The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 26, Issue 3
Displaying 1-7 of 7 articles from this issue
Regular Paper
  • Hyung Sik KIM, Soon-Young HAN, Sun Dong YOO, Byung Mu LEE, Kui Lea PAR ...
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 111-118
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    The potential estrogenic activities of bisphenol-A were investigated in vitro (E-screen and estrogen receptor competitive binding bioassays) and in vivo (uterotrophic assay). Uterotrophic responses were evaluated using mature ovariectomized Sprague-Dawley female rats treated subcutaneously with bisphenol A (1, 5, 10, 50, and 100 mg/kg/day), E2 (0.3 μg/kg), and DES (0.3 μg/kg) for 3 consecutive days. In a MCF-7 cell proliferation assay, E2 and DES used as positive estrogens induced maximum proliferation of MCF-7 cells at 1.0 nM, whereas BPA slightly induced MCF-7 cell proliferation at a higher level of 0.1μM and maximum proliferation at 10μM. In a competitive binding assay, E2 and DES showed inhibition of 17 β-[3H]estradiol binding to the rat uterus ER with an IC50 of 1.0 nM and 0.5 nM, respectively. However, BPA had an IC50 of 5 μM, which was approximately 5,000 or 10,000-fold greater than the IC50 of E2 and DES. In uterotrophic assays, uterus (wet and blotted) and vagina weights were significantly increased at the dose of BPA 100 mg/kg/day in OVX Sprague-Dawley rats. These studies demonstrate that BPA exhibits weak estrogenic activity in all experimental systems, and thus its migration from epoxy resins or polycarbonate products should be controlled not to exceed a safety levels for humans.
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  • Masanori MURAKOSHI, Rie IKEDA, Norio FUKUI
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 119-127
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    The effect of chlormadinone acetate (CMA), a synthetic steroidal antiandrogen, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Male beagle dogs (5-8 years old) were divided into four experimental groups. Group 1 consisted of untreated controls. Groups 2 and 3 received CMA 0.03 and 0.1 mg/kg/day, p.o., respectively, for 6 months. In group 1, glandular hyperplasia of the prostate was clearly detected. The glandular epithelial cells showed uniformly intense nuclear staining for androgen receptor (AR). AR was also localized in the nuclei of the fibro-muscular stromal cells. In groups 2 and 3, CMA produced marked atrophy of the glandular epithelium. The interacinar fibro-muscular stroma was prominent. The nuclear staining for AR in both epithelial and stromal cells was remarkably decreased. In addition, a histopathological study showed that CMA medication for 6 months exerted no effect on the testes and adrenal glands or on immunoreactive positive cells to LH- and ACTH-antibody (pituitary LH- and ACTH-cells). Therefore, it is concluded that CMA (0.03 and 0.1 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes, adrenal glands or pituitary LH- and ACTH-cells.
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  • Takatoshi KOUJITANI, Kazuo YASUHARA, Toru TAMURA, Hiroshi ONODERA, His ...
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 129-139
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    To investigate the modifying effects of eugenol (EUG), a component of cigarette smoke, on lung carcinogenesis, male and female transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) were given a single intraperitoneal injection of 250 mg/kg urethane (UR) or saline, followed by a diet containing 6,000 ppm EUG or basal diet for 26 weeks. Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. In both male and female rasH2 mice, alveolar/bronchiolar hyperplasias, adenomas and carcinomas were observed in all UR-treated groups. However, there were no significant intergroup differences in the incidences and multiplicities of these lesions between the UR alone and UR+EUG groups. In non-Tg mice, alveolar/bronchiolar hyperplasias, adenomas or carcinomas were sporadically observed in UR-treated groups of both sexes, with no significant differences in the incidences and multiplicities between the UR alone and UR+EUG groups. There were no intergroup differences between them in the PCNA-positive ratios of adenomas or carcinomas and the areas of adenomas or carcinomas to the whole lung area examined. The present results suggest that the EUG treatment does not exert modifying effects on lung carcinogenesis induced by UR in both male and female rasH2 mice and non-Tg mice.
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  • Yasuna KOBAYASHI, Michiya SUZUKI, Naomi OHSHIRO, Takashi SUNAGAWA, Tad ...
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 141-150
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    We examined the effect of climbazole on the induction of rat hepatic microsomal cytochrome P450 (P450), and compared the induction potency with other N-substituted azole drugs such as clorimazole. We found that climbazole is found to be a potent inducer of rat hepatic microsomal P450 as clorimazole. Induced level of P450 by climbazole was almost similar in extent to clorimazole when compared with other imidazole drugs in a dose- and time-dependent manner. Parallel to the increase in P450, climbazole increased aminopyrine and erythromycin N-demethylase, ethoxycoumarin O-deethylase, and androstenedione 16β- and 15α/6β hydroxylase activities; however, clorimazole did not induce aminopyrine N-demethylase activity irrespective of its marked increase in P450 content. Immunoblot analyses revealed that climbazole induced CYP2B1, 3A2 and 4A1. The present findings indicate that climbazole is a new potent inducer of hepatic microsomal P450 and drug-metabolizing enzymes like clorimazole, but it may have some differential mechanism(s) for these enzymes’ induction in rat liver.
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  • Tetsuyo KAJIMURA, Hiroshi SATOH, Gen WATANABE, Kazuyoshi TAYA
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 151-161
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    The histology and porphyrin concentrations of Harderian glands and plasma prolactin levels were examined in B6C3F1 mice castrated or isografted with pituitaries in combination with the administration of bromocriptine (2-bromo-á-ergocryptine), a potent suppressor of prolactin. Four pituitaries were transplanted underneath the bilateral kidney capsules of each mouse. Furthermore, we investigated Harderian porphyrins and plasma testosterone levels in mice that were castrated or treated with neuroleptic butyrophenone (timiperone), a potent accelerator of prolactin, and treated concurrently with bromocriptine. Light microscopically, pituitary grafts increased the concretion of porphyrin pigments within the Harderian gland lumina. Pituitary grafts or castration increased both Harderian porphyrin concentrations and plasma prolactin levels compared with the intact control mice. In pituitary-grafted or castrated mice, bromocriptine distinctly prevented the rise in both porphyrins and prolactin levels. Administration of butyrophenone did not result in any marked change in testosterone levels, although Harderian gland porphyrins were significantly increased. The present results indicate that in mice prolactin stimulates the porphyrin production of the Harderian gland and has an important role in the regulation of Harderian gland porphyrins.
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  • Kimiyoshi KITAMURA, Kazuyuki YOSHIKAWA, Masahiko IWAMA, Minako NAGAO
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 163-168
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    Measurement of blood dioxin levels to monitor human exposure is tedious and expensive work, although high-resolution mass spectrometers equipped with high-resolution gas chromatography are becoming relatively common in Japan. The Ministry of Health and Welfare and the Environmental Agency require measurement of 17 dioxins, seven PCDDs and 10 PCDFs, according to a statement in “Dioxin Measurement Guidelines” published in 1997. Additionally, three coplanar polychlorinated biphenyls, for which TEFs were determined, have been included for measurement ad libitum. Recently, we have examined 316 blood samples from four groups of subjects, living in areas 5 km away from any incinerator (A), within 2 km from incinerators that emitted slightly higher levels of dioxins than the allowed level (higher than 80 ng/Nm3) (B), within 2 km of an incinerator which emitted a high level of dioxin (C), and workers at this incinerator (D), for dioxin levels by measuring 20 congeners, including three coplanar PCBs. The average pg TEQ/g lipid values were 23.8±12.3, 25.6±11.6, 39.1±18.8 and 100.7±127.4 for A, B, C and D, respectively. It was found that more than 90% of the total TEQs of the subjects in all groups were accounted for by eight congeners, 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 1,2,3,6,7,8-HxCDD, 2,3,4,7,8-PeCDF, 3,3',4,4',5-PeCB, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF and 2,3,4,6,7,8-HxCDF. This is also the case for a further 30 blood samples that had no connection with incinerators. Further, regression analysis of the 346 samples leads to an equation of y=1.109x−1.077, with a correlation coefficient, r=0.9996. Here, y=total pg TEQ of 20 congeners/g lipid of blood, and x=total pg TEQs of eight congeners/g lipid. Accordingly, we propose that measurement of eight instead of 20 congeners is appropriate to obtain dioxin TEQ values of blood, at low cost, with high accuracy and with high efficiency, in a short time.
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  • Masayuki OKUDA, Ichiro KUNITSUGU, Setsu KOBAYAKAWA, Tatsuya HOBARA
    Article type: Regular paper
    Subject area: Others
    2001 Volume 26 Issue 3 Pages 169-176
    Published: 2001
    Released on J-STAGE: October 31, 2002
    JOURNAL FREE ACCESS
    Peripheral neuropathy may remain for some time after 1,1,1-trichloroethane exposure. A variety of Ca2+ channels gives sensory neurons many kinds of transmitting sensory information. We measured calcium currents in sensory neurons from neonatal rat dorsal root ganglion using whole-cell patch-clamp recordings. Trichloroethane reversibly reduced the low-voltage-activated (LVA) and high-voltage-activated (HVA) calcium. The half-inhibitory concentration (IC50) of the HVA and LVA currents was 5.76×10-3 M and 3.99×10-3 M, respectively. The Hill coefficient of the HVA and LVA currents was 0.61 and 1.04, respectively. In assessing voltage dependence for activation and inactivation of calcium currents, only the HVA calcium current was inactivated at greater negative potentials. This may be one of the mechanisms to reduce HVA current. However, activation and inactivation of the LVA currents were not affected by trichlorothane, so inhibition of the LVA currents may have other mechanisms. Calcium currents are thought to be involved in the control of neuronal excitability and neurotransmitter release. The inhibitory effect of trichloroethane on calcium currents may be involved in trichloroethane-induced sensory discomfort.
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