 2000 ppm for ethyl acetate and 8000 ppm for n-butyl acetate. The potency order was similar in the FOB where ethyl acetate was more potent in disrupting the neurobehavioral measures. The FOB profile of effects for all three acetates included changes in posture, decreased arousal, increased tonic/clonic movements, disturbances in gait, delayed righting reflexes, and increased sensorimotor reactivity. Furthermore, handling-induced convulsions were produced in some mice acutely exposed to each of these acetates. Recovery from the acute effects of these acetates was rapid and began within minutes of removal from the exposure chamber. The acetates produced a profile of neurobehavioral effects that were different from those reported for depressant solvents (i.e., toluene, 1,1,1-trichloroethane) that are subject to abuse. Evidence is emerging for qualitative differences in the acute neurobehavioral effects of various volatile chemicals.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"52 1","pages":"189-96"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85616255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Effect of dexamethasone on ciprofibrate-induced cell proliferation and peroxisome proliferation. 地塞米松对环丙贝特诱导的细胞增殖和过氧化物酶体增殖的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/35.1.78

M. Rao, V. Subbarao

{"title":"Effect of dexamethasone on ciprofibrate-induced cell proliferation and peroxisome proliferation.","authors":"M. Rao, V. Subbarao","doi":"10.1093/toxsci/35.1.78","DOIUrl":"https://doi.org/10.1093/toxsci/35.1.78","url":null,"abstract":"Peroxisome proliferators cause liver cell proliferation in addition to other pleiotropic effects such as peroxisome proliferation and induction of certain peroxisomal and cytosolic enzymes in liver. Since dexamethasone has been shown to inhibit mitogen-induced liver cell hyperplasia, we examined whether dexamethasone inhibits only cell proliferation without affecting peroxisome proliferation induced by peroxisome proliferators such as ciprofibrate. Livers of rats fed a diet containing ciprofibrate (0.025%) with or without added dexamethasone (0.5 mg or 1 mg/kg diet) for 1 week were evaluated for hepatocyte proliferation and peroxisome proliferation. Dexamethasone administration resulted in abrogation of ciprofibrate-induced cell proliferation as shown by bromodeoxyuridine (BrdU) labeling and mitoses counts. The hepatocyte proliferative index measured after administration of a single dose of BrdU was 18.3 +/- 1.1 and 2.3 +/- 0.7% (p < 0.01) in ciprofibrate and ciprofibrate + dexamethasone treated rats, respectively. With multiple injections of BrdU (daily injections for 7 days) the proliferative index was 225 +/- 10 and 183 +/- 2% (p < 0.02), respectively, in these two groups. Interestingly, whereas the levels of peroxisome proliferator-induced Mr 80,000 polypeptide and catalase and peroxisomal bifunctional enzyme, and the corresponding mRNAs and peroxisome volume density were unaffected. These results show that dexamethasone selectively inhibits only cell proliferation without inhibiting the peroxisome proliferation caused by ciprofibrate. This model should be useful for examining the role of cell proliferation versus oxidative stress in peroxisome proliferator-induced hepatocarcinogenesis.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"11 1","pages":"78-83"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81854244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Promotion of altered hepatic foci by 2,3',4,4',5-pentachlorobiphenyl in Sprague-Dawley female rats. 2,3'，4,4'，5-五氯联苯对Sprague-Dawley雌性大鼠肝灶改变的促进作用。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01

M Haag-Grönlund, L Wärngård, S Flodström, G Scheu, T Kronevi, U G Ahlborg, R Fransson-Steen

{"title":"Promotion of altered hepatic foci by 2,3',4,4',5-pentachlorobiphenyl in Sprague-Dawley female rats.","authors":"M Haag-Grönlund, L Wärngård, S Flodström, G Scheu, T Kronevi, U G Ahlborg, R Fransson-Steen","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The tumor promotion potential of 2,3',4,4',5-pentachlorobiphenyl (PCB-118) was studied in a two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The animals were initiated by intraperitoneal administration of N-nitrosodiethylamine after partial hepatectomy. After 5 weeks of recovery, the promotion period commenced by once-weekly subcutaneous administrations of PCB-118 at six dose levels (10, 40, 160, 640, 2500, and 10,000 microg/kg body weight/week) for 20 weeks. In addition, three of these dose levels (40, 640, and 10,000 microg/kg body weight/week) were administered for 52 weeks. Evaluation of hepatic foci positive for glutathione S-transferase P demonstrated that the mono-ortho chlorine substituted congener PCB-118 significantly increased the number of foci/cm3 of liver in the two highest dose groups after 20 weeks, but did not significantly increase the percentage of the liver occupied by foci. After 52 weeks of treatment, both the percentage and the number of foci/cm3 were significantly increased in the highest dose group. A toxic equivalency factor based on foci development during 20 weeks of treatment would be less than 0.00002. Altered relative liver and thymus weights were observed after treatment with both substances as well as an induction of methyl cholanthrene- and phenobarbital-inducible isoenzymes of cytochrome P450 monooxygenase. These results show that PCB-118 has a potency to enhance foci growth in rat liver, although the potency is low compared to that of structurally related compounds.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"35 1","pages":"120-30"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19984925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs. 狗鞘内注入重组甲硫基人脑源性神经营养因子的动力学和安全性研究。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/38.1.89

T. Yaksh, M. Rathbun, J. C. Dragani, S. Malkmus, A. Bourdeau, P. Richter, H. Powell, R. Myers, C. Lebel

{"title":"Kinetic and safety studies on intrathecally infused recombinant-methionyl human brain-derived neurotrophic factor in dogs.","authors":"T. Yaksh, M. Rathbun, J. C. Dragani, S. Malkmus, A. Bourdeau, P. Richter, H. Powell, R. Myers, C. Lebel","doi":"10.1093/toxsci/38.1.89","DOIUrl":"https://doi.org/10.1093/toxsci/38.1.89","url":null,"abstract":"To define the kinetics and safety of spinally infused recombinant-methionyl human brain-derived neurotrophic factor (r-metHuBDNF), beagle dogs were prepared with lumbar intrathecal catheters passed through the cisternal membrane to the L1-L4 lumbar level. For kinetic studies, r-metHuBDNF was delivered by bolus or infusion through one catheter and lumbar CSF was sampled periodically through a second. As a lumbar bolus, r-metHuBDNF displayed a biphasic clearance with t(1/2)a = 0.7 hr and t(1/2)b = 7. 9 hr. Lumbar to cisternal concentrations after bolus delivery were approximately 60:1. For safety studies, dogs received continuous intrathecal infusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNF at 200 (n = 6), 800 (n = 6), or 2000 (n = 7) microg/day. Control dogs showed no changes. Intrathecally infused r-metHuBDNF produced a dose-dependent increase in muscle tone and decreased coordination. Low-dose r-metHuBDNF was associated with moderate increases in muscle tone after 22-28 days of infusion. No clinically important changes were noted in rectal temperature, arterial pressure, respiration and heart rate, body weight, food consumption, stool or urine output, or change in blood chemistries measured throughout the study. Cisternal CSF protein and glucose sampled at 28 days were not different between dose groups and all cultures were negative. Histopathological examination of the spinal cord typically revealed some degree of chronic inflammation around the catheter, including fibrotic adhesions and focal accumulations of lymphoid and plasma cells, but these effects were not dose dependent. In other dogs receiving r-metHuBDNF (2000 or 4000 microg/day), termination of infusion resulted in significant recovery.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"38 1","pages":"89-100"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74692177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Effect of dosing vehicle on the developmental toxicity of bromodichloromethane and carbon tetrachloride in rats. 给药载体对溴二氯甲烷和四氯化碳大鼠发育毒性的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/40.1.30

M. G. Narotsky, R. Pegram, R. Kavlock

{"title":"Effect of dosing vehicle on the developmental toxicity of bromodichloromethane and carbon tetrachloride in rats.","authors":"M. G. Narotsky, R. Pegram, R. Kavlock","doi":"10.1093/toxsci/40.1.30","DOIUrl":"https://doi.org/10.1093/toxsci/40.1.30","url":null,"abstract":"Several halocarbons have been shown to cause full-litter resorption (FLR) in Fischer-344 rats when administered orally in corn oil. Since halocarbons often occur as contaminants of drinking water, we sought to determine the influence of the vehicle, aqueous versus lipid, on the developmental toxicity of two of these agents. In separate assays, bromodichloromethane (BDCM) and carbon tetrachloride (CCl4) were administered by gavage to Fischer-344 rats on gestation days (GD) 6-15 at 0, 25, 50, or 75 mg/kg/day in either corn oil or an aqueous vehicle containing 10% Emulphor EL-620. Dams were allowed to deliver and the litters were examined postnatally. Uteri of females that did not deliver were stained with 10% ammonium sulfide to detect FLR. Effects of both agents on maternal weight gain were slightly more pronounced in the aqueous vehicle at lower doses, but at the highest dose, CCl4 was more maternally toxic in corn oil. Developmentally, both agents caused FLR at 50 and 75 mg/kg in both vehicles. At 75 mg/kg, dams receiving corn oil had significantly higher rates of FLR (83% for BDCM, 67% for CCl4) compared to their aqueous-vehicle counterparts (21% for BDCM, 8% for CCl4). Blood concentrations of BDCM following GD-6 gavage revealed a shorter elimination half-life in the aqueous dosing vehicle (2.7 h) compared to the oil vehicle (3.6 h). Benchmark doses of CCl4 were similar for the oil (18.9 mg/kg) and aqueous (14.0 mg/kg) vehicles. For BDCM, the corn oil vehicle yielded a less conservative (i.e., higher) value (39.3 mg/kg) than the aqueous vehicle (11.3 mg/kg), reflecting different confidence intervals around the estimated 5%-effect dose levels.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"1 2","pages":"30-6"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91426591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 31

The influence of vehicle gavage on seasonality of immune system parameters in the B6C3F1 mouse. 整车灌胃对B6C3F1小鼠免疫系统参数季节性的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/38.2.116

M. M. Dozier, H. Ratajczak, R. Sothern, P. Thomas

{"title":"The influence of vehicle gavage on seasonality of immune system parameters in the B6C3F1 mouse.","authors":"M. M. Dozier, H. Ratajczak, R. Sothern, P. Thomas","doi":"10.1093/toxsci/38.2.116","DOIUrl":"https://doi.org/10.1093/toxsci/38.2.116","url":null,"abstract":"Seasonal hyporesponsiveness and other immune system variations were observed in female B6C3F1 mice during routine screening tests for immunomodulation. In a retrospective assessment, 4 years of data from over 1200 naive, vehicle, and immunosuppressed (cyclophosphamide-treated) control mice were compiled and analyzed for uniformity and significant circannual pattern of immune response. Endpoints included body, spleen, and thymus weights and an immunotoxicity assessment which enumerates specific antibody plaque-forming cells (PFC) in the spleen following immunization with sheep red blood cells. Dosing vehicles were water, corn oil, or 1% methyl cellulose instilled by oral gavage in a 5-20 ml/kg volume once daily for 5 days. Four days later, terminal organ and body weights were recorded and PFC were quantitated. Upon analysis, individual datapoints were arrayed in consistent circannual and seasonal patterns. In naive mice, the yearly peak response in circannual rhythm (acrophase) for body weight and PFC parameters occurred in the summer, with acrophases for spleen and thymus weights located in the spring. Vehicle gavage modulated the circannual/seasonal means and acrophases of all measured endpoints in distinct patterns which varied by vehicle. Body weight was the endpoint least affected by vehicle treatment. Corn oil was the vehicle resulting in the most dramatic effects on natural rhythm. As expected, the naive mice receiving an ip injection of cyclophosphamide exhibited significant decreases (p </= 0.05) in circannual mean values for PFC response and relative organ weights when compared to naive controls and the elimination of significant expression of rhythm for PFC parameters. Our results indicate that dosing vehicles alter normal seasonal patterns of biological responses in the mouse. These effects on natural rhythms should be considered in toxicity evaluations, especially when comparing datapoints collected at different times of the year.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"57 1","pages":"116-22"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83186479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Effect of administration of malathion for 14 days on macrophage function and mast cell degranulation. 马拉硫磷14天对巨噬细胞功能及肥大细胞脱颗粒的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/37.1.95

K. Rodgers, S. Xiong

{"title":"Effect of administration of malathion for 14 days on macrophage function and mast cell degranulation.","authors":"K. Rodgers, S. Xiong","doi":"10.1093/toxsci/37.1.95","DOIUrl":"https://doi.org/10.1093/toxsci/37.1.95","url":null,"abstract":"Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T-cell-dependent antigen, mitogenic responses, macrophage function, and mast cell degranulation. While administration of malathion for 14 days did not affect the generation of an immune response to antigen, it was possible that macrophage and mast cell functions were affected. In this report, the effect of malathion administration for 14 days upon these parameters were assessed. This treatment regimen increased the respiratory burst capacity to a maximal level at a dose of 1 mg/kg/day or greater. The effect of oral administration of malathion for 14 days on the degranulation of mast cells in various organs (heart, skin, and small intestine) and peritoneal lavage fluid was also assessed. At doses of 1 mg/kg/day and above, the number of mast cells that was undegranulated decreased and the number that was severely degranulated increased. There was no change in mast cell integrity in biopsies from heart and skin, and in peritoneal fluid after 14-day administration of 0.1 mg/kg/day. However, the number of mast cells associated with the small intestine that had undergone degranulation was increased at this dose of malathion. These data indicate that repeated administration of malathion increased macrophage function at doses as low as 1 mg/kg/day and led to mast cell degranulation at doses as low as 0.1 mg/kg/day.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"56 1","pages":"95-9"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74672757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 18

Expression of the immediate-early genes, c-fos, c-jun, and c-myc: a comparison in rats of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens. 即刻早期基因、c-fos、c-jun和c-myc的表达:非遗传毒性肝癌原与非致癌肝有丝分裂原在大鼠中的比较

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/40.1.129

S. Hasmall, I. Pyrah, A. Soames, R. Roberts

{"title":"Expression of the immediate-early genes, c-fos, c-jun, and c-myc: a comparison in rats of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens.","authors":"S. Hasmall, I. Pyrah, A. Soames, R. Roberts","doi":"10.1093/toxsci/40.1.129","DOIUrl":"https://doi.org/10.1093/toxsci/40.1.129","url":null,"abstract":"The involvement of the immediate-early (IE) genes c-fos, c-jun, and c-myc in regenerative liver hyperplasia is accepted, but their involvement in direct hyperplasia is uncertain. We have examined the hypothesis that the ability to induce IE genes may reflect the hepatocarcinogenic potential of a chemical. The ability of 1,4-dichlorobenzene (DCB) (300 mg/kg) (a noncarcinogenic rat liver mitogen), diethylhexyl phthalate (DEHP) (950 mg/kg), and chlorendic acid (120 mg/kg) (both nongenotoxic hepatocarcinogens) to induce c-fos, c-jun, and c-myc expression in rat liver was determined by Northern blot analysis and by in situ hybridization. Results were correlated to hepatic labeling index (LI) as determined by incorporation of BrdU in each of three lobes for each of three male F344 rats per group. Carbon tetrachloride (CCl4) (2 ml/kg) was used as a positive control. Increased LI was preceded by elevated expression of all three IE genes after CCl4, but also after DCB and DEHP, although induction by these was less marked. In all cases, there was considerable interanimal variation within groups, but little interlobe variation. Interestingly, there was a good correlation (r2 > or = 0.85) between c-myc expression and LI, but not between LI and c-fos or c-jun. Despite the disparate carcinogenic potential of DEHP and DCB, both chemicals induced similar patterns of IE gene expression, suggesting that this cannot distinguish hepatocarcinogenic liver mitogens from noncarcinogenic liver mitogens. These data assist in the evaluation of IE gene expression both as a marker of direct versus regenerative hyperplasia and as an indicator of the hepatocarcinogenic potential of liver mitogens.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"19 1","pages":"129-37"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78810557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

Benzene-induced hematotoxicity and bone marrow compensation in B6C3F1 mice. 苯致B6C3F1小鼠血液毒性及骨髓代偿。

Fundamental and applied toxicology : official journal of the Society of Toxicology Pub Date : 1997-01-01 DOI: 10.1093/toxsci/36.2.119

G. Farris, S. Robinson, K. Gaido, B. Wong, V. Wong, W. Hahn, R. Shah

{"title":"Benzene-induced hematotoxicity and bone marrow compensation in B6C3F1 mice.","authors":"G. Farris, S. Robinson, K. Gaido, B. Wong, V. Wong, W. Hahn, R. Shah","doi":"10.1093/toxsci/36.2.119","DOIUrl":"https://doi.org/10.1093/toxsci/36.2.119","url":null,"abstract":"Long-term inhalation exposure of benzene has been shown to cause hematotoxicity and an increased incidence of acute myelogenous leukemia in humans. The progression of benzene-induced hematotoxicity and the features of the toxicity that may play a major role in the leukemogenesis are not known. We report the hematological consequences of benzene inhalation in B6C3F1 mice exposed to 1, 5, 10, 100, and 200 ppm benzene for 6 hr/day, 5 days/week for 1, 2, 4, or 8 weeks and a recovery group. There were no significant effects on hematopoietic parameters from exposure to 10 ppm benzene or less. Exposure of mice to 100 and 200 ppm benzene reduced the number of total bone marrow cells, progenitor cells, differentiating hematopoietic cells, and most blood parameters. Replication of primitive progenitor cells in the bone marrow was increased during the exposure period as a compensation for the cytotoxicity induced by 100 and 200 ppm benzene. In mice exposed to 200 ppm benzene, the primitive progenitor cells maintained an increased percentage of cells in S-phase through 25 days of recovery compared with controls. The increased replication of primitive progenitor cells in concert with the reported genotoxicity induced by benzene provides the components necessary for producing an increased incidence of lymphoma in mice. Furthermore, we propose this mode of action as a biologically plausible mechanism for benzene-induced leukemia in humans exposed to high concentrations of benzene.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"57 1","pages":"119-29"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81050452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 39