Infertility is a devastating experience for both partners as they try to conceive. Historically, when a couple could not conceive, the woman has carried the stigma of infertility; however, men and women are just as likely to contribute to the couple's infertility. With the development of assisted reproductive technology (ART), the treatment burden for male and unexplained infertility has fallen mainly on women. Equalizing this burden requires reviving research on male infertility to both improve treatment options and enable natural conception. Despite many scientific efforts, infertility in men due to sperm dysfunction is mainly diagnosed by a semen analysis. The semen analysis is limited as it only examines general sperm properties such as concentration, motility, and morphology. A diagnosis of male infertility rarely includes an assessment of internal sperm components such as DNA, which is well documented to have an impact on infertility, or other components such as RNA and centrioles, which are beginning to be adopted. Assessment of these components is not typically included in current diagnostic testing because available treatments are limited. Recent research has expanded our understanding of sperm biology and suggests that these components may also contribute to the failure to achieve pregnancy. Understanding the sperm's internal components, and how they contribute to male infertility, would provide avenues for new therapies that are based on treating men directly for male infertility, which may enable less invasive treatments and even natural conception.
A large proportion of infertility and miscarriage causes are unknown. One potential cause is a defective sperm centriole, a subcellular structure essential for sperm motility and embryonic development. Yet, the extent to which centriolar maladies contribute to male infertility is unknown due to the lack of a convenient way to assess centriole quality. We developed a robust, location-based, ratiometric assay to overcome this roadblock, the Fluorescence-based Ratiometric Assessment of Centrioles (FRAC). We performed a case series study with semen samples from 33 patients, separated using differential gradient centrifugation into higher-grade (pellet) and lower-grade (interface) sperm fractions. Using a reference population of higher-grade sperm from infertile men with morphologically standard sperm, we found that 79% of higher-grade sperm of infertile men with substandard sperm morphology have suboptimal centrioles (P = 0.0005). Moreover, tubulin labeling of the sperm distal centriole correlates negatively with age (P = 0.004, R = −0.66). These findings suggest that FRAC is a sensitive method and that patient age and sperm morphology are associated with centriole quality.
The sperm competition theory, as proposed by Geoff Parker, predicts that sperm evolve through a cascade of changes. As an example, internal fertilization is followed by sperm morphology diversification. However, little is known about the evolution of internal sperm structures. The centriole has an ancient and evolutionarily conserved canonical structure with signature 9-fold, radially symmetric microtubules that form the cell’s centrosomes, cilia, and flagella. Most animal spermatozoa have two centrioles, one of which forms the spermatozoan flagellum. Both are delivered to the egg and constitute the embryo’s first two centrosomes. The spermatozoa of mammals and insects only have one recognizable centriole with a canonical structure. A second sperm centriole with an atypical structure was recently reported in both animal groups and which, prior to this, eluded discovery by standard techniques and criteria. Because the ancestors of both mammals and insects reproduced by internal fertilization, we hypothesized that the transition from two centrioles with canonical composition in ancestral sperm to an atypical centriolar composition characterized by only one canonical centriole evolved preferentially after internal fertilization. We examined fish because of the diversity of species available to test this hypothesis–as some species reproduce via internal and others via external fertilization–and because their spermatozoan ultrastructure has been extensively studied. Our literature search reports on 277 fish species. Species reported with atypical centriolar composition are specifically enriched among internal fertilizers compared to external fertilizers (7/34, 20.6% versus 2/243, 0.80%; p < 0.00001, odds ratio = 32.4) and represent phylogenetically unrelated fish. Atypical centrioles are present in the internal fertilizers of the subfamily Poeciliinae. Therefore, internally fertilizing fish preferentially and independently evolved spermatozoa with atypical centriolar composition multiple times, agreeing with Parker’s cascade theory.
The mechanisms underlying male infertility are poorly understood. Most mammalian spermatozoa have two centrioles: the typical barrel-shaped proximal centriole (PC) and the atypical fan-like distal centriole (DC) connected to the axoneme (Ax). These structures are essential for fertility. However, the relationship between centriole quality and subfertility (reduced fertility) is not well established. Here, we tested the hypothesis that assessing sperm centriole quality can identify cattle subfertility. By comparing sperm from 25 fertile and 6 subfertile bulls, all with normal semen analyses, we found that unexplained subfertility and lower sire conception rates (pregnancy rate from artificial insemination in cattle) corelate with abnormal centriolar biomarker distribution. Fluorescence-based Ratiometric Analysis of Sperm Centrioles (FRAC) found only four fertile bulls (4/25, 16%) had positive FRAC tests (having one or more mean FRAC ratios outside of the distribution range in a group’s high-quality sperm population), whereas all of the subfertile bulls (6/6, 100%) had positive FRAC tests (P=0.00008). The most sensitive biomarker was Acetylated Tubulin, which had a novel labeling pattern between the DC and Ax. These data suggest that FRAC and Acetylated Tubulin labeling can identify bull subfertility that remains undetected by current methods and may provide insight into a novel mechanism of subfertility.
Centrioles are subcellular organelles with an evolutionarily conserved structure and a shock absorber-like function. In sperm, centrioles are found at the flagellum base and are essential for embryo development in basal animals. Yet, sperm centrioles have evolved diverse forms, sometimes acting like a transmission system, as in cattle, and sometimes becoming dispensable, as in house mice. How the essential sperm centriole evolved to become dispensable in some organisms is unclear. Here, we test the hypothesis that this transition occurred through a cascade of evolutionary changes to the proteins, structure, and function of sperm centrioles and was possibly driven by sperm competition. We found that the last steps in this cascade are associated with a change in the primary structure of the centriolar luminal protein FAM161A in rodents. This information provides the first insight into the molecular mechanisms and adaptive evolution underlying a major evolutionary transition within the internal structure of the mammalian sperm neck.
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