Although glycolysis is highly conserved, it is remarkable that several unique isozymes in this central metabolic pathway are found in mammalian sperm. Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDS) is the product of a mouse gene expressed only during spermatogenesis and, like its human ortholog (GAPD2), is the sole GAPDH isozyme in sperm. It is tightly bound to the fibrous sheath, a cytoskeletal structure that extends most of the length of the sperm flagellum. We disrupted Gapds expression by gene targeting to selectively block sperm glycolysis and assess its relative importance for in vivo sperm function. Gapds ؊/؊ males were infertile and had profound defects in sperm motility, exhibiting sluggish movement without forward progression. Although mitochondrial oxygen consumption was unchanged, sperm from Gapds ؊/؊ mice had ATP levels that were only 10.4% of those in sperm from WT mice. These results imply that most of the energy required for sperm motility is generated by glycolysis rather than oxidative phosphorylation. Furthermore, the critical role of glycolysis in sperm and its dependence on this sperm-specific enzyme suggest that GAPDS is a potential contraceptive target, and that mutations or environmental agents that disrupt its activity could lead to male infertility. glycolysis ͉ gene targeting ͉ infertility S perm motility is essential for normal fertilization, and asthenozoospermia, or low sperm motility, is common in infertile men. In a recent study of 1,085 sperm samples from infertile men, 81% had defects in motility, and 19% had asthenozoospermia without other defects in sperm number or morphology (1). Motility is generated by the extremely long flagellum that comprises Ͼ90% of the length of a mammalian sperm. This process requires substantial ATP to support coordinated movement of the central axoneme and surrounding flagellar structures (2). ATP is hydrolyzed by dynein ATPases, which function as force-generating molecular motors along the axoneme. Although quiescent in the epididymis, mammalian sperm display vigorous forward movement, termed activated or progressive motility, immediately upon ejaculation or collection into physiological medium. The motility waveform changes in the female reproductive tract, with increases in both the amplitude and asymmetry of flagellar bending. These changes result in a whiplash-like motion, termed hyperactivated motility, which facilitates sperm transport in the oviduct and penetration of the zona pellucida surrounding the oocyte (3).Potential sources of ATP to support sperm motility are compartmentalized in distinct regions along the length of the flagellum. Oxidative phosphorylation is confined to the proximal segment of the flagellum where the mitochondria are localized (middle piece). In contrast, glycolysis appears to be restricted to the principal piece, which is distal to the middle piece and is the longest segment of the sperm flagellum (4-8). Several glycolytic enzymes in mammalian sperm are distinct from the isozymes present in somatic tissues. Thr...

We are coming to appreciate that at fertilization human spermatozoa deliver the paternal genome alongside a suite of structures, proteins and RNAs. Although the role of some of the structures and proteins as requisite elements for early human development has been established, the function of the sperm-delivered RNAs remains a point for discussion. The presence of RNAs in transcriptionally quiescent spermatozoa can only be derived from transcription that precedes late spermiogenesis. A cross-platform microarray strategy was used to assess the profile of human spermatozoal transcripts from fertile males who had fathered at least one child compared to teratozoospermic individuals. Unsupervised clustering of the data followed by pathway and ontological analysis revealed the transcriptional perturbation common to the affected individuals. Transcripts encoding components of various cellular remodeling pathways, such as the ubiquitin-proteosome pathway, were severely disrupted. The origin of the perturbation could be traced as far back as the pachytene stage of spermatogenesis. It is anticipated that this diagnostic strategy will prove valuable for understanding male factor infertility.

BackgroundResearch has suggested an association with ambient air pollution and sperm quality.ObjectivesWe investigated the effect of exposure to ozone (O3) and particulate matter < 2.5 μm in aerodynamic diameter (PM2.5) on sperm quality.MethodsWe reexamined a previous cohort study of water disinfection by-products to evaluate sperm quality in 228 presumed fertile men with different air pollution profiles. Outcomes included sperm concentration, total sperm per ejaculate (count), and morphology, as well as DNA integrity and chromatin maturity. Exposures to O3 and PM2.5 were evaluated for the 90–day period before sampling. We used multivariable linear regression, which included different levels of adjustment (i.e., without and with season and temperature) to assess the relationship between exposure to air pollutants during key periods of sperm development and adverse sperm outcomes.ResultsSperm concentration and count were not associated with exposure to PM2.5, but there was evidence of an association (but not statistically significant) with O3 concentration and decreased sperm concentration and count. Additionally, a significant increase in the percentage of sperm cells with cytoplasmic drop [β = 2.64; 95% confidence interval (CI), 0.21–5.06] and abnormal head (β = 0.47; 95% CI, 0.03–0.92) was associated with PM2.5 concentration in the base model. However, these associations, along with all other sperm outcomes, were not significantly associated with either pollutant after controlling for season and temperature. Overall, although we found both protective and adverse effects, there was generally no consistent pattern of increased abnormal sperm quality with elevated exposure to O3 or PM2.5.ConclusionsExposures to O3 or PM2.5 at levels below the current National Ambient Air Quality Standards were not associated with statistically significant decrements in sperm outcomes in this cohort of fertile men. However, some results suggested effects on sperm concentration, count, and morphology.