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F Kari

Publications and source records attributed to F Kari.

9 recordsLinked to original sources
PubMed1997

Dietary restriction mitigates ozone-induced lung inflammation in rats: a role for endogenous antioxidants.

Studies were undertaken to determine whether dietary restriction protects against acute pulmonary oxidant challenge. Male F344 rats were fed NIH-31 diet either ad libitum or at restricted levels equal to 75% that of ad libitum intake. After 3 wk of dietary adaptation, animals were exposed by inhalation to 2.0 ppm ozone (O3) for 2 h or chamber air and evaluated for cellular and biochemical indices of pulmonary toxicity. Compared to air controls, bronchoalveolar lavage fluid (BALF) from O3 exposed ad libitum fed rats contained increased protein (145 versus 380 microg/ml), PMN infiltration (0 versus 11%) and fibronectin (45 versus 607 U/ml). Diet restriction abrogated these indicators of pulmonary inflammation induced by ozone. Binding of 18O3 to BALF protein and cells was significantly decreased in diet restricted rats while BALF ascorbate and glutathione levels, but not alpha-tocopherol or urate, were elevated compared to ad libitum fed rats. Taken together, these results indicate that dietary restriction affords protection against O3-induced oxidant toxicity. Protection is mediated partially by increases in ascorbate in the fluid bathing the lung surface, thereby providing an antioxidant sink which minimizes the ability of O3 to reach biological targets.

Animals↗
PubMed1995

Long-term exposure to the anti-inflammatory agent phenylbutazone induces kidney tumors in rats and liver tumors in mice.

Long-term toxicity and carcinogenicity of phenylbutazone, a nonsteroidal anti-inflammatory drug, were evaluated in F344/N rats and B6C3F1 mice. In 2-year studies, phenylbutazone was given in corn oil by gavage 5 days per week to groups of 50 rats of each sex at doses of 0, 50, or 100 mg/kg body weight, and to groups of 50 mice at doses of 0, 150, or 300 mg/kg body weight. Body weights and survival were similar among groups. Major target organs are kidneys in rats and liver in mice. Kidney: inflammation, papillary necrosis, and mineralization in both sexes of rats, and hyperplasia and dilatation of the pelvis epithelium, and cysts in female rats. Uncommon tubular cell tumors of the kidney were found in 13 exposed rats: 5 in the 50 mg group and 4 in the 100 mg group of males; 4 in dosed female rats; none in controls. In female rats, dose-related increases in hyperplasia of the pelvis transitional epithelium, and 2 carcinomas were discovered. Urinary bladder: papillomas of the transitional epithelium were seen in 2 low-dose male and in 1 low-dose female rats. Forestomach: ulcers in rats, with acanthosis, hyperkeratosis, and basal cell hyperplasia in female rats; however, no neoplasms were associated with these lesions. Liver: primarily in male mice exposed to phenylbutazone, hemorrhage, centrilobular cytomegaly and karyomegaly, fatty metamorphosis, cellular degeneration, and coagulative necrosis were seen; clear cell foci were observed in male mice. In summary, under the conditions of these 2-year oral intubation studies, phenylbutazone is associated with renal carcinogenicity in rats, as evidenced by increases in tubular cell neoplasms in both sexes. Evidence of carcinogenicity for male mice was shown by increased incidences and multiplicity of liver tumors. No carcinogenic activity was found for female mice.

Adenoma↗
PubMed1993

Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride.

Methylene chloride has been the subject of recent toxicological and carcinogenesis studies because of significant human exposure and widespread use in industrial processing, food preparation and agriculture. In this study, liver and lung tumors, induced in female B6C3F1 mice by inhalation of 2000 p.p.m. methylene chloride (6 h/day, 5 days/week continuous exposure), were examined for the presence of activated ras proto-oncogenes. DNA was isolated from 49 spontaneous and 50 methylene chloride-induced liver tumors and screened by oligonucleotide hybridization of PCR amplified H-ras gene fragments for codon 61 mutations. In the chemically induced tumors, 38 mutations were detected, 16 C to A transversions in base 1, 16 A to G transitions in base 2 and 6 A to T transversions in base 2. This mutation profile was similar to that identified for the H-ras gene in the spontaneous liver tumors and suggests that methylene chloride acts in liver by promoting cells with spontaneous lesions. Tumors in which H-ras codon 61 mutations were not detected were examined for the presence of transforming genes by the nude mouse tumorigenicity assay. Except for activated K-ras genes detected in DNA from two methylene chloride induced tumors and one spontaneous tumor, no other transforming genes were identified. DNA from 54 lung tumors was screened by direct sequencing of PCR amplified DNA fragments of the K-ras gene for first and second exon mutations, and 12 mutations were identified, 5 in exon one and 7 in exon 2. The low number of spontaneous tumors available in this study limits the interpretation of the data, and thus the frequency and spectrum of K-ras activation in the methylene chloride induced tumors was not significantly different from that in the seven spontaneous tumors analyzed. Since K-ras activation was not detected in 80% of the tumors, the nude mouse tumorigenicity assay was used to examine the lung tumors for the presence of other transforming genes. At present no transforming genes other than ras genes were identified in either liver or lung tumors.

3T3 Cells↗
PubMed1993

Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice.

Mutations of the p53 tumor suppressor gene are the most common defined genetic alterations seen in a wide variety of human cancers. In contrast, little is known about the importance of the p53 gene in chemically induced tumors of rodents, which are widely used as models for the evaluation of human health risks. In this study we examined 54 methylene chloride-induced and seven spontaneously arising lung tumors from female B6C3F1 mice for losses of heterozygosity (LOH) at markers near the p53 gene on chromosome 11. LOH was detected in seven methylene chloride-induced lung carcinomas by Southern analysis of a restriction fragment length polymorphism and PCR analysis of five simple sequence length polymorphisms. In each case allele loss was observed at all six markers; thus, these chromosomal alterations were likely to have resulted from mitotic nondisjunction. In contrast, LOH was not detected in 20 liver tumors from methylene chloride-treated mice at the Acrb locus, which is tightly linked to the p53 gene on chromosome 11. In addition single strand conformation polymorphism analysis was performed to screen for mutations in the most conserved regions of the p53 gene (exons 5 to 8). Consequently, potential mutations identified by direct sequencing, were only detected in four of the seven tumor samples with LOH, but not in any of the remaining lung tumors. Overexpression of the p53 protein by immunohistochemical staining was detected only in the four tumors that contained p53 point mutations and in a focal area of another tumor. Finally, using a simple sequence length polymorphism within the retinoblastoma tumor suppressor gene, LOH on mouse chromosome 14 was also detected in three lung carcinomas and one liver tumor. Inactivation of p53 and possibly the retinoblastoma tumor suppressor gene appear to be infrequent events in lung and liver tumors from methylene chloride treated mice.

Animals↗
PubMed1993

Inhalation exposure to a hepatocarcinogenic concentration of methylene chloride does not induce sustained replicative DNA synthesis in hepatocytes of female B6C3F1 mice.

We have used methylene chloride as a model to study cellular and molecular processes responsible for liver tumor induction by chlorinated hydrocarbons. Because of current interest in the role of enhanced cell proliferation in tumor induction, measurement of S-phase hepatocytes was incorporated into recently conducted toxicity and carcinogenicity studies. In prechronic studies, female B6C3F1 mice were exposed to 0, 1000, 2000 or 8000 p.p.m. methylene chloride by inhalation, 5 days per week, for up to 4 weeks followed by a 1 and 2 week recovery period. Mice exposed to concentrations of 2000, 4000 or 8000 p.p.m. methylene chloride had sustained increased liver weight commencing after 1 week of exposure and returning to normal after the 1 or 2 week recovery period. The increased liver weight was attributed to hepatocellular hypertrophy secondary to intracellular glycogen accumulation. Tritiated thymidine was administered by osmotic minipumps to label S-phase hepatocytes over a 6 day period. At most intervals examined there was decreased hepatocyte labeling in mice exposed to methylene chloride. However, there was a transitory increased number of S-phase hepatocytes observed at the 2 week interval in the 1000, 4000 and 8000 p.p.m. methylene chloride groups. In a chronic study, female mice were exposed to 2000 p.p.m. methylene chloride for up to two years. Following labeling with BRDU using 6 day minipumps, a statistically significant decrease in S-phase hepatocytes was observed after 13 weeks of methylene chloride exposure. A minor increased labeling index (LI) observed at 52 weeks was not considered to be a methylene chloride treatment-related effect. Retrospective immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in liver sections containing foci of cellular alteration allowed demonstration of S-phase hepatocytes in these clonally expanded preneoplastic lesions. While foci frequently had higher LI's than surrounding normal hepatocytes, there was no difference in the mean LI of foci from methylene chloride-treated mice versus foci occurring spontaneously in control mice. The absence of a sustained increase in S-phase hepatocytes in female B6C3F1 mice suggests that enhanced cell proliferation is not a major mechanistic factor associated with the observed hepatocarcinogenicity of methylene chloride.

Administration, Inhalation↗
PubMed1993

Effect of methylene chloride inhalation on replicative DNA synthesis in the lungs of female B6C3F1 mice.

In the National Toxicology Program 2-year inhalation study of dichloromethane (DCM), there was a significant increase in pulmonary neoplasms in female B6C3F1 mice exposed to 2000 ppm (overall rates of 30/48 versus 5/50 in control). Replicative DNA synthesis was examined to evaluate the potential role of treatment-induced lung cell proliferation on pulmonary carcinogenicity. Tritiated thymidine incorporation was assessed in methacrylate plastic sections after 1, 2, 3, or 4 weeks of inhalation exposure to 2000 ppm or 8000 ppm DCM. Similar measurements of labeling indexes were made after 13 and 26 weeks of exposure to 2000 ppm DCM using bromodeoxyuridine as the labeling agent. In all cases the labeling agent was delivered over a 6-day period using osmotic minipumps. The labeling index (LI) of bronchiolar epithelium (two branches proximal to the terminal bronchiole) of mice exposed to 2000 ppm DCM for 2-26 weeks decreased to 40-60% of the control. Terminal bronchioles showed a similar decrease in LI. Mice exposed to 8000 ppm DCM had a less dramatic decrease in LI. No pathological change was found in the exposed lungs. It is concluded that inhalation exposure to DCM for up to 26 weeks reduces cell turnover of bronchiolar cells in female B6C3F1 mice.

Administration, Inhalation↗
PubMed1990

Cytogenetic analyses of mice exposed to dichloromethane.

Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. No increase in the frequency of either sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a single subcutaneous injection of 2,500 or 5,000 mg/kg DCM. Inhalation exposure to DCM for 10 days at concentrations of 4,000 or 8,000 ppm resulted in significant increases in frequencies of SCEs in lung cells and peripheral blood lymphocytes, CAs in lung and bone marrow cells, and micronuclei (MN) in peripheral blood erythrocytes. Lung cell CAs and blood erythrocyte MN reached frequencies of approximately two times control levels. Following a 3-month inhalation exposure to 2,000 ppm DCM, mice showed small but significant increases in lung cell SCEs and peripheral blood erythrocyte MN. These findings suggest that genotoxicity may play a role in the carcinogenicity of DCM in the lungs of B6C3F1 female mice.

Administration, Inhalation↗