This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Sawamoto, O. Articles by Kurisu, K. Search for Related Content PubMed PubMed Citation Articles by Sawamoto, O. Articles by Kurisu, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CYSTEINE Medline Plus Health Information Testicular Disorders Social Bookmarking                         What's this?

Development of Sperm Granulomas in the Epididymides of L-Cysteine-Treated Rats

Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc, Naruto, Tokushima, Japan, sawamoos{at}otsukakj.co.jp, Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka, Japan

Jyoji Yamate

Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka, Japan

Mitsuru Kuwamura

Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka, Japan

Takao Kotani

Laboratory of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Osaka, Japan

Kazunobu Kurisu

Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc, Naruto, Tokushima, Japan

We investigated the histopathological effects of excess L-cysteine on the male rat reproductive tract during sexual maturation. Male 6-week-old Sprague—Dawley rats were injected intraperitoneally daily with L-cysteine, 1,000 mg/kg body weight, for 1, 2, 3, and 4 weeks. L-Cysteine-treated rats developed sperm granulomas in the epididymides at an incidence of 0% (0/6), 50% (3/6), 83% (5/6), and 100% (6/6) in rats examined at study weeks 1, 2, 3, and 4, respectively. These sperm granulomas were unilateral or bilateral, and most frequently involved the proximal cauda region of the epididymides. Interestingly, small ducts, indicative of immaturity, were seen frequently in L-cysteine-treated rats. These findings suggest that the maturation of epididymides in L-cysteine-treated rats might be delayed. Additionally, dilated ducts and interstitial edema, suggestive of an increase in intraluminal pressure, were seen often in the epididymides of L-cysteine-treated rats. Labeling spermatozoa and epithelial cells with monobromobimane indicated no influence of the thiol—disulfide status of L-cysteine to the epididymides. The testes and prostate glands also showed no effects, suggesting that inhibited epididymis maturation was not a result of hormonal deficiencies. We speculate that defective development of the ducts might result in aberrant fluid flow, leading to ductal rupture in the epididymides. In that case, sperm granulomas might form around leaked spermatozoa.

Key Words: L-Cysteine • sperm granuloma • epididymis • amino acid • apoptosis • rat.

References

• Agrawal YP, Vanha-Perttula T. (1988). Gamma-glutamyl transpeptidase, glutathione, and L-glutamic acid in the rat epididymis during postnatal development. Biol Reprod 38: 996—1000.[Abstract]
• Ando J., Ishihara R., Imai S., Takano S., Kitamura T., Takahashi M., Yoshida M., Maekawa A. (1997). Thirteen-week subchronic toxicity study of thiamphenicol in F344 rats. Toxicol Lett 91: 137—146.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Bedford JM, Calvin HI (1974). The occurrence and possible functional significance of -S-S-crosslinks in sperm heads, with particular reference to eutherian mammals. J Exp Zool 188: 137—155.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Benevenga NJ, Steele RD (1984). Adverse effects of excessive consumption of amino acids. Annu Rev Nutr 4: 157—181.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Benson WR, Clare FS (1966). Regenerative changes and spermatic granulomas in the rat testis after treatment with DL-ethionine. Am J Pathol 49: 981—995.[Web of Science][Medline] [Order article via Infotrieve]
• Betzalel M., Shalgi R., Moav B. ( 1986). Protamine in the rat, its fate in vivo, and its degradation in vitro by egg homogenate. Gamete Res 14: 293—306.[CrossRef][Web of Science]
• Bhathal PS, Gerkens JF, Mashford ML (1974). Spermatic granuloma of the epididymis in rats treated with guanethidine. J Pathol 112: 19—26.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Calvin HI (1976). Comparative analysis of the nuclear basic proteins in rat, human, guinea pig, mouse and rabbit spermatozoa. Biochim Biophys Acta 434: 377—389.[Medline] [Order article via Infotrieve]
• Chapin RE, White RD, Morgan KT, Bus JS (1984). Studies of lesions induced in the testis and epididymis of F-344 rats by inhaled methyl chloride. Toxicol Appl Pharmacol 76: 328—343.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Chaturapanich G., Sujarit K., Pholpramool C. (1999). Effects of sulphapyridine on sperm transport through the rat epididymis and contractility of the epididymal duct. J Reprod Fertil 117: 199—205.[Abstract/Free Full Text]
• Creasy DM, Foster PMD (1991). Male reproductive system. In: Handbook of Toxicologic Pathology, Haschek WM, Rousseaux CG (eds). Academic Press, San Diego, CA, pp 829—889.
• Ericsson RJ (1970). Male antifertility compounds: U-5897 (-chlorohydrin) as a rat chemosterilant. J Reprod Fertil 22: 213—222.[Abstract/Free Full Text]
• Gainer H., Kosower NS (1980). Histochemical demonstration of thiols and disulfides by the fluorescent labeling agent, monobromobimane: An application to the hypothalamo-neurohypophysial system. Histochemistry 68: 309—315.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Greaves P (ed) (2000). Male genital tract. In: Histopathology of Preclinical Toxicity Studies, Interpretation and Relevance in Drug Safety Evaluation, 2nd ed. Elsevier, Amsterdam, pp 627—675.
• Hinton BT (1990). The testicular and epididymal luminal amino acid microenvironment in the rat. J Androl 11: 498—505.[Abstract/Free Full Text]
• Hinton BT, Turner TT (1988). Is the epididymis a kidney analogue? News Physiol Sci 3: 28—31.[Abstract/Free Full Text]
• Ikezaki S., Nishikawa A., Furukawa F., Imazawa T., Enami T., Mitsui M., Takahashi M. (1994). 13-week subchronic toxicity study of L-histidine monohydrochloride in F344 rats. Bull Natl Inst Health Sci 112: 57—63 (in Japanese).
• Ishii H., Usami S., Fujimoto T., Moriyuki H., Hashimoto S., Ichimura M. (1980). Subacute toxicity study of lentinan in rats. 5-week intravenous treatment. J Toxicol Sci (Suppl): 11—31 (in Japanese).
• Jiang FX, Temple-Smith P., Wreford NG (1994). Postnatal differentiation and development of the rat epididymis: A stereological study. Anat Rec 238: 191—198.[CrossRef][Medline] [Order article via Infotrieve]
• Karlsen RL, Grofova I., Malthe-Sorenssen D., Fonnum F. (1981). Morphological changes in rat brain induced by L-cysteine injection in newborn animals. Brain Res 208: 167—180.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Klavins JY (1967). Pathology of amino acid excess. II. Effects of administration of excessive sulphur containing amino acid: L-cysteine. Br J Exp Pathol 44: 516—520.
• Klinefelter GR, Hess RA (1998). Toxicology of the male excurrent ducts and accessory sex glands. In: Reproductive and Developmental Toxicology, Korach KS (ed). Marcel Dekker, New York, pp 553—591.
• Klinefelter GR, Laskey JW, Roberts NR, Slott V., Suarez JD (1990). Multiple effects of ethane dimethanesulfonate on the epididymis of adult rats. Toxicol Appl Pharmacol 105: 271—287.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Mason KE, Young JO (1967). Effects of cadmium upon the excurrent duct system of the rat testis. Anat Rec 159: 311—323.[CrossRef][Medline] [Order article via Infotrieve]
• McDonald SW (2000). Cellular responses to vasectomy. Int Rev Cytol 199: 295—339.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Olney JW (1993). Role of excitotoxins in developmental neuropathology. Acta Pathologica, Microbiologica, et Immunologica Scandinavica 110 (Suppl. 40): 103—112.
• Olney JW, Zorumski C., Price MT, Labruyare J. (1990). L-Cysteine, a bicarbonate-sensitive endogenous excitotoxin. Science 248: 596—599.[Abstract/Free Full Text]
• Pholpramool C., Triphrom N., Din-Udom A. (1984). Intraluminal pressures in the seminiferous tubules and in different regions of the epididymis in the rat. J Reprod Fertil 71: 173—179.[Abstract/Free Full Text]
• Povysil C. (1976). Spermatic granulomas of ischemic origin in the rat epididymis. Invest Urol 14: 219—224.[Web of Science][Medline] [Order article via Infotrieve]
• Puka-Sundvall M., Eriksson P., Nilsson M., Sandberg M., Lehmann A. (1996). Neurotoxicity of cysteine: Interaction with glutamate. Brain Res 705: 65— 70.
• Rotruck JT, Boggs RW (1977). Effects of excess dietary L-methionine and N-acetyl-L-methionine on growing rats. J Nutr 107: 357—362.[Abstract/Free Full Text]
• Said S., Funahashi H., Niwa K. ( 1999). DNA stability and thiol-disulphide status of rat sperm nuclei during epididymal maturation and penetration of oocytes. Zygote 7: 249—254.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Seligman J., Kosower NS, Shalgi R. (1997). Effects of castration on thiol status in rat spermatozoa and epididymal fluid. Mol Reprod Dev 47: 295— 301.
• Seligman J., Shalgi R. (1991). Protein thiols in spermatozoa and epididymal fluid of rats. J Reprod Fertil 93: 399—408.[Abstract/Free Full Text]
• Shalgi R., Seligman J., Kosower NS (1989). Dynamics of the thiol status of rat spermatozoa during maturation: Analysis with the fluorescent labeling agent monobromobimane. Biol Reprod 40: 1037—1045.[Abstract]
• Shapre LG, Olney JW, Ohlendorf C., Lyss A., Zimmerman M., Gale B. ( 1975). Brain damage and associated behavioral deficits following the administration of L-cysteine to infant rats. Pharmacol Biochem Behav 3: 291— 298.
• Sun EL, Flickinger CJ (1979). Development of cell types and of regional differences in the postnatal rat epididymis. Am J Anat 154: 27—55.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Van Cauteren H., Vandenberghe J., Herin V., Vanparys P., Marsboom R. (1985). Toxicological properties of closantel. Drug Chem. Toxicol 8: 101— 123.
• Wen RQ, Wong PY ( 1988). Reserpine treatment increases viscosity of fluid in the epididymis of rats. Biol Reprod 38: 969—974.[Abstract]
• Wong PY (1990). Abnormal fluid transport by the epididymis as a cause of obstructive azoospermia. Reprod Fertil Dev 2: 115—127.[CrossRef][Medline] [Order article via Infotrieve]
• Yamate J., Okado A., Kuwamura M., Tsukamoto Y., Ohashi F., Kiso Y., Nakatsuji S., Kotani T., Sakuma S., LaMarre J. (1998). Immunohistochemical analysis of macrophages, myofibroblasts, and transforming growth factor-β localization during rat renal interstitial fibrosis following long-term unilateral ureteral obstruction. Toxicol Pathol 26: 793—801.[Abstract/Free Full Text]
• Yeung CH, Oberlander G., Cooper TG (1994). Maturation of hamster epididymal sperm motility and influence of the thiol status of hamster and rat spermatozoa on their motility patterns. Mol Reprod Dev 38: 347—355.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Yokota F., Matsuno N., Suzue R. (1979). Developmental and convalescent changes of the anemia caused by excess methionine in the rat. J Nutr Sci Vitaminol 25: 411—417.[Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 31, No. 3, 281-289 (2003)
DOI: 10.1080/01926230390204315


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				Y. Tani, P. M. Foster, R. C. Sills, P. C. Chan, S. D. Peddada, and A. Nyska Epididymal Sperm Granuloma Induced by Chronic Administration of 2-Methylimidazole in B6C3F1 Mice Toxicol Pathol, April 1, 2005; 33(3): 313 - 319. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Sawamoto, O. Articles by Kurisu, K. Search for Related Content PubMed PubMed Citation Articles by Sawamoto, O. Articles by Kurisu, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CYSTEINE Medline Plus Health Information Testicular Disorders Social Bookmarking                         What's this?