Reproductive Pathology and Sperm Physiology in Acid Sphingomyelinase-Deficient Mice

Abstract

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 midpieceprinciple 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. 1 Type A NPD is a severe, neurodegenerative form of the disorder that generally leads to death by ϳ3 years of age. In contrast, patients with type B NPD have little or no neurological involvement and may survive into adolescence or adulthood. ASM belongs to a family of sphingomyelinases that catabolize sphingomyelin (SPM) to ceramide and phosphorylcholine. 2,3 It is presumed that the pathophysiology in NPD is primarily because of the accumulation of SPM and other metabolically related lipids (eg, cholesterol) within the cells and tissues of affected patients, although signaling through the ceramide pathway may also be disrupted.

Nuclear oxysterol receptors, LXRs, are involved in the maintenance of mouse caput epididymidis structure and functions

“…However, oil-red O staining of the LXR / animals did reveal that lipidic inclusions are present within the caput epithelium, suggesting that lipidic transfer systems are impaired in the transgenic animals. In a similar way to that observed in the RXR knockout model, lipid metabolism was found to be impaired in the epididymis of mice deficient for apoB gene expression (Huang et al 1996), apoER2 gene expression (Andersen et al 2003) or the acid sphingomyelinase gene (Butler et al 2002). ApoB, apo E and apoER2 (receptor 2 of apolipoprotein E) genes encode proteins that, together with ATP-binding cassette (ABC) transporters, are involved in the cellular export of cholesterol.…”

Essential Role of the Apolipoprotein E Receptor-2 in Sperm Development

“…Sperm with defective cell volume decrease fail to counteract water influx when released into hypo-osmotic conditions, causing cell swelling and coiling of the tail. The swelling is relieved upon perforation of the sperm membrane with detergents, resulting in tail straightness (20,21).…”

“…Similarly, heterozygosity for the apoB gene defect (45) or homozygous deletion of the acid sphingomyelinase gene (21) affects the lipid metabolism of the epididymis and the spermatozoa, resulting in sperm immotility. In particular, the latter model exhibits close resemblance to apoER2-deficient mice inasmuch as the sperm are characterized by detergent-reversible tail angulation (21). Unfortunately, no information is available on the expression of PHGPx protein in this mouse model.…”

A Mutation inAf4Is Predicted to Cause Cerebellar Ataxia and Cataracts in the Robotic Mouse

“…Types A and B are caused by deficient acid sphingomyelinase activity (Levran et al, 1991), and type C is caused by mutations in NPC1, a gene thought to be involved in intracellular trafficking of cholesterol (Carstea et al, 1997). Mouse models of related lipid storage disorders such as Tay-Sachs disease also exhibit reproductive impairment (Trasler et al, 1998), and recent studies of the ASMKO line revealed defects in sperm physiology attributable to lipid-filled vacuoles present in the testis and epididymis (Butler et al, 2002).…”