The making of abnormal spermatozoa: cellular and molecular mechanisms underlying pathological spermiogenesis

Abstract

Fertilization in mammals occurs via a series of well-defined events in the secluded environment of the female reproductive tract. The mode of selection of the fertilizing spermatozoon nevertheless remains unknown. As has become evident during in vitro fertilization by sperm microinjection into the oocyte, abnormal spermatozoa can successfully fertilize oocytes. Under these extreme conditions, post-fertilization events, early embryonic development and implantation are significantly compromised indicating that the contribution of spermatozoa extends beyond sperm penetration. Microscopic identification of normal spermatozoa is a well-standardized procedure but insights into the mechanisms that lead to aberrant sperm differentiation and into the subcellular nature of sperm abnormalities have only recently begun to be obtained. The spermatozoon is the result of a complex development in which spermatid organelles give rise to various structural components with characteristic functions. Similar to other differentiated cells, the spermatozoon has a specific pathology that is most clearly identified by ultrastructural evaluation coupled with immunocytochemistry and molecular techniques. This multidisciplinary approach allows the precise characterization of sperm abnormalities, including structural, molecular and functional aspects. We summarize here studies of the physiopathology of spermiogenesis in two abnormal sperm phenotypes of infertile men: dysplasia of the fibrous sheath and acephalic spermatozoa/abnormal head-tail attachment. The characterization of the abnormalities of the tail cytoskeleton and centrioles has uncovered aspects of the subcellular basis of pathological spermiogenesis, has suggested experimental approaches to explore the nature of these anomalies and has opened the way for genetic studies that will ultimately lead to the design of the therapeutic tools of the future.

Head-base bending and disjointed spermatozoa in the emu (Dromaius novaehollandiae): A morphological comparison of two closely related defects

“…Based on the above observations [33,38,39], we propose that disjointed sperm are closely related to dislocated, flexed, decapitated and acephalic sperm as described in mammals.…”

“…A number of other mammalian sperm defects, such as acephalic sperm, decapitated sperm and the flexed head defect, are believed to originate from eccentric implantation of the head and neck, or structural deficiencies of the neck region [33]. Similarly Chemes and Rawe [35,39] reported on sperm with misaligned head-midpiece junctions, stating that different degrees of incorrect alignment results in either acephalic sperm (the most severe form of the defect) or sperm where the head is misaligned. They further ascribed the misalignment to the lack or abnormal implantation of the centrioles during the early stages of spermiogenesis.…”

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

“…Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18).Several features of the human "acephalic spermatozoa," including its uniform phenotype, origin as a systematic alteration of spermiogenesis, unresponsiveness to hormonal treatment, and familial incidence, suggest a genetic origin of this condition (8,16,(18)(19)(20). Mice lacking Odf1, a gene encoding outer dense fiber protein 1, display fragile sperm connecting pieces in addition to a disorganized mitochondrial sheath and defective outer dense fibers (ODFs) (21).…”

“…Several features of the human "acephalic spermatozoa," including its uniform phenotype, origin as a systematic alteration of spermiogenesis, unresponsiveness to hormonal treatment, and familial incidence, suggest a genetic origin of this condition (8,16,(18)(19)(20). Mice lacking Odf1, a gene encoding outer dense fiber protein 1, display fragile sperm connecting pieces in addition to a disorganized mitochondrial sheath and defective outer dense fibers (ODFs) (21).…”

“…Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14).…”