The Journal of Toxicological Sciences
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Volume 31 , Issue 3
August
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  • Kilarkaje NARAYANA, Narayan PRASHANTHI, Arunkumar NAYANATARA, Laxminar ...
    Volume 31 (2006) Issue 3 Pages 177-189
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Methyl parathion (MP) is an organophosphate pesticide used in agriculture, although quite often illegally used indoors to contain insects. The present study was planned to investigate the effects of MP on rat testis. Adult male Wistar rats (13-14 weeks) were treated with MP as follows. Experiment 1-0, 1.75, 3.5 or 7 mg/kg i.p. for 5 days and sacrificed on Day 14; experiment 2 and 3- 0, 0.5, or 1 mg/kg i.p. for 12 days, and sacrificed on Days 130 and 77, respectively; experiment 4- 0, 0.75, or 1.5 mg/kg i.p. for 25 days, and sacrificed on Day 17; experiment 5- 0 or 3.5 mg/kg po for 25 days, and sacrificed on Day 17, after the last exposure. MP decreased the body weight and the testis weight in experiments 4 and 5 (p<0.05-0.001) due to decreased food intake and tubular atrophy respectively. MP increased the intra-testicular testosterone level and decreased the LH level in experiments 4 and 5. The seminiferous epithelium showed sloughing of germ cells, vacuoles, focal necrosis, and formation of multinucleated giant cells, cellular degeneration (nuclear pyknosis, halo appearance and shrinkage of nuclei) and tubular atrophy, especially in experiment 4. The degree of testicular damage was higher in experiment 4>5>1>3>2 indicating more effect of prolonged i.p. treatment. Homogenization-resistant spermatid count was decreased in experiments 1, 4 and 5, and MP also decreased the tubular diameter, and epithelial height (p<0.05-0.001). Incidences of stage XIV tubules, number of meiotic figures and elongating spermatids were also decreased, whereas the incidence of tubules showing epithelial sloughing increased (p<0.05-0.001). We conclude that MP is a reproductive toxicant in male rats which causes significant testicular damage in the testis.
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  • Itaru SATO, Koichiro SERA, Tadahiko SUZUKI, Haruo KOBAYASHI, Shuji TSU ...
    Volume 31 (2006) Issue 3 Pages 191-195
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Determination of the exposure level of environmental pollutants is essential in studies on environmental toxicology. If concentrations of exposed pollutants in tissues are not affected by formalin-preservation, a preserved specimen will provide not only histopathological information but also the exposure level of environmental pollutants. In the present study, concentrations of nine elements in the liver and kidney were compared between fresh and formalin- or neutral formalin-preserved specimens to validate the ultimate analysis of the preserved specimens. After one year of preservation, various elements had diffused from the specimens into the solutions. The concentrations of iron, copper, zinc (in the case of neutral formalin) and selenium in the central region of the specimens showed no alterations, suggesting that the diffusions of these elements were limited to the surface of the specimens. Therefore, preserved specimens may be available for the determination of these elements if the specimens are large enough for their surface to be removed. Concentrations of other elements in the preserved specimens were different from the original ones, because the diffusion or infiltration also occurred in the deep region of the specimens.
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  • Tomoyuki MORIYAMA, Hideo MIYAZAWA, Masayuki TOMOHIRO, Noboru FUJIKAKE, ...
    Volume 31 (2006) Issue 3 Pages 197-206
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Moderate food restriction (FR) has been established as a nutritionally appropriate and well-controlled method with long-term beneficial effects in conducting toxicity and carcinogenicity studies in rodents. This study describes the early effects of moderate FR on toxicity study parameters in rats and on the variability of these parameters. Physical signs, body weight, food and water consumption, and clinical pathology parameters were examined in a 4-week study in which rats were moderately food-restricted or fed ad libitum (AL). There were no diet-related differences in physical signs, hematology or urinalysis. FR-related changes were observed in body weight and serum biochemistry; however, most of the changes involved anti-aging alterations and/or physiological adjustment to FR. Moderate FR resulted in low variability and good reproducibility in body weight. The present results indicate that moderate FR does not impair study parameters and increases statistical sensitivity. Therefore, a moderate FR feeding regimen is beneficial not only for long-term but also for short-term toxicity studies in rats.
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  • Yuka KOHDA, Yoshiko MATSUNAGA, Ryugo SHIOTA, Tomohiko SATOH, Yuko KISH ...
    Volume 31 (2006) Issue 3 Pages 207-217
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Zinc is an essential nutrient that can also be toxic. We have previously reported that zinc-related renal toxicity is due, in part, to free radical generation in the renal epithelial cell line, LLC-PK1 cells. We have also shown that an MEK1/2 inhibitor, U0126, markedly inhibits zinc-induced renal cell injury. In this study, we investigated the role of an upstream MEK/ERK pathway, Raf-1 kinase pathway, and the transcription factor and ERK substrate Elk-1, in rat renal cortical slices exposed to zinc. Immediately after preparing slices from rat renal cortex, the slices were incubated in medium containing Raf-1 and MEK inhibitors. ERK1/2 and Elk-1 activation were determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 and phosphorylated Elk-1 (pElk-1) in nuclear fractions prepared from slices exposed to zinc. Zinc caused not only increases in 4-hydroxynonenal (4-HNE) modified protein and lipid peroxidation, as an index of oxidant stress, and decreases in PAH accumulation, as that of renal cell injury in the slices. Zinc also induced a rapid increase in ERK/Elk-1 activity accompanied by increased expressions of pERK and pElk-1 in the nuclear fraction. A Raf-1 kinase inhibitor and an MEK1/2 inhibitor U0126 significantly attenuated zinc-induced decreases PAH accumulation in the slices. The Raf-1 kinase inhibitor and U0126 also suppressed ERK1/2 activation in nuclear fractions prepared from slices treated with zinc. The present results suggest that a Raf-1/MEK/ERK1/2 pathway and the ERK substrate Elk-1 are involved in free radical-induced injury in rat renal cortical slices exposed to zinc.
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  • Bradley R. HERRIN, Jessica E. HALEY, R. Clark LANTZ, Mark L. WITTEN
    Volume 31 (2006) Issue 3 Pages 219-228
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    C57BL/6 mice were nose-only exposed to JP-8 jet fuel at average concentrations of 45, 267, and 406 mg JP-8/m3 for 1 hr/d for 7 days to further test the hypothesis that exposure to JP-8 concentrations below the current permissible exposure level (PEL) of 350 mg/m3 will induce lung injury, and to validate a new "in-line, real-time" total hydrocarbon analysis system capable of measuring both JP-8 vapor and aerosol concentrations. Pulmonary function and respiratory permeability tests were performed 24 to 30 hr after the final exposures. No significant effects were observed at 45 or 267 mg/m3. The only significant effect observed at 406 mg/m3 was a decrease in inspiratory dynamic lung compliance. Morphological examination and morphometric analysis of distal lung tissue demonstrated that alveolar type II epithelial cells showed limited cellular damage with the notable exception of a significant increase in the volume density of lamellar bodies (vacuoles), which is indicative of increased surfactant production, at 45 and 406 mg/m3. The terminal bronchial epithelium showed initial signs of cellular damage, but the morphometric analysis did not quantify these changes as significant. The morphometric analysis techniques appear to provide an increased sensitivity for detecting the deleterious effects of JP-8 as compared to the physiological evidence offered by pulmonary function or respiratory permeability tests. These observations suggest that the current 350 mg/m3 PEL for both JP-8 jet fuel and for other more volatile petroleum distillates should be reevaluated and a lower, more accurate PEL should be established with regard human occupational exposure limits.
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  • Tatsuru FUKUDA, Yoshifumi NAKASHIMA, Miwa HARADA, Shigeki TOYOSHIMA, O ...
    Volume 31 (2006) Issue 3 Pages 229-234
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Although the toxic effects of citrate including hemodynamic and cardiovascular changes result from a decrease in ionized calcium levels in serum due to chelating action, these effects of citrate on blood coagulation have not yet been fully clarified. The present study examines whether serum citrate and ionized calcium levels affect whole blood clotting time in rats using the test tube method in which citrate is administered by rapid intravenous infusion. Citrate was infused via the tail vein into 10 rats at 3, 4 or 5 mmol/kg/hr for 1 hr, and then whole blood clotting time, serum citrate and ionized calcium levels were determined. Whole blood clotting time did not significantly change at citrate infusion rates of 3 and 4 mmol/kg/hr. However, at 5 mmol/kg/hr, whole blood clotting time was significantly prolonged by a factor of 2.1 relative to the untreated group, when the serum citrate level was 10.03 ± 1.39 mmol/l (59.0-fold higher than that in the untreated group) and the serum-ionized calcium level was 0.29 ± 0.02 mmol/l (0.2-fold lower than that in the untreated group). These results suggest that whole blood clotting time is significantly prolonged in rats with severe ionized hypocalcemia.
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  • Masahiro HAYASHI, Yoshitika SHIRAI, Tsutomu BANDOH, Kaori IWAMASA, Nao ...
    Volume 31 (2006) Issue 3 Pages 235-246
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    The present studies sought to investigate the effect of tryptophan alone or coadministration of tryptophan and ethanol on the interaction of central frontal cortex and dorsal raphe nucleus serotonergic functional activities by utilizing in vivo microdialysis. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, a metabolite of serotonin (5-HT), in the dorsal raphe nucleus, but not in the frontal cortex. Coadministration of tryptophan and ethanol caused very marked increases in 5-hydroxyindoleacetic acid (5-HIAA) levels in both the frontal cortex and the dorsal raphe nucleus, although ethanol (1.25 g/kg) did not change 5-HIAA levels in both areas. Moreover, the application of WAY100635 (10 μM), 5-HT1A antagonist, into the frontal cortex after coadministration caused a marked increase in 5-HIAA levels in the frontal cortex and a decrease in the levels in the dorsal raphe nucleus, although WAY100635 alone had no effect on these levels. This may suggest that WAY100635-induced increase of 5-HIAA levels in the frontal cortex resulted from negative feedback following the blockade of serotonergic 5-HT1A autoreceptors, and that this increase in 5-HIAA levels decreased 5-HIAA levels in the dorsal raphe nucleus by preventing the activation of dorsal raphe 5-HT1A autoreceptors. WAY100635 into the dorsal raphe nucleus did not significantly change 5-HIAA levels in both areas. This may indicate that the blockade of dorsal raphe 5-HT1A autoreceptors by WAY100635 resulted in unchanged 5-HIAA levels in the frontal cortex. Behavioral sign of teeth-chattering was markedly observed following the coadministration and in combination with WAY100635.
    These results may suggest that the increased 5-HIAA levels in both areas after coadministration are indicative of the interrelation via activation of serotonergic neurons, and that the increased levels are partly responsible for behavioral activation of rats.
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  • Michiharu MATSUMOTO, Yumi UMEDA, Hideki SENOH, Masaaki SUZUKI, Hirokaz ...
    Volume 31 (2006) Issue 3 Pages 247-264
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Carcinogenicity and chronic toxicity of ortho-chloronitrobenzene (o-CNB) were examined by feeding groups of 50 F344 rats and 50 BDF1 mice of both sexes o-CNB-containing diets for 2 years. The dietary concentration of o-CNB was 0, 80, 400 or 2000 ppm (w/w) for rats and 0, 100, 500 or 2500 ppm for mice. The 2-year administration of o-CNB produced a dose-dependent increase in incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and hepatoblastomas in mice of both sexes. Incidences of altered cell foci in the liver were increased in the o-CNB-fed rats of both sexes. Metastasis from mouse malignant liver tumors occurred predominantly in the lung. The hepatocarcinogenic response to o-CNB was found to be more potent in mice than in rats. Marginally increased incidences of renal cell adenomas in the 2000 ppm-fed female rats and renal cell carcinomas in the 2000 ppm-fed male rats were noted, together with a significantly increased incidence of atypical tubule hyperplasias. Spontaneous, age-related chronic progressive nephropathy was exacerbated in a dose-related manner, and caused the death of 47 male rats fed 2000 ppm before the end of the 2-year administration period. The highest dose levels of o-CNB except for the administration of 2000 ppm to male rats were thought to meet the criteria of the maximum tolerated dose set by both NCI and IARC guidelines. Causative factors of o-CNB-induced carcinogenicity were discussed with reference to our previous rodent studies of subchronic toxicity of o-CNB and carcinogenicity and chronic toxicity of para-chloronitrobenzene.
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  • Hidetoshi SHINDOH, Akira KAWASHIMA, Nobuyuki SHISHIDO, Kounosuke NAKAN ...
    Volume 31 (2006) Issue 3 Pages 265-285
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 μg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 μg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 μg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 μg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.
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  • Akiko KIMURA, Kazuaki OHASHI, Reiko YAMAMOTO, Akira NAGANUMA
    Volume 31 (2006) Issue 3 Pages 287-290
    Released: September 08, 2006
    JOURNALS FREE ACCESS
    cDNA microarray analysis indicated that mRNA levels of Fit2p and Fit3p, proteins involved in iron retention within the yeast cell wall, were markedly increased by treatment of Saccharomyces cerevisiae with cisplatin. Expression of FIT2 and FIT3 is known to be transcriptionally regulated by Aft1p. Northern blotting demonstrated a time- and concentration-dependent increase in the mRNA levels of both proteins following treatment with cisplatin. However, overexpression or disruption of the FIT2 or FIT3 genes had little effect on the susceptibility of yeast to cisplatin. Although Fit2p and Fit3p do not appear to be directly involved in protecting against the toxic effects of cisplatin, the present results suggest the existence of an activation system of gene expression in response to cisplatin within yeast cells.
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