The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 25 , Issue SpecialIssue
Showing 1-28 articles out of 28 articles from the selected issue
  • Toshiharu SAKAI, Michihito TAKAHASHI, Kunitoshi MITSUMORI, Kazuo YASUH ...
    2000 Volume 25 Issue SpecialIssue Pages 1-21
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The National Institute of Health Sciences and 28 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA) have conducted a validation study intended to examine whether or not lesions in the male reproductive organs noted in 4-week treatment studies can also be detected after 2-week treatment. In this study, lesions in the male reproductive organs after 2-week treatment were, therefore, compared with those after 4-week treatment. A total of 24 test substances was evaluated, these being nucleic acid modulators, cell division inhibitors, central hormonal modulators, hormonal drugs and their antagonists, other drugs and general chemicals. Among these substances, theophylline did not cause any appreciable lesions in the male reproductive organs even after 4-week treatment in the preliminary studies. With busulfan, data reported in the literature was not reproduced in the preliminary study and all animals died. Therefore, detailed examinations were not conducted for busulfan and theophylline. The remaining 22 test substances, when given to animals for 2 weeks at doses equal to or higher than for 4-week treatment, caused lesions similar to those noted after 4 weeks. It is evident from these findings that effects of pharmaceuticals on the male reproductive organs can be detected in most cases with 2-week treatment.
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  • Junko HATA, Hiroyuki TAKAHASHI, Chiho NAKAHARA, Ayumi NAMIKI, Hiroshi ...
    2000 Volume 25 Issue SpecialIssue Pages 23-31
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    As part of a collaborative project to assess whether a 2-weeks administration period is sufficient to detect testicular toxicity of various compounds, male rats were subcutaneously administered 0, 5, 20, 50 or 100μg/kg of estradiol benzoate (E2B), a known testicular toxicant, daily for 2 or 4 weeks. After 4-weeks, suppression of body weight gain, increase in the weight of the adrenal gland, and gross changes such as decrease in size of the prostate and seminal vesicles, and increase in size of the adrenal gland were observed in the 5, 20, 50 and 100μg/kg groups. On histopathological examination, degeneration/necrosis of Pachytene spermatocytes, atrophy of Leydig cells, mature spermatid retention (Lee, et al., 1993) at stages IX, X and XI, and atrophy of ducts of the epididymides were also observed in the 5, 20, 50 and 100μg/kg groups After 2-weeks, the same changes were also observed with 20, 50 and 100μg/kg, but not 5μg/kg. These results indicate that the toxic effects of E2B are detectable by administration for 2 weeks at an appropriate dose level.
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  • Yohei MIYAMOTO, Kohei UEDA, Keiyu OSHIDA, Eiji OHMORI
    2000 Volume 25 Issue SpecialIssue Pages 33-42
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Parameters of ethinylestradiol-induced testicular toxicity were evaluated with organ weight determination, histopathological examination and quantitative morphometry. Male Sprague-Dawley rats were administered ethinylestradiol orally at 3 or 10 mg/kg/day for 2 weeks and 3 mg/kg/day for 4 weeks. Final body weights in all treated groups were lower than in the respective control group. Decreased absolute and /or relative organ weights of epididymides, prostate, seminal vesicles and testes were observed in all treated groups. In the testes, apoptosis of round spermatids, atrophy of seminiferous tubules, exfoliation of spermatids or spermatocytes, and vacuolar degeneration of Sertoli cells were only observed with 4 weeks treatment. Apoptosis of pachytene spermatocytes and atrophy of Leydig cells were also more marked in the 4 week treated group than after 2 weeks. Therefore, degenerative histopathological changes in testes were more remarkable after 4 weeks treatment than in the 2 weeks treatment groups. However, retention of spermatids was less after 4 weeks treatment and the TUNEL index, calculated as the number of TUNEL-positive spermatocytes or spermatids, was increased in all treated groups. These results suggest that ethinylestradiol-induced testicular toxicity can bc detected in male rats administered the compound for 2 weeks and that the TUNEL method for in situ detection of apoptosis is effective for evaluation of testicular toxicity.
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  • Toshiko KINOMOTO, Miwa SAWADA, Shuji OGAWA, Ayako IGUCHI, Akiko MATSUI ...
    2000 Volume 25 Issue SpecialIssue Pages 43-49
    Published: October 25, 2000
    Released: February 21, 2008
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    Male Sprague-Dawley rats were subcutaneously administered 0.3 and 3.0 mg/kg/day of ethinylestradiol for 2 and 4 weeks. Two weeks treatment decreased body weight gain, food consumption, absolute weights of testis, epididymis, prostate and seminal vesicle, and relative weights of epididymis, prostate and seminal vesicle. On the other hand, it increased absolute and relative weights of pituitary and adrenal glands, and induced atrophy of Leydig cells, degeneration/necrosis of pachytene spermatocytes, vacuolar degeneration of Sertoli cells, and retention of spermatids. In addition to the changes found after 2 weeks treatment, 4 weeks treatment induced exfoliation of germinal cells, decreases in spermatid and multi-nucleated giant cell formation and relative weights of testis. These results suggest that examination of prostate and seminal vesicle weights and histopathological changes in the testis are important for evaluation of male reproductive toxicity of ethinylestradiol and 2 weeks treatment is sufficient to detect toxicity on male reproductive organs.
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  • Hiroto KAWASHITA, Kazuyuki HIRATSUKA, Junji KURODA, Yoshihito ASADA, T ...
    2000 Volume 25 Issue SpecialIssue Pages 51-62
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Doses of 0, 30 and 60 mg/kg/day of fadrozole hydrochloride (Afema○|R】 : non-steroidal aromatase inhibitor, antitumor agent) were given perorally by gavage to HanIbm WIST male rats from 6 or 8weeks of age for 2 weeks, and from 6 weeks of age for 4 weeks. In all treatment groups, reduced weights of seminal vesicle, prostate and epididymis, and degeneration/necrosis of the pachytene spermatocytes in stages VII or VIII seminiferous tubules, were dose-relatedly observed. Effects could also be assessed quantitatively by staging analysis with the result of a reduction in the numbers of stage VII pachytene spermatocytes at 30 and 60 mg/kg/day. Epididymal sperm examination revealed no treatment-related changes in any groups. The effects of 4-week treatment on male reproductive organs were similar to those of 2-week treatment at the same dose levels, except for the weight of seminal vesicle and prostate, which were more reduced by 4-week treatment than by 2-week treatment. There was no notable difference in detectability of toxicity in male reproductive organs between 2-week treatment from 6 weeks of age and 2-week treatment from 8 weeks of age. It was concluded that the changes observed in the rat male reproductive organs following 4 weeks of treatment with fadrozole hydrochloride could be detected also with 2 weeks of treatment.
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  • Akihiko OKAHARA, Akio NOMURA, Hidetoshi TANIOKA, Hiroshi SAKAMOTO, Kiy ...
    2000 Volume 25 Issue SpecialIssue Pages 63-70
    Published: October 25, 2000
    Released: February 21, 2008
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    Flutamide, a nonsteroidal antiandrogen, was administered orally to 8-week (for the 2 week study) and 6-week-old (for the 4 week study) male Crj:CD(SD) rats at dose levels of 0 mg/kg, 60 mg/kg and 200 mg/kg daily for 2 weeks or 4 weeks in order to determine whether a 2 week treatment period is sufficient for detection of drug effects on the male reproductive system. Flutamide treatment for 4 weeks resulted in decreased organ weights of the epididymides and prostate, decreased sperm counts and Leydig cell proliferation in the testes at 60 mg/kg and 200 mg/kg. Decreased sperm motility and histological lesions in the seminiferous tubules were observed at 200 mg/kg. FIutamide treatment for 2 weeks decreased organ weight of epididymides and prostate and caused Leydig cell proliferation in the testes at 60 mg/kg and 200 mg/kg. Decreased sperm counts and sperm motility, and histological lesions in seminiferous tubules were observed at 200 mg/kg. The results of this study showed that 2 weeks treatment with flutamide causes histological lesions of testes and disorders of sperm parameters similar to those observed with 4 weeks treatment, indicating that 2 weeks treatment is sufficient for detection of effects of flutamide on the male reproductive system.
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  • Shin KOHGE, Shinsuke HAGI, Hiroyuki UTSUMI, Kiyoshi TAKEGAWA, Shiro TA ...
    2000 Volume 25 Issue SpecialIssue Pages 71-77
    Published: October 25, 2000
    Released: February 21, 2008
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    Haloperidol, a neuroleptic, was orally given to Sprague-Dawley rats for 2 or 4 weeks, starting at 8 and 6 weeks of age. The dose levels were 0, 30 and 60 mg/kg/day for the 4-week treatment groups, and 0, 30, 60 and 80 mg/kg/day for the 2-week treatment groups. On the day after the last administration, rats were anesthetized and sacrificed at 10 weeks of age. The absolute weights of the testes and epididymides were decreased after 2-and 4-weeks at 30 mg/kg/day or above. The absolute and relative weights of the prostate and seminal vesicles were also decreased after 2-weeks at 60 mg/kg/day or above, and 4-weeks at 30 mg/kg/day or above. The histopathological alterations observed after 2-weeks at 30 mg/kg/day were as follows : atrophy of Leydig cells, numerous necrotic pachytene spermatocytes in seminilferous tubules of stage VII, retention of mature spermatids, exfoliation of round spermatids in lumina of scminiferous tubules, cell debris in lumina of the epididymis. At 60 mg/kg/day or above, these alterations were pronounced. Histopathological changes were comparable to those detected after 4-weeks treatment. It was concluded that alterations of the male reproductive organs are detectable by a 2-week administration of haloperidol in rats to almost the same degree as after 4-weeks treatment.
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  • Kenji YAMAUCHI, Yumi TAKAURA, Takahisa NOTO, Tadashi SAEGUSA, Shunji N ...
    2000 Volume 25 Issue SpecialIssue Pages 79-85
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To assess the efficacy of different period of treatment for evaluating male reproductive toxicity in rats, reserpine was subcutaneously administered on a daily basis to male Sprague-Dawley rats at dosages of 0.05, 0.1 or 0.2 mg/kg for 2 weeks or at dosages of 0.05 or 0.1 mg/kg for 4 weeks. At the end of the administration period the animals were sacrificed and sperm counts, organ weights and histopathological changes in the reproductive organs were examined. The sperm number in the caudal epididymis and genital organ weights were not affected by reserpine with either 2- or 4-weeks treatment. In the 4-weeks study, histopathological examination of the testes revealed retention of step 19 spermatids in the seminiferous tubules of stages IX to XII and decreased secretory content of the prostate in the 0.05 and 0.1 mg/kg groups. In the 2-weeks study, although no distinct histopathological changes were observed in the 0.05 mg/kg group, decreased secretory content of the prostate, apoptosis of spermatocytes in the seminiferous tubules of stage VII and cell debris of the epididymis were observed in the 0.1 and 0.2 mg/kg groups. These results suggested that 2-weeks treatment with reserpine is sufficient for detection of testicular toxicity, although higher dosage levels are appropriate than for 4-weeks treatment.
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  • Nobuyuki KAWAMURA, Shunsuke TSUTSUMI, Shuji TAKESHITA
    2000 Volume 25 Issue SpecialIssue Pages 87-94
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To obtain information on the validity and the limitations of 2-weeks repeated-dose toxicity studies to detect effects on the male genital organs of rats, reserpine was administered daily at 0.05 and 0.1 mg/kg by subcutaneous injection to Crj:CD(SD)IGS male rats for 2 and 4 weeks (2-weeks and 4-weeks studies). In the 2-weeks study, suppression of body weight gain was observed in the reserpine 0.1 mg/kg group. In the 4-weeks study, suppression of body weight gain and a decrease in prostate weight were observed in ne reserpine 0.1 mg/kg group. Slight to moderate retention of step 19 spermatids in the seminiferous tubules (stages IX-XI) was observed in a few animals of both the reserpine 0.05 and 0.1 mg/kg groups in both the 2- and 4-weeks studies. However, seminiferous tubule atrophy with degeneration of germ sells was observed sporadically not only in the reserpine groups but also in the control group, and this change might have been the cause of the spermatid retention. Therefore, we were unable to reach a clear conclusion with regard to whether it is possible to detect reserpine toxicity on spermatogenesis in rats after 2-weeks administration.
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  • Tamiko ADACHI, Tomonari NISHIMURA, Hiroshi IMAHIE, Takaaki YAMAMURA
    2000 Volume 25 Issue SpecialIssue Pages 95-101
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The present study was performed to determine whether testicular toxicity can be detected of the administration of adriamycin (ADR), an anticancer drug, for 2 weeks. ADR was intravenously administered to Slc:SD male rats at 1 mg/kg once a week for 4 or 2 weeks, and 2 mg/kg once a week for 2 weeks. Suppression of body weight gain was observed in the 1 mg/kg/week (4w) and 2 mg/kg/week (2w) groups. The testes weights in these groups were also lower than those of the control group. On histological examination, a decrease in spermatogonia was observed in the 1 mg/kg/week (4w) and 2 mg/kg/week (2w)groups. No abnormalities were detected in the control and 1 mg/kg/week (2w) groups. Stage analysis of seminiferous tubules was performed for control and 1 mg/kg/week (2w) groups. In the 1 mg/kg/week (2w) group, the numbers of spermatogonia in stages II-III, V and XII-XIII were significantly decreased. The numbers of preleptotene spermatocytes in stage VII and zygotene spermatocytes in XII-XIII were also significantly reduced in the same group. These findings suggest that the testicular toxicity of ADR can be detected after 2 weeks administration at a sufficient high dosage, if simplified morphometrical analysis is used.
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  • Ichiro TSUNENARI, Mamoru KAWACHI, Takehisa MATSUMARU, Shoji KATSUKI
    2000 Volume 25 Issue SpecialIssue Pages 103-115
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The present study was performed to clarify whether toxic effects of the antitumor drug, adriamycin (ADR) on the male genital organ can be adequately detected 2 and 4 weeks after a single intravenous administration in the rat. ADR was intravenously administered once to 10 Crj:CD (SD) male rats/group aged 6 weeks (4-week group) and 8 weeks (2-week group) at doses of 0, 2 and 6 mg/kg. The rats were sacrificed at the age of 10 weeks. For comparison 10 rats/group were killed 2 weeks after a single intravenous administration at the age of 4 weeks (immature group). Saline was administered to control rat. Histopathological examination and a quantitative morphometry were carried out after measurement of testes weights at necropsy. In rats of the 4-week and 2-week groups, mean absolute testicular weight in all groups was significantly decreased. However, changes in mean relative weight were not evident in the 2-week group. Disappearance of seminiferous epithelial cells was observed histopathologically in rats dosed with 2 and 6 mg/kg in the 2-week group. The change was more severe in the 4-week group, when reduction of spermatogenesis and giant cells were also observed at 6 mg/kg. The quantitative morphometry in the 2-week group showed decreases in the numbers of spermatogonia and spermatocytes in stages X and XII at 2 mg/kg, and in the numbers of spermatogonia in all stages and spermatocytes in all stages except stage V at 6 mg/kg. Moreover, the numbers of spermatogonia and spermatocytes in all stages and spermatids in stages II-III and V were decreased with dose related manner in the 4-week group. In contrast, no obvious change in testes weights was apparent in the immature group. However, the numbers of spermatogonia and spermatocytes in all stages were decreased at 6 mg/kg. In conclusion, testicular toxicity of ADR could be detected 2 weeks after a single administration. Susceptibility of the testes of immature rats to ADR might be less than that of older animals.
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  • Yasuyuki MISAWA, Kazuto WATANABE, Takayuki SAKURAI, Etsuko FUJII, Kozu ...
    2000 Volume 25 Issue SpecialIssue Pages 117-127
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A novel platinum complex, compound C, developed as an antitumor agent, was intravenously administered at 10 mg/kg/day to 6-week-old and 8-week-old rats. After 4 weeks of administration to the former, testicular enlargement was observed at a similar incidence as testicular atrophy and dilatation or atrophy of the seminiferous tubules was observed. Degeneration/necrosis of the seminiferous epithelium, decrease of seminiferous epithelium, formation of multinucleated giant cells, and vacuolar degeneration of Sertoli cells were also seen. These lesions were more marked in seminiferous tubules with atrophy than in those without atrophy. After 2-week administration to 8-week-old rats, slight initial-phase findings such as dilatation of seminiferous tubules and degeneration/necrosis of the seminiferous epithelium were noted in all rats. In rats administered 20 mg/kg/day, for which the administration period was shortened to 1 week due to marked weight loss, very slight initial lesions were similarly observed. However, these lesions were not easy to detect in these rats. Following single administration of a sublethal dose (80 mg/kg), testicular lesions were clearly observed 14 days after administration, but the incidence and grade of lesions were very low at 7 days. In conclusion, testicular toxicity of compound C can be clearly detected after 2-week administration, although the progression of lesions differed from the case with 4-week administration.
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  • Takao WATANABE, Norikazu YAMAGUCHI, Tomohide AKIBA, Masahiro TANAKA, M ...
    2000 Volume 25 Issue SpecialIssue Pages 129-137
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To determine what is an appropriate administration period for evaluation of the testicular toxicity of cyclophosphamide, the compound was administered orally to male Crj:(CD)SD rats at doses of 5, 10, 20 and 40 mg/kg/day for 2 weeks and at doses of 2.5, 5 and lO mg/kg/day for 4 weeks. All animals in the 2-week treatment group given 40 mg/kg/day died during the treatment period. After repeated dosing, weights of testes and epididymides did not change significantly in either 2-week or 4-week treatment groups. On conventional histopathological examination, changes in spermatogonia were too subtle to allow simple quantitative evaluation. Therefore the quantitative analysis described by Matsui et al. (l995) was employed. After 4-weeks treatment all types of germ cells decreased significantly in all stages of seminiferous tubules examined in the 10 mg/kg/day group. Spermatogonia type A in all stage seminiferous tubules examined and spermatogonia type B in stage V seminiferous tubules decreased significantly in the 5 mg/kg/day group. With 2-weeks treatment, spermatogonia type A in all stage seminiferous tubules examined were similarly decreased significantly in 10 mg/kg/day or more groups. Spermatogonia type B and pachytene spermatocytes in stage V, preleptotene spermatocytes in stage VII and zygotene spermatocytes in stage Xll were decreased in 20 mg/kg/day group. Sertoli cells and the Leydig cells and epididymides were not affected in any treatment group. In conclusion, testicular toxicity induced by cyclophosphamide could be detectable after 2-weeks as well as after 4-weeks treatment if precise histopathological examination including quantitative analysis of spermatocytes are conducted.
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  • Satoshi MATSUMOTO, Meiko HIRAKAWA, Takasumi SHIMOMOTO, Makoto SATO, Ke ...
    2000 Volume 25 Issue SpecialIssue Pages 139-143
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    As part of a collaborative effort to evaluate whether effects on male reproductive organs of chemicals can be detected within two-week in toxicity studies, eight-week-old male Sprague-Dawley rats were given a single oral administration of 100 mg/kg of Cyclophosphamide (Cp), and sacrificed at 1, 3, 7 and 14 days thereafter. The numbers of seminiferous epithelial cells were counted in the seminiferous tubules of stages II-III, V, VII and XII of the spermatogenic cycle. Animals showed decreased spermatogonia at Day 3, decreased spermatogonia and preleptotene spermatocytes at Day 7, and decreased spermatogonia and zygotene spermatocytes at Day l4. We also detected decrease of zygotene spermatocytes on careful routine/traditional histopathological examination at Day l4. These results suggest that the testicular toxicity of Cp can be detected within two weeks after treatment with a sufficient dose in rats.
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  • Masako KAWAGUCHI, Yuki NAGAOKA, Masataka KAGAWA, Yasuhiro KASAI, Masay ...
    2000 Volume 25 Issue SpecialIssue Pages 145-153
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    In order to examine whether effects on male reproductive organs following 2-weeks administration of Etoposide (ET) are detectable, ET was administered intravenously once a week to rats for 2 and 4 weeks at 5 and 10 mg/kg/week. No deaths and no drug-related changes in body weight or in gross pathology were observed. However, decreased testis and/or thymus weights were noted. And histopathological examination revealed decrease and/or loss of spermatogonia and spermatocytes in the testes. It was evident that the target cells of the test article in the male reproductive organs are spermatogonia. Atrophy of the medulla and increase of immature lymphocytes in the cortex of the thymus and increase of fatty cells and increase of immature hematopoietic cells in the bone marrow were also apparent. The histological changes in the testis, thymus and bone marrow suggest that ET inhibits cellular mitosis which reflects its mechanism of action as an anticancer agent. lt is concluded that effects of ET on male reproductive organs can be detectcd by histopathological examination of the testes after 2-weeks repeated administration.
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  • Shigenari OZAWA, Ryohei YOKOI, Tsuyoshi KITAMURA, Kazuya KURIYAMA, Kaz ...
    2000 Volume 25 Issue SpecialIssue Pages 155-162
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    This study was conducted to assess whether a 2-week treatment period is as effective as 4-week treatment for detection of drug-induced toxicity on the male rat reproductive organs using methyl methanesulfonate (MMS). A two-week study at dose levels of 20 or 40 mg/kg and a 4-week study with 20 mg/kg were conducted. The results can be summarized as follows. No deaths and no apparent clinical signs were observed. Body weights and food consumption were decreased at 40 mg/kg in the 2-week study along with testis and epididymis weights. In the 4-week study, epididymis weights were decreased at 20 mg/kg. The rats treated with 20 mg/kg in the 4-week study and those treated with 40 mg/kg in the 2-week study showed decrease of germ cells, exfoliation of germ cells, vacuolar degeneration of Sertoli cell and cell debris in epididymal ducts on histopathological observation. MMS impairment of spermatogenesis was confirmed by stage analysis. It was concluded that a treatment period of 2 weeks is sufficient to allow evaluation of toxic effects of MMS on the male reproductive organs.
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  • Masakazu FURUKAWA, Toshio KARAKAMA, Masayoshi KAJI, Shinobu GOMITA, Ma ...
    2000 Volume 25 Issue SpecialIssue Pages 163-171
    Published: October 25, 2000
    Released: February 21, 2008
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    Since morphological changes in the testes were observed in a 4 week rcpeated dose toxicity study of carmofur in rats, male Sprague-Dawley rats were administered the compound orally at 200 mg/kg by gavage for, 11 days to assess the possibility of detecting abnormalities in spermatogenesis within a 2 week period. For comparison two studies were performed, treatment groups of fifteen and fourteen rats being given carmofur for 28 and 11 days, respectively. There were seven and nine rats that died or were killed in a moribund condition with 28 and 11 days treatment, respectively. Histopathologically, vacuolar degeneration of Sertoli cells, degeneration of elongated spermatids, exfoliation of round spermatids and multinucleated giant cell formation were observed in the testes of all animals and cell debris in ductus epididymidis was noted in almost all rats in the 28 days study. Exfoliation of round spermatids and multinucleated giant cell formation were detectable in two of five rats in the 11 days study, and vacuolar degeneration of Sertoli cells was also evident in four, though the changes were slight. No abnormalities were observed in the epididymides in the 11 days study. These results suggest that effects of carmofur on spermatogenesis can be detected with a treatment period of less than 2 weeks using histopathological examination of the testes. Therefore a 2-week repeated dose toxicity study has validity for detection of effects of carmofur on the male reproductive organs in the rats.
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  • Kazuhiro HAYAKAWA, Toshifumi TASHIRO, Kunio SATO, Tomiharu KATSURAYAMA ...
    2000 Volume 25 Issue SpecialIssue Pages 173-178
    Published: October 25, 2000
    Released: February 21, 2008
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    E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide), a sulfonamide antitumor agent that inhibits tubulin polymerization, was orally administered to male Slc:SD rats at doses of 50 and 75 mg/kg once a day for 2 weeks. E7010 at a dose of 75 mg/kg induced severe testicular lesions characterized by marked decrease and/or loss of seminiferous epithelial cells, which sometimes resulted in tubules with only Sertoli cells. In the 50 mg/kg group, alteration of germ cells was evident at various stages of spermatogenesis, and apoptotic figures of meiotic spermatocytes at stage XIV were frequently observed. Single dose treatment of 50 mg/kg was also performed and was revealed a decrease of round spermatids in stage VII at necropsy after 1 week. Thus the target cells were considered to be meiotic spermatocytes at stage XIV. The present study indicates that 2-weeks repeated dosing is sufficient to detect the testicular toxicity of E7010.
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  • Akira INOMATA, Hirotaka MATSUMOTO, Ikuo HORII
    2000 Volume 25 Issue SpecialIssue Pages 179-186
    Published: October 25, 2000
    Released: February 21, 2008
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    Oral repeated toxicity studies were conducted to compare the effects of 5-fluorouracil (5-FU) administered for 4 or 2 weeks on male reproductive organs of Sprague-Dawley (SD) rats. In both studies, decrease of feces, abnormal fur and emaciation were observed. On gross autopsy examination, softening/atrophy of the testis as well as atrophy of accessory reproductive organs were noted, and absolute organ weights of male reproductive organs were almost all reduced in both studies. Histopathologically, degeneration of the seminiferous epithelium in the testis and desquamated cell debris in the epididymal ducts were apparent after both time periods. In the 2-week study, furthermore, exfoliation of the seminiferous epithelium, formation of multinucleated giant cells and vacuolation of Sertoli cells in the seminiferous tubules in the testis, and decrease of sperms in the epididymal ducts were observed. The present results indicated that a 2-week study is sufficient to detect effects on the male reproductive organs of 5-FU treatment. In our study, however, changes in associated parameters after 2-week treatment of 8-week-old rats were greater than those after 4 weeks in 6-week-old rats. Thus, for detection of 5-FU-induced male reproductive toxicity, we can evaluate more accurately by using maturated rats of the same age.
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  • Kazuo KIZAWA, Shinichi FURUBO, Takahiro SANZEN, Yasuhito KAWAMURA
    2000 Volume 25 Issue SpecialIssue Pages 187-194
    Published: October 25, 2000
    Released: February 21, 2008
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    The toxicity of Enoxacin (ENX), a fluoroquinolone antibacterial agent, on the testis and epididymis was studied in rats. ENX was administered to 5 male rats orally once daily for 2 weeks at the dose level of 3000 mg/kg/day. ENX-treated rats showed a marked decrease in body weight, and two of them died on Day 10. At the end of the dosing period, absolute weights of the epididymis were decreased;in contrast, relative weights of testis were increased in the ENX-treated group. On histopathological examination, testis of ENX-treated rats exhibited the following regressive changes : degeneration of spermatids and spermatocytes, retention of Step 19 spermatids, chromatin margination in nuclei of spermatids, multinucleated giant cell formation, and/or vacuolar degeneration of Sertoli cells. Additionally, desquamated cell debris was observed in the epididymis. Degenerative spermatids and spermatocytes were strongly positive by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). From these results, it is concluded that a 2-week treatment is sufficient to detect toxic effects of ENX on rcproductive organs in male rats, and that testicular toxicity induced by ENX is associated with germ cell apoptosis.
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  • Kyoko ITO, Satoru SASAKI, Kohsuke YOSHIDA, Aisuke NII, Hideaki OKAMIYA ...
    2000 Volume 25 Issue SpecialIssue Pages 195-201
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Nitrofurazone (NF) has been previously demonstrated to induce testicular toxicity with 4 weeks of oral administration in rats. In the present study, rats were administered NF to assess whether testicular toxicity becomes evident with a 2-week administration period. Male Sprague-Dawley rats were administered oral doses of NF at 50 mg/kg for 2 or 4 weeks. Another group was administered NF at 100 mg/kg for 2 weeks. The control animals received the vehicle (0.5% methylcellulose) for 4 weeks. Organ weights of the testis and epididymis were significantly decreased in all NF-administered animals, and seminiferous tubules were severely atrophied, due to a total absence of spermatids and degeneration and desquamation of spermatocytes. In the epididymis, decreased numbers of spermatozoa were evident in the ducts. In rats that were administered NF at 50 mg/kg, the changes in the epididymis in the 2-week group were less prominent than those in the 4-week group. In the testis, however, the changes were similar in both groups. Thus it was demonstrated that NF-induced testicular toxicity comparable to that observed after 4 weeks of administration is also detectable after 2 weeks.
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  • Yoshinori MURAKAMI, Masashi TAKEDA, Yoshiharu SUZUKI, Hisako FUJII, Hi ...
    2000 Volume 25 Issue SpecialIssue Pages 203-210
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Pyrimethamine (PYR), clinically used as an antimalarial or antiparasitic agent, is known to exert testicular toxicity in rats on oral administration for 8 weeks. This study was performed to examine whether 2-weeks daily repeated doses of PYR might induce detectable toxicity on the male reproductive organs in rats. PYR was orally administered to Slc:SD male rats at doses of 12.5, 25 or 50 mg/kg for 2 weeks, or 6.25, 12.5 or 25 mg/kg for 4 weeks. No effects were seen in any group on physical examination and body weight measurement. Gross findings in autopsy exhibited no abnormalities in any of the animals. There were no meaningful changes in the weights of reproductive organs, or in the number and activity of sperm in the epididymides. Loss and degenerative changes of pachytene spermatocytes in stages I to III seminiferous tubules were observed in the rats given 50 mg/kg PYR for 2 weeks. From the results obtained, it is concluded that 2-weeks repeated dosing with PYR is sufficient to detect toxicity on male reproductive organs in rats using histopathological examination.
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  • Hitoshi FUNABASHI, Michi FUJIOKA, Mami KOHCHI, Yumi TATEISHI, Nobuo MA ...
    2000 Volume 25 Issue SpecialIssue Pages 211-221
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.
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  • Satoshi KUDO, Hirofumi TANASE, Masakazu YAMASAKI, Maiko NAKAO, Yuki MI ...
    2000 Volume 25 Issue SpecialIssue Pages 223-232
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To assess the validity and limitations of 2-week repeated daily dosing to detect toxic effects on male reproductive organs in rodents, a comparative 2- and 4-week oral repeated dosing study of boric acid, a known testicular toxicant, was given to 6- or 8-week-old Crj:Wistar rats at daily levels of 0, l25, 250 and 500 mg/kg. The ages of the rats were selected so that they were all sacrificed at 10 weeks of age. The testes and epididymides were weighed at necropsy; histopathological specimens were prep(ared in a routine manner and stained with H&E or PAS-H. In addition, the sperm number and motility rates were evaluated. There were no boric acid-induced effects on reproductive organ weights and on gross behavior/appearance in any groups in either the 2- or 4-week studies. The sperm number and motility rate were not decreased in any group after 2 weeks, while both decreased in the 250 and 500 mg/kg groups after 4 weeks. Histopathologically, as evidence of toxicity at the early stage of boric acid exposure, retention of step l9 spermatids of stages IX - XI was observed in the testes of almost all rats treated with 500 mg/kg after both 2 weeks and 4 weeks. Degenerative/necrotic germ cells and multinucleated giant cell formation were observed in 2 weeks, though to a lesser extent than in 4 weeks. On stage analysis of germinal cells in 2 weeks, spermatogonia and spermatids of stage VII were found to be decreased, and pachytene spermatocytes of stage X were increased. In conclusion, the results indicate that if the selection of doses is appropriate, testicular toxicity of boric acid can be detected even after only 2 weeks of repeated daily oral treatment.
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  • Ryo FUKUDA, Mitsuhiro HIRODE, Ikuo MORI, Fumio CHATANI, Hideki MORISHI ...
    2000 Volume 25 Issue SpecialIssue Pages 233-239
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To assess whether or not male reproductive toxicity can be evalutaed in a 2-week administration study, boric acid was administered daily by oral gavage to male Jcl:Wistar rats at dosage levels of 0, 300 and 500 mg/kg for 2 and 4 weeks, and the results obtained with the two different treatment schedules were compared. After a 2-week administration, decreased testis weights were observed in the 50O mg/kg group. Histopathologically, exfoliation of round spermatids, retention of step 19 spermatids and increased numbers of residual body-like structures in the seminiferous tubules and cell debris in the cranial epididymal ducts were observed in the 300 and 500 mg/kg groups. Distorted cytoplasmic lobes of step 19 spermatids, debris in the seminiferous tubules and focal atrophy of the seminiferous tubules with multinucleated giant cells formation and necrosis of spermatocytes were also observed in the 500 mg/kg group. After a 4-week administration, testis and epididymis weights were decreased in the 300 and 500 mg/kg groups. Histopathological changes in the 300 mg/kg group were similar to those found in the 300 and 500 mg/kg groups after a 2-week administration. Diffuse atrophy of the seminiferous tubules was additionally observed in the 500 mg/kg group. These results suggest that 2 weeks is a sufficient treatment period for the detection of the testicular toxicity caused by boric acid.
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  • Takayuki TSUCHIYA, Naoki OOYAMA, Tomoko MURAKAMI, Fumiko SANO, Jiro SU ...
    2000 Volume 25 Issue SpecialIssue Pages 241-249
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    To assess the sensitivity of rats to a testicular toxicant, 2- and 4-week repeated-dose studies using dibromoacetic acid (DBAA) were performed. Four groups of 6- or 8- week old male SD rats were given DBAA at a daily dosage of 0, 5, 50 or 250 mg/kg. The highest dose was given for 2 weeks, and the others for 2 and 4 weeks. There were no effects on body or testicular weights in any of the DBAA-treated groups. However, the mean absolute epididymal weight in the 250 mg/kg group was significantly lower than that of the control group. Histopathologically, atypical residual bodies (ARBs) and retention of Step 19 spermatids were evident with this high dose. In the same group, ARBs in the epididymal ducts and narrowing of these lumina were also observed. Retention of Step 19 spermatids was similarly apparent in the testes of animals given 50 mg/kg for 2 or 4 weeks, and in one animal given 5 mg/kg for 4 weeks. Based on these data, DBAA testicular toxicity is histopathologically detectable within 2-weeks or repeated dosing at an appropriate dose.
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  • Kenji IRIMURA, Masahiro YAMAGUCHI, Hidenobu MORINAGA, Shigeo SUGIMOTO, ...
    2000 Volume 25 Issue SpecialIssue Pages 251-258
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    As part of a collaborative work, male rats were administered 1, 3-dinitrobenzene (1, 3-DNB) daily at 0, 25 and 50 mg/kg/day from the age of 6 weeks for 4 weeks ( 4-week exp.), or at 25, 50 and 75 mg/kg/day from the age of 8 weeks for 2 weeks ( 2-week exp.). After the end of each administration period, all survivors were sacrificed, and their testes and epididymides were removed, weighed and examined histopathologically. The following results were obtained. In the 4-week exp. : At 50 mg/kg/day, the weights of testes and epididymides showed decrease with macroscopic atrophy. The testicular spermatogenic epithelium showed decrease in the number of sperm∼spermatocytes, degeneration/necrosis, giant cell formation and vacuolation, reduction in sperm counts also being evident in the ducts of the epididymides. In the 2-week exp. : At 50 and 75 mg/kg/day, the weights of testes and/or epididymides showed decrease with macroscopic atrophy. Several histopathological changes in the testes and epididymides were essentially the same changes as in the group given 50 mg/kg/day in the 4-week exp., with a clear relation. These results indicate that a 2-week administration period is sufficient to detect testicular and epididymal histopathological changes induced by 1, 3-dnitrobenzene in male rats.
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  • Atsushi WATANABE, Yuji NAKANO, Takako ENDO, Norihiro SATO, Kiyonori KA ...
    2000 Volume 25 Issue SpecialIssue Pages 259-266
    Published: October 25, 2000
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    As part of a collaborative project to determine the minimum administration period to detect compound effects on male reproductive organs in Sprague-Dawley (Crj:CD(SD)) male rats, 6- and 8- week-old rats were administered ethylene glycol monomethyl ether (EGME) daily at 100 and 200 mg/kg/day for 2 weeks or 100 mg/kg/day for 4 weeks, and histopathological changes in the testes and epididymides were examined. Testis and epididymis weights in the 2-week 200 mg/kg and 4-week 100 mg/kg groups were obviously decreased. On histopathological examination, severe degenerative changes in the testis such as atrophy of the seminiferous tubules and multinucleated giant cell formation were observed in all 2-week 200 mg/kg group rats. Degeneration of pachytene spermatocytes in Stages X IV-II, III and a decrease in the number of germ cells was observed with both 2 and 4 weeks treatments at 100 mg/kg/day. In the epididymides, the number of sperm in the caput decreased with 100 mg/kg/day groups after both 2 and 4 weeks. In addition, degeneration of pachytene spermatocytes induced by EGME was found to be exclusively due to apoptotic death. Similar testicular and epididymal changes were observed with 2 and 4 weeks treatments at 100 mg/kg/day of EGME. Therefore, we conclude that a 2 weeks administration period is sufficient for detection of EGME effects on male reproductive organs.
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