Abstract:The pathogenesis of sperm granulomas is very complicated, and leakage of spermatozoa into extraluminal tissues is regarded as a crucial event. We previously reported that sperm granulomas were frequently induced in the epididymides of pubertal rats by excessive dose of L-cysteine (L-Cys). Here, we compared the incidence of sperm granulomas between L-Cys-treated pubertal (6-week-old) and adult (11-week-old) rats by intraperitoneally injecting daily with L-Cys (800 mg/kg body weight) for 4 weeks. L-Cys-induced sperm granulomas were seen in 6 rats of 10 L-Cystreated pubertal rats, whereas only one rat in 40 L-Cys-treated adult rats developed a sperm granuloma, indicating agedependent decrease in the frequency. In L-Cys-treated pubertal rats, additionally, small ducts (indicative of immaturity), dilated ducts, and interstitial edema were frequently seen, but such findings were rarely present in L-Cys-treated adult rats. The accumulation of spermatozoa in epididymal ducts was often observed both in L-Cys-treated pubertal and adult rats. These findings indicated that the administration with a large amount of L-Cys might have disturbed the luminal microenvironments, with greater influence on pubertal rats than adult rats. Particularly, the findings, that the incidences of small ducts and sperm granulomas were high in L-Cys-treated pubertal rats and low in L-Cys-treated adult rats, suggested that the prerequisite for sperm granuloma formation might be associated mainly with the delayed maturation of epididymal ducts seen exclusively in pubertal rats due to excessive dose of L-Cys. (J Toxicol Pathol 2003; 16: 123-127) Key words: L-cysteine, sperm granuloma, epididymis, adult rat Sperm granuloma is a chronic granulomatous lesion to spermatozoa released into the extraluminal tissue of the reproductive tract [1][2][3] . The granulomas were composed mainly of monocyte-like and epithelioid macrophages whose cytoplasm had many fragmented spermatozoa in an electron microscopy, indicating a high phagocytic activity of these macrophages 4 . The anatomical and histological characteristics of L-Cys-induced rat sperm granulomas bore a close resemblance to those of human sperm granulomas following vasectomy 5 . The pathogenesis of sperm granulomas is very complicated, consisting of rupture of the reproductive tract at the early stages and granulomatous reaction to released spermatozoa at the subsequent stages.Previously, we have shown that repeated injection of Lcysteine (L-Cys, 1,000 mg/kg, intraperitoneally), a sulfurcontaining amino acid, to pubertal rats at the age of 6 weeks induced sperm granulomas in the epididymides at a high frequency 6 . Because immature type (developing) epididymal ducts were still observed often in L-Cys-treated rats, we considered that development of the lesions might be associated with prolonged maturation of epididymal ducts resulting in obstruction of semen flow and a rise in intraluminal pressure; this condition might be responsible for ductal rupture and subsequent leakage of spermatozoa...