The control of human fertility would be revolutionised by the development of a safe, effective, long-acting contraceptive vaccine. The pursuit of this objective has involved the selection of appropriate targets within the reproductive process that are amenable to interference with antibodies. To date, three major targets have been researched. The zona pellucida (ZP) plays key roles in folliculogenesis, fertilisation and early development, and is comprised of powerful cell-specific antigens. The induction of infertility requires high ZP antibody titres that are difficult to maintain without inducing ovarian pathology characterised by a premature loss of primordial follicles. As a premature menopause would be a high price to pay for long-term contraception, this approach to a vaccine cannot progress until the cause of the ovarian pathology has been resolved. Sperm surface antigens represent another promising approach to contraceptive vaccine development. While there is some clinical data to support the likely efficacy of this strategy, none of the gamete-specific molecules characterised to date have fulfilled this promise. Anti-human chorionic gonadotropin (hCG) vaccines terminate pregnancy by preventing the maternal recognition of pregnancy. This vaccine has reached the stage of clinical trials, and preliminary indications are that the approach is safe and potentially effective. However, reliability may be an issue, given the observed inter-individual variability in antibody generation. The future of contraceptive vaccine development will clearly involve a continuation of the intense search for suitable targets and the development of improved immunisation procedures that exploit the latest innovations in vaccine technology.
Recent evidence has shown that the sperm epigenome is vulnerable to dynamic modifications arising from a variety of paternal environment exposures and that this legacy can serve as an important determinant of intergenerational inheritance. It has been postulated that such exchange is communicated to maturing spermatozoa via the transfer of small non-protein-coding RNAs (sRNAs) in a mechanism mediated by epididymosomes; small membrane bound vesicles released by the soma of the male reproductive tract (epididymis). Here we confirm that mouse epididymosomes encapsulate an impressive cargo of >350 microRNAs (miRNAs), a developmentally important sRNA class, the majority (~60%) of which are also represented by the miRNA signature of spermatozoa. This includes >50 miRNAs that were found exclusively in epididymal sperm and epididymosomes, but not in the surrounding soma. We also documented substantial changes in the epididymosome miRNA cargo, including significant fold changes in almost half of the miRNAs along the length of the epididymis. Finally, we provide the first direct evidence for the transfer of several prominent miRNA species between mouse epididymosomes and spermatozoa to afford novel insight into a mechanism of intercellular communication by which the sRNA payload of sperm can be selectively modified during their post-testicular maturation.
Can Chlamydia be found in the testes of infertile men?Chlamydia can be found in 16.7% of fresh testicular biopsies and 45.3% of fixed testicular biopsies taken from a selection of infertile men.Male chlamydial infection has been understudied despite male and female infections occurring at similar rates. This is particularly true of asymptomatic infections, which occur in 50% of cases. Chlamydial infection has also been associated with increased sperm DNA damage and reduced male fertility.We collected diagnostic (fixed, n = 100) and therapeutic (fresh, n = 18) human testicular biopsies during sperm recovery procedures from moderately to severely infertile men in a cross-sectional approach to sampling.The diagnostic and therapeutic biopsies were tested for Chlamydia-specific DNA and protein, using real-time PCR and immunohistochemical approaches, respectively. Serum samples matched to the fresh biopsies were also assayed for the presence of Chlamydia-specific antibodies using immunoblotting techniques.Chlamydial major outer membrane protein was detected in fixed biopsies at a rate of 45.3%. This was confirmed by detection of chlamydial DNA and TC0500 protein (replication marker). C. trachomatis DNA was detected in fresh biopsies at a rate of 16.7%, and the sera from each of these three positive patients contained C. trachomatis-specific antibodies. Overall, C. trachomatis-specific antibodies were detected in 72.2% of the serum samples from the patients providing fresh biopsies, although none of the patients were symptomatic nor had they reported a previous sexually transmitted infection diagnosis including Chlamydia.No reproductively healthy male testicular biopsies were tested for the presence of Chlamydia DNA or proteins or Chlamydia-specific antibodies due to the unavailability of these samples.Application of Chlamydia-specific PCR and immunohistochemistry in this human male infertility context of testicular biopsies reveals evidence of a high prevalence of previously unrecognised infection, which may potentially have a pathogenic role in spermatogenic failure.Funding for this project was provided by the Australian NHMRC under project grant number APP1062198. We also acknowledge assistance from the Monash IVF Group and Queensland Fertility Group in the collection of fresh biopsies, and the Monash Health and co-author McLachlan (declared equity interest) in retrieval and sectioning of fixed biopsies. E.M. declares an equity interest in the study due to financing of fixed biopsy sectioning. All other authors declare no conflicts of interest.N/A.
In recent years considerable effort has been devoted to understanding the epigenetic control of sperm development, leading to an increased appreciation of the importance of RNA interference pathways, and in particular miRNAs, as key regulators of spermatogenesis and epididymal maturation. It has also been shown that sperm are endowed with an impressive array of miRNA that have been implicated in various aspects of fertilization and embryo development. However, to date there have been no reports on whether the sperm miRNA signature is static or whether it is influenced by their prolonged maturation within the male reproductive tract. To investigate this phenomenon, we employed next-generation sequencing to systematically profile the miRNA signature of maturing mouse spermatozoa. In so doing we have provided the first evidence for the posttesticular modification of the sperm miRNA profile under normal physiological conditions. Such modifications include the apparent loss and acquisition of an impressive cohort of some 113 and 115 miRNAs, respectively, between the proximal and distal epididymal segments. Interestingly, the majority of these changes occur late in maturation and include the uptake of novel miRNA species in addition to a significant increase in many miRNAs natively expressed in immature sperm. Because sperm are not capable of de novo transcription, these findings identify the epididymis as an important site in establishing the sperm epigenome with the potential to influence the peri-conceptual environment of the female reproductive tract, contribute to the inheritance of acquired characteristics, and/or alter the developmental trajectory of the resulting offspring.
The purpose of this study was to determine parental attitudes regarding engagement with video games by their children with autism spectrum disorder (ASD) and whether attitudes vary based on ASD symptom severity.Online survey methodology was used to gather information from parents of children with ASD between the ages of 8 and 12 years. The finalized data set included 152 cases. Descriptive statistics and frequency analyses were used to examine participant demographics and video game play. Descriptive and inferential statistics were used to evaluate questions on the theory of planned behavior. Regression analyses determined the predictive ability of the theory of planned behavior constructs, and t tests provided additional descriptive information about between-group differences.Children with ASD play video games. There are no significant differences in the time, intensity, or types of games played based on severity of ASD symptoms (mild vs. moderate). Parents of children with ASD had positive attitudes about video game play.Parents of children with ASD appear to support video game play. On average, parents indicated video game play was positive for their children with ASD, particularly if they believed the games were having a positive impact on their child's development.
Female reproductive potential is dictated by the size of the primordial follicle pool and the correct regulation of oocyte maturation and activation—events essential for production of viable offspring. Although a substantial body of work underpins our understanding of these processes, the molecular mechanisms of follicular and oocyte development are not fully understood. This review summarizes recent findings which have improved our conception of how folliculogenesis and oocyte competence are regulated, and discusses their implications for assisted reproductive techniques. We highlight evidence provided by genetically modified mouse models and in vitro studies which have refined our understanding of Pi3k/Akt and mTOR signalling in the oocyte and have discovered a role for Jak/Stat/Socs signalling in granulosa cells during primordial follicle activation. We also appraise a novel role for the metal ion zinc in the regulation of meiosis I and meiosis II progression through early meiosis inhibitor (Emi2) and Mos-Mapk signalling, and examine studies which expand our understanding of intracellular calcium signalling and extrinsic Plcζ in stimulating oocyte activation.
One of the most common lesions present in the spermatozoa of human infertility patients is an idiopathic failure of sperm-egg recognition. Although this unique cellular interaction can now be readily by-passed by assisted reproductive strategies such as intracytoplasmic sperm injection (ICSI), recent large-scale epidemiological studies have encouraged the cautious use of this technology and highlighted the need for further research into the mechanisms responsible for defective sperm-egg recognition. Previous work in this field has established that the sperm domains responsible for oocyte interaction are formed during spermatogenesis prior to being dynamically modified during epididymal maturation and capacitation in female reproductive tract. While the factors responsible for the regulation of these sequential maturational events are undoubtedly complex, emerging research has identified the molecular chaperone, heat shock protein A2 (HSPA2), as a key regulator of these events in human spermatozoa. HSPA2 is a testis-enriched member of the 70 kDa heat shock protein family that promotes the folding, transport, and assembly of protein complexes and has been positively correlated with in vitro fertilization (IVF) success. Furthermore, reduced expression of HSPA2 from the human sperm proteome leads to an impaired capacity for cumulus matrix dispersal, sperm-egg recognition and fertilization following both IVF and ICSI. In this review, we consider the evidence supporting the role of HSPA2 in sperm function and explore the potential mechanisms by which it is depleted in the spermatozoa of infertile patients. Such information offers novel insights into the molecular mechanisms governing sperm function.
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