Reproductive pathology and sperm physiology in acid sphingomyelinase-deficient mice
Reproductive pathology and sperm physiology in acid sphingomyelinase-deficient mice
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DOI：
10.1016/s0002-9440(10)64267-8
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发表时间：
2002-09-01
影响因子：
6
通讯作者：
Schuchman, EH
中科院分区：
文献类型：
--
作者：
Butler, A;He, XX;Schuchman, EH
A型和B型尼曼-匹克病（NPD）是由酸性鞘磷脂酶（ASM）的活性缺陷引起的溶酶体贮积症。在本文中，我们报告了NPD基因敲除小鼠模型中雄性性腺组织和精子的病理生物学，并证明了ASM对正常精子成熟和功能的重要性。在-/-小鼠睾丸生精小管和附睾上皮细胞的光学显微镜照片中，特征性的充满脂质的空泡是明显的。电子显微镜照片扩展了这些发现，并揭示了睾丸曲细精管支持细胞内的储存囊泡。-/-小鼠的成熟精子表现出明显的ASM缺乏和鞘磷脂和胆固醇水平升高。流式细胞术分析显示，受影响的精子破坏了质膜和顶体膜，线粒体膜去极化。它们也没有经过适当的能力培养。形态学异常，如扭结和弯曲的中段，主片交界处是明显的精子从受影响的小鼠，随之而来的缺陷，在运动。值得注意的是，突变精子恢复正常形态温育在温和的洗涤剂，表明弯曲缺陷是膜脂质积累的直接后果。这些异常的机制，建议在性腺中的脂质积累的结果在发育中的精子的调节体积减少缺陷，和调节体积减少缺陷，反过来，导致所观察到的精子形态和功能的异常。这些结果提供了体内证据表明，ASM活性在精子成熟和功能中起着关键作用，并为性成熟男性NPD患者的类似研究奠定了基础。
Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders resulting from the deficient activity of acid sphingomyelinase (ASM). In this manuscript we report the pathobiology of male gonadal tissue and sperm in a knockout mouse model of NPD and demonstrate the importance of ASM for normal sperm maturation and function. Characteristic lipid-filled vacuoles were evident in light micrographs of testis' seminiferous tubules and epithelial cells lining the epididymis of -/- mice. Electron micrographs extended these findings and revealed storage vesicles within Sertoli cells of the seminiferous tubules. Mature spermatozoa from -/- mice showed marked ASM deficiency and elevated levels of sphingomyelin and cholesterol. Flow cytometric analysis revealed that affected spermatozoa had disrupted plasma and acrosome membranes, and mitochondrial membrane depolarization. They also did not undergo proper capacitation. Morphological abnormalities such as kinks and bends at the midpiece-principle piece junction were evident in spermatozoa from affected mice, with consequent deficits in motility. Notably, the mutant sperm regained normal morphology on incubation in mild detergent, demonstrating that the bending defects were a direct consequence of membrane lipid accumulation. A mechanism for these abnormalities is proposed that suggests lipid accumulation in the gonads results in regulatory volume decrease defects within the developing sperm, and that regulatory volume decrease defects, in turn, lead to the observed abnormalities in sperm morphology and function. These results provide in vivo evidence that ASM activity plays a critical role in sperm maturation and function, and a basis for similar studies in sexually mature, male NPD patients.