The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 30 , Issue 2
May
Showing 1-6 articles out of 6 articles from the selected issue
Review
  • Akinobu OKADA, Tomomi SATO, Yasuhiko OHTA, Taisen IGUCHI
    2005 Volume 30 Issue 2 Pages 75-89
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans. Some of these chemicals exhibit estrogenic activity by binding to the estrogen receptors. The developing organism is particularly sensitive to estrogenic chemicals during the critical period in which the induction of long-term changes and persistent molecular alterations in female reproductive tracts occur. Perinatal mouse and rat models can be utilized as indicators for determining the consequences of exposure to exogenous estrogenic agents, including possible xenoestrogens or environmental endocrine disruptors. Estrogen receptors (ER) and estrogen responsive genes, therefore, need to be identified in order to understand the molecular basis of estrogenic actions. Recent identifications of ER subtypes and isoforms make understanding target organ responses to these estrogenic chemicals even more difficult. Indeed, many reports suggest that these chemicals do affect the reproductive and developmental processes of female laboratory rodents that had been perinatally exposed, and that interactions between sex steroid hormone receptors occur. Much information concerning the expression of sex steroid receptors in rodents has been reported concerning the normal development of the M?llerian duct. Thus, accumulated information on the expression of ER subtypes and isoforms as well as that of progesterone and androgen receptors in laboratory rodents is herein reviewed, in addition to the presentation of our own data.
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Regular paper
  • Kazuya KURIYAMA, Ryohei YOKOI, Kazuo KOBAYASHI, Satoshi SUDA, Morimich ...
    2005 Volume 30 Issue 2 Pages 91-102
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at doses of 20, 30, and 40 mg/kg. During the recovery period of 5 weeks, males were evaluated for multiple endpoints such as organ weights, fertility, and sperm parameters. The 5-week recovery periods are designated as follows: Day 1 (1 day after final treatment); Week 1, Week 2, Week 3, Week 4, and Week 5 (first, second, third, fourth, and fifth week after final treatment). A clear time-course of dominant lethals was observed. The peak severities of the dominant lethals were observed in Week 2. It was judged that the most sensitive cellular targets for the dominant lethals are late spermatids. Sperm examination revealed a clear time-course and dose-dependent changes in the frequency of sperm morphological abnormalities. The peak severities of the sperm morphological alterations in cauda epididymis were observed in Week 4. Sensitive cellular stages for the induction of sperm morphological abnormalities were judged to be late spermatocytes and early spermatids. The most frequently observed type of morphologically abnormal spermatozoa was tailless sperm, followed by no-hook head sperm. Although the initial cause for both sperm morphological alterations and dominant lethals was suggested to be genetic insult to the germ cells, there were no obvious relationships observed between these two findings.
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  • Nobuaki MATSUI, Kazumi KASAJIMA, Masazumi HADA, Tomomi NAGATA, Nobuko ...
    2005 Volume 30 Issue 2 Pages 103-110
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    The aim of this study was to determine whether nuclear factor-κB (NF-κB) inhibitors are efficient against hepatic ischemia/reperfusion (I/R) injury. We previously demonstrated that xanthine oxidase-derived reactive oxygen species activate NF-κB during ischemia. However, the role of NF-κB activation during ischemia in post-reperfusion injury remains unclear. Therefore, while we examined the effects of NF-κB inhibitors, sulfasalazine and pyrrolidinedithiocarbamate on hepatic I/R injury using a rat lobar hepatic I/R model, we estimated the relationship between NF-κB activation during ischemia and following hepatic damage caused by reperfusion. The portal vein and the hepatic artery were clamped for 1 hr followed by reperfusion for up to 24 hr. NF-κB activation was determined by Western blot analysis. NF-κB activation was observed in the ischemic lobe of the liver, and the activation was prevented by pre-administration with NF-κB inhibitors. Although the serum ALT level, hepatic MPO activity and BSP clearance, as an index of hepatic injury, were increased after reperfusion, the increase was attenuated by pre-administration with NF-κB inhibitors. These findings suggest that NF-κB activation during ischemia is relevant to hepatic I/R injury. Moreover, we first showed that pre-administration with NF-κB inhibitors is effective against hepatic I/R injury.
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  • Toshinori YAMAMOTO, Tamio FUKUSHIMA, Rie KIKKAWA, Hiroshi YAMADA, Ikuo ...
    2005 Volume 30 Issue 2 Pages 111-126
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    The utilization of safety biomarkers to predict the possibility of compound-related toxicity provides several advantages for drug discovery and development, especially at an early stage. The objectives of this study were to investigate the effects of male reproductive toxicants on protein expression profiles in the rat testes and to identify potential biomarker candidates. Four well-known reproductive toxicants, ethylene glycol monomethyl ether (EGME), cyclophosphamide (CP), sulfasalazine (SASP) and 2,5-hexanedione (2,5-HD), were administered to male rats in a single dose, and protein expression profiles were investigated after 24 hr by two-dimensional gel electrophoresis (2DE). Histopathological examination of the testes and serum concentration analysis were also performed. From the results of the comparison of 2D-gels among different doses of a compound and among compounds, 52, 20, 24 and 111 spots were nominated as differentially expressed spots with EGME, CP, SASP and 2,5-HD treatments, respectively. Several spermatogenesis-involved proteins were identified, including glutathione S-transferase (GST), testis-specific heat shock protein 70-2 (HSP70-2), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and phosphatidylethanolamine-binding protein (PEBP). Some of them were altered by more than one compound. In summary, remarkable histopathological findings were observed only in the EGME high-dose group, and most of the protein changes were detected before histopathological changes occurred. Therefore, the proteins identified in this study could potentially serve as biomarkers to evaluate male reproductive toxicity at an early stage of drug discovery and development.
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  • Katsumi KOBAYASHI
    2005 Volume 30 Issue 2 Pages 127-134
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    The data obtained from toxicity studies are examined for homogeneity of variance, but, usually, they are not examined for normal distribution. In this study I examined the measured items of a carcinogenicity/chronic toxicity study with rats for both homogeneity of variance and normal distribution. It was observed that a lot of hematology and biochemistry items showed non-normal distribution. For testing normal distribution of the data obtained from toxicity studies, the data of the concurrent control group may be examined, and for the data that show a non-normal distribution, non-parametric tests with robustness may be applied.
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  • Yoshiko MATSUNAGA, Yoshiko KAWAI, Yuka KOHDA, Munekazu GEMBA
    2005 Volume 30 Issue 2 Pages 135-144
    Published: 2005
    Released: May 31, 2005
    JOURNALS FREE ACCESS
    Zinc is employed as a supplement; however, zinc-related nephropathy is not generally known. In this study, we investigated zinc-induced renal cell injury using a pig kidney-derived cultured renal epithelial cell line, LLC-PK1, with proximal kidney tubule-like features, and examined the involvement of free radicals and extracellular signal-regulated kinase (ERK) in the cell injury.
    The LLC-PK1 cells showed early uptake of zinc (30 μM), and the release of lactate dehydrogenase (LDH), an index of cell injury, was observed 24 hr after uptake. Three hours after zinc exposure, generation of reactive oxygen species (ROS) was increased. An antioxidant, N, N'-diphenyl-p-phenylenediamine (DPPD), inhibited a zinc-related increase in ROS generation and zinc-induced renal cell injury. An NADPH oxidase inhibitor, diphenyleneiodonium (DPI), inhibited a zinc-related increase in ROS generation and cell injury. We investigated translocation from the cytosol fraction of the p67phox subunit, which is involved in the activation of NADPH oxidase, to the membrane fraction, and translocation was induced 3 hr after zinc exposure.
    We examined the involvement of ERK1/2 in the deterioration of zinc-induced renal cell injury, and the association between ERK1/2 and an increase in ROS generation. Six hours after zinc exposure, the activation (phosphorylation) of ERK1/2 was observed. An antioxidant, DPPD, inhibited the zinc-related activation of ERK1/2. An MAPK/ERK kinase (MEK1/2) inhibitor, U0126, almost completely inhibited zinc-related cell injury (the release of LDH), but did not influence ROS generation.
    These results suggest that early intracellular uptake of zinc by LLC-PK1 cells causes the activation of NADPH oxidase, and that ROS generation by the activation of the enzyme leads to the deterioration of renal cell injury via the activation of ERK1/2.
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