RESUMEN
The time-dependent brain damage induced in adult rats by a single dose of L-cysteine was examined morphologically. Five-week-old male Sprague-Dawley rats that received 1500 mg/kg of L-cysteine by intraperitoneal injection were examined at 12 and 24 h and 3, 7, and 14 days after administration. Pathological changes were seen in the cerebral and cerebellar cortex. Neuronal karyopyknosis was observed in the granular and molecular layers of the superficial cerebellar cortex at 12 h, and well-demarcated infarct-like lesions were seen with a widespread distribution in the cerebral cortex at 24 h. A large number of lipid phagocytes and glial cell proliferation were noted in the affected regions on days 3 to 14. The neuronal cell death observed in the cerebellar granular layer cells was demonstrated to be due to apoptosis by histopathological and ultrastructural examinations as well as by the terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL) method and agarose gel electrophoresis for DNA laddering. It was found that L-cysteine induced brain lesions mainly in the cerebral and cerebellar cortex in adult rats, in contrast to lesions in various regions as observed in neonatal rats. The histopathological findings reported here suggest that the pathogenesis of the brain damage induced by L-cysteine in adult rats differs from that in neonatal rats. It appears likely that L-cysteine-induced brain damage is secondary to impairment of blood flow or other unknown factors that are responsible for the subsequent development of brain lesions.
Asunto(s)
Encéfalo/efectos de los fármacos , Cisteína/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Encéfalo/patología , Encéfalo/ultraestructura , Fragmentación del ADN , Etiquetado Corte-Fin in Situ , Masculino , Microscopía Electrónica , Ratas , Ratas Sprague-DawleyRESUMEN
We previously reported infertility in female rats that received N-acetyl-L-cysteine (NAC) intravenously at a dosage of 1000 mg/kg/day. Unfertilized oocytes and gestation day 1 and 2 embryos were assessed morphologically, and the results suggested that absence or thinning of the zona pellucida (ZP) is related to infertility. However, the morphological characteristics of oocytes before ovulation and recovery from the effects of NAC were not clarified. In the present study, the ovarian follicles were histopathologically examined and the recovery of reproductive function was evaluated to investigate the effects of NAC. Female Sprague-Dawley rats at 10 weeks of age received NAC intravenously at 1000 mg/kg/day for more than 1 week. Thinning of the ZP was observed in the ovarian follicles in all stages of growth by light microscopy. Outflow of the components of the ZP between the corona radiata and disarrangement of the corona radiata were more pronounced in growing follicles than in large secondary follicles. Similar findings were observed by electron microscopy, and the effects of NAC were limited to the ZP. Infertility and thinning of the ZP were observed in the no-recovery NAC group, but not in the recovery NAC group, in which animals recovered within four estrous cycles after NAC administration. It has been reported that the ZP is expressed by oocytes or by both oocytes and granulosa cells, but no changes were noted in these cells. The present findings suggest that NAC affects the ZP directly and that reproductive function may recover from the effects of NAC.
Asunto(s)
Acetilcisteína/toxicidad , Fertilidad/efectos de los fármacos , Depuradores de Radicales Libres/toxicidad , Infertilidad Femenina/inducido químicamente , Oocitos/patología , Folículo Ovárico/patología , Zona Pelúcida/efectos de los fármacos , Acetilcisteína/administración & dosificación , Animales , Ciclo Estral/efectos de los fármacos , Femenino , Depuradores de Radicales Libres/administración & dosificación , Células de la Granulosa/efectos de los fármacos , Infertilidad Femenina/fisiopatología , Masculino , Oocitos/ultraestructura , Folículo Ovárico/ultraestructura , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Zona Pelúcida/patologíaRESUMEN
Although the pathogenesis of sperm granulomas is complicated, the leakage of spermatozoa into extraluminal tissues is regarded as a crucial event. It has been previously shown that pubertal rats injected with L-cysteine develop interstitial edema followed by sperm granulomas in the epididymis. In this study we investigated the relationships between these two lesions in 6-week old rats given daily intraperitoneal injections of L-cysteine (1,000 mg/kg body weight) for 4 weeks. Rats were examined during weeks 0, 1, 2, 3 and 4 after the first injection. Interstitial edema (moderate or severe) and sperm granulomas were seen in the corpus and cauda epididymis of L-cysteine-treated rats in study weeks 2, 3, and 4. There was no marked alteration of basement membrane of the epididymal ducts in the edematous tissues as shown by immunohistochemistry with an antilaminin antibody. However, the extravasation of Evans blue dye given I hour before necropsy suggested that the severe interstitial edema was due to increased vascular permeability. In addition, a small number of neutrophils were seen in the edematous tissues, suggesting that they might play a role in the increased vascular permeability and leakage of epididymal fluid. Interestingly, slight interstitial edema was observed in the caput epididymis in both control and L-cysteine-treated rats in early study weeks 0, 1, and 2. It is speculated that this change was related to the leakage of epididymal fluid due to increased intraluminal pressure depending on rat epididymal maturation. Taken together, these findings suggest that the severe interstitial edema results from increased vascular permeability. This, along with increased intraluminal pressure, might be the trigger for duct rupture, the prerequisite for sperm granuloma formation associated with excessive doses of L-cysteine.
Asunto(s)
Cisteína/toxicidad , Edema/patología , Epidídimo/patología , Granuloma/patología , Espermatozoides/patología , Enfermedades Testiculares/patología , Animales , Permeabilidad Capilar/efectos de los fármacos , Colorantes/farmacocinética , Cisteína/administración & dosificación , Modelos Animales de Enfermedad , Edema/metabolismo , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Azul de Evans/farmacocinética , Extravasación de Materiales Terapéuticos y Diagnósticos , Granuloma/etiología , Granuloma/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratas , Ratas Sprague-Dawley , Espermatozoides/efectos de los fármacos , Enfermedades Testiculares/etiología , Enfermedades Testiculares/metabolismoRESUMEN
A 4-week intravenous repeated dose toxicity study of L-cysteine (L-Cys) was conducted in male Sprague-Dawley rats to investigate in detail the toxic effects of this compound and to determine the dose level at which these toxic effects are observed following repeated intravenous administration. Male rats were randomly allocated to 4 groups to receive L-Cys by intravenous administration at dosages of 0, 100, 300, and 1,000 mg/kg body weight/day. Body weight gain was significantly suppressed throughout the study period in the 1,000-mg/kg group, although food consumption was reduced only on study day 3. A decrease in spontaneous activity, salivation, stereotypy, ptosis, and tremor were observed in the 1,000-mg/kg group. Mild anemia characterized by decreases in hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and an increase in the reticulocyte count was also noted in the 1,000-mg/kg group. Histopathological examination showed sperm granulomas in the epididymis and necrosis of the Purkinje cells and granular layer in the cerebellum in the 1,000-mg/kg group. Slight tubular basophilia with blood or hyaline casts was observed in the kidney in the 300-mg/kg and 1,000-mg/kg groups, associated with proteinuria or occult blood in urinalysis. Additional studies are needed to clarify the causes for these toxicological findings by excess of L-Cys.
Asunto(s)
Cisteína/toxicidad , Animales , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Peso Corporal/efectos de los fármacos , Cisteína/administración & dosificación , Cisteína/orina , Ingestión de Alimentos/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
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.