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204 Characterization of Acrylamide Mediated Testicular Toxicity in Rat: Light and Electron ... September 2011 studies that reported a significant decrease in testis weight following AA treatment. These decreases were most likely due to severe atrophy of the testes [6, 8, 25] . The findings of this study as regards the epididymal sperm count and morphology tend to support results reported in a previous study by Yang et al [6,7] . The results of the current study were also consistent with the observations made by Sakamoto and Hashimoto [25] conducted on male mice, which showed a significant reduction in sperm count and an increase in abnormal sperm morphology following the administration of the highest dose of AA (1.2 mM) in the drinking water. The results of present study are in agreement with these previous findings of Yang et al [7] . Although the percentage of abnormal sperm was not calculated in the current study, it was observed that all of the AA treated groups showed an abnormal sperm morphology, characterized by (i) detached heads, (ii) coiled and fragile tails and (iii) cleaved tails. The most striking AA induced morphological change was the appearance of intersegmented tails, a response to AA that has not been previously reported to the best of our knowledge, and requires further substantiation and investigation. The histopathological findings of this study were similar to the reports of other investigators [6, 7] in rat studies and [8] in a mouse study. Hashimoto et al reported a normal histological appearance of the epididymis (although there was slight reduction in relative weights of the epididymis) following AA treatment of male mice at 1.5 mmol/kg (106.6 mg/ kg, twice weekly by oral gavage for 8 - 10 weeks) [8] . An attempt has been made by Rotter et al [26] to explain the mechanism underlying the appearance of MNG cells in the lumen of the seminiferous tubules of treated mice. They postulated that primary 4N spermatocytes were unable to undergo meiotic division to generate haploid sperm cells and instead underwent DNA replication only, giving rise to MNG cells. The consequence of Sertoli cell injury, which has been detected as Sertoli cell vacuolations in this study, is evident in the form of sloughing and shedding of germinal epithelium, leading to the appearance of aggregates of cellular material in the lumen [27] . Most Sertoli cell toxicants alter germ cell attachment to the Sertoli cell, resulting in loss of germ cell attachment to the seminiferous epithelium and hence, the presence of germ cells in the lumen. The results of the pilot EM study were highly consistent with the detected histopathological changes observed by light microscopy. All changes, including some that had not been detected previously, were consistent with acute cell injury. Excessive lipid droplets in the Sertoli cell cytoplasm are indicative of germ cell degeneration [28] . One of the atypical forms of the principal piece detected in control sperm appeared to be an intersegmented tail when viewed with EM. There was a partial or complete dissolution of the circumferential ribs of the fibrous sheath, which probably, led to the inability of Wright or Rose Bengal stains to colorize the internal structure of the axoneme. This gave the appearance of an intersegmented tail under light microscopy. This abnormality was detected in this study to some extent in control rats; however, its frequency increased with AA treatment. Possibly, the genotoxic effect of AA is exerted mainly on stages of late spermatid and early spermatozoa formation [17] and hence results in abnormal sperm morphology. Several mechanisms of toxicity were proposed and one of these is mediated by an AA metabolite (glycidamide) as it induces significant levels of DNA damage as per Hansen et al [29] who have shown that human lymphocytes are more susceptible to glycidamide-induced lesions than mouse cells. Although the histological examination of testis by light microscopy hinted at Leydig cell toxicity, with the aid of EM, Leydig cell atrophy was clearly detected. Furthermore, the signs of insult to Sertoli cells after AA treatment were signs of Sertoli cell death. This might be due to a direct influence of AA on Sertoli cells or may be due to testosterone reduction resulting from Leydig cell atrophy, or both. Abnormal spermatogenesis due to a reduction in testosterone hormone resulting from Leydig cell atrophy might be another factor for these abnormal sperms. Another consequence of testosterone reduction would be abnormal Sertoli cells, because testosterone influences the Sertoli cell to undergo normal spermatogenesis [30] . Consequently, this abnormality in Sertoli cell structure and function results in abnormal spermatogenesis, while impairment of intercellular junctions leads to sloughing of germ cells and the formation of large vacuoles that occupy the basal and adluminal compartments. In severe cases, Sertoli cells might be released from epithelium after death, leaving large basal vacuoles. Regarding the effect of AA on the widening of intercellular spaces, Cheville [31] reported dissociations of desmosomes-like structures (present normally between cells), and of hemidesmosomes (present between the cells and the basement membrane), with subsequent detachment of cells from the basement membrane and widening of intercellular spaces, usually signs of acute cell injury. Widening of spaces surrounding the seminiferous tubules in histological examinations were believed to be due to Leydig cell atrophy, and with the aid of EM, Leydig cell atrophy was clearly detected. This pilot EM study of the AA treated group (45 mg/kg for five days) needs to be replicated and validated with additional studies using larger numbers of exposed and control rats.
September 2011 KUWAIT MEDICAL JOURNAL 205 ACKNOWLEDGMENT Conflict of interest: The authors declare that no conflict of interest exists. REFERENCES 1. SNAFA. Swedish National Food Administration, 2002. Swedish National Food Administration, 24 April 2002. Information About Acrylamide in Food. Available: http://www.slv.se/engdefault.asp. 2. Blank I. Current status of Acrylamide research in food: Measurement, safety assessment, and formation. Ann N Y Acad Sci 2005; 1043:30-40. 3. Tareke E, Rydberg P, Karlsson P. Analysis of acrylamide, a carcinogen formed in heated food stuffs. J Agric Food Chem 2002; 50:4998-5006. 4. Ohara-Takada A, Matsuura-Endo C, Yoshihiro C, et al. Change in content of sugars and free amino acids in potato tubers under short-term storage at low temperature and the effect on Acrylamide level after frying. Biosci Biotechnol Biochem 2005; 69:1232-1238. 5. Dearfield KL, Abernathy CO, Ottley MS, Brantner JH. 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Hansen SH, Olsen AK, Soderlund EJ, Brumborg G, et al. In vitro investigations of glycidamide-induced DNA lesions in mouse male germ cells and in mouse and human lymphocytes. Mutat Res 2010; 696:55-61. 30. Johnson MH, Everitt BJ. Essential reproduction. 5th edition. Blackwell Science; 2000:196-197. 31. Cheville NF. Ultra structural Pathology: An introduction to interpretation. Cheville NF, editor. Iowa State University Press, Ames, IA, 1994, pp. 51-76.
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