ORCID Profile
0000-0002-1199-0375
Current Organisation
The University of Newcastle
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Zoology | Animal Developmental and Reproductive Biology | Cell Development, Proliferation and Death | Cell Metabolism
Reproductive System and Disorders | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Biological Sciences |
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2020
DOI: 10.1101/2020.02.03.925677
Abstract: Stress granules (SG) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SG act as a protective mechanism to cope with acute stress, but persistent SG have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Importantly, knockout of the MAGE-B2 mouse ortholog confers hypersensitivity of the male germline to heat stress in vivo . Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermo-sensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress through fine-tuning phase separation and could aid in the development of male fertility therapies.
Publisher: The Company of Biologists
Date: 2017
DOI: 10.1242/DEV.146928
Abstract: Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and formation of progenitors as the initial step in production of differentiated cells. However, the mechanisms guiding the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets with the ID4-EGFPBright population being mostly, if not purely, SSCs while the ID4-EGFPDim population is in transition to the progenitor state. These subsets are also distinguishable by transcriptome signatures. Moreover, using a conditional overexpression mouse model, we found that transition from the stem cell to immediate progenitor state requires down-regulation of Id4 coincident with a major change in the transcriptome. Collectively, our results demonstrate that the level of ID4 is predictive of stem cell or progenitor capacity in spermatogonia and dictates the interface of transition between the different functional states.
Publisher: Oxford University Press (OUP)
Date: 02-2015
DOI: 10.1095/BIOLREPROD.114.122820
Abstract: With increasing periods of time following ovulation, the metaphase II (MII)-stage oocyte experiences overproduction of reactive oxygen species and elevated levels of lipid peroxidation that are implicitly linked with functional deficiencies acquired during postovulatory oocyte aging. We have demonstrated that the electrophilic aldehydes 4-hydroxynonenal (4HNE), malondialdehyde, and acrolein are by-products of nonenzymatic lipid peroxidation in the murine MII-stage oocyte, adducting to multiple proteins within the cell. The covalent modification of oocyte proteins by these aldehydes increased with extended periods of time postovulation the mitochondrial protein succinate dehydrogenase (SDHA) was identified as a primary target for 4HNE adduction. Time- and dose-dependent studies revealed that exposure to elevated levels of electrophilic aldehydes causes mitochondrial reactive oxygen species production, lipid peroxidation, loss of mitochondrial membrane potential, and eventual apoptosis within the MII oocyte, presumably as a consequence of electron transport chain collapse following SDHA adduction. Additionally, we have determined that short-term exposure to low doses of 4HNE dramatically impairs the oocyte's ability to participate in fertilization and support embryonic development however, this loss of functionality can be prevented by supplementation with the antioxidant penicillamine. In conclusion, this study has revealed that the accumulation of electrophilic aldehydes is linked to postovulatory oocyte aging, causing reduced fertility, oxidative stress, and apoptosis of this highly specialized cell. These data highlight the importance of timely fertilization of the mammalian oocyte postovulation and emphasize the potential advantages associated with antioxidant supplementation of oocyte culture medium in circumstances where reinsemination of oocytes may be desirable (i.e., rescue intracytoplasmic sperm injection), or where in vitro fertilization may be delayed.
Publisher: Springer New York
Date: 2017
Publisher: Elsevier BV
Date: 08-2020
Publisher: CSIRO Publishing
Date: 22-03-2021
DOI: 10.1071/RD20303
Abstract: Information on the morphology and histology of the male reproductive system of the Crocodylia species is necessary to determine the role of these tissues in the production of functional spermatozoa. Accordingly, in this study we examined the gross morphology and microanatomy of the testis and the male excurrent duct system through which spermatozoa pass before ejaculation. The data demonstrate that the reproductive system in male saltwater crocodiles comprises paired testes, which convey spermatozoa distally via the rete testis into an excurrent duct system comprising ductuli efferentes, ductuli epididymides, ductus epididymidis and ductus deferens. The epithelium delineating the male tract was dominated by non-ciliated and ciliated cells structured into a simple columnar lining of the ductuli efferentes and ductuli epididymides, through to the high pseudostratified columnar epithelium of the ductus epididymidis and ductus deferens. The morphology and histochemical staining of these ducts suggest their involvement in seminal fluid production and/or its modification, which likely contributes to the nourishment, protection and/or storage of crocodile spermatozoa. As a reflection of their common Archosaurs ancestry, the overall structural characteristics we describe for the crocodile male excurrent duct system share closer similarities to those of the Aves than other clades within the Reptilia class or Mammalia.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 06-2021
Publisher: Bioscientifica
Date: 08-2017
DOI: 10.1530/REP-17-0034
Abstract: Spermatogonial stem cells (SSCs) and progenitor spermatogonia encompass the undifferentiated spermatogonial pool in mammalian testes. In rodents, this population is comprised of A single , A paired and chains of 4–16 A aligned spermatogonia. Although traditional models propose that the entire A single pool represents SSCs, and formation of an A paired syncytium symbolizes irreversible entry to a progenitor state destined for differentiation recent models have emerged that suggest that the A single pool is heterogeneous, and A paired /A aligned can fragment to produce new SSCs. In this review, we explore evidence from the literature for these differing models representing SSC dynamics, including the traditional ‘A single ’ and more recently formed ‘fragmentation’ models. Further, based on findings using a fluorescent reporter transgene ( eGfp ) that reflects expression of the SSC-specific transcription factor ‘inhibitor of DNA binding 4’ ( Id4 ), we propose a revised version of the traditional model in which SSCs are a subset of the A single population the ID4-eGFP bright cells (SSC ultimate ). From the SSC ultimate pool, other A single and A paired cohorts arise that are ID4-eGFP dim. Although the SSC ultimate possess a transcriptome profile that reflects a self-renewing state, the transcriptome of the ID4-eGFP dim population resembles that of cells in transition (SSCtransitory) to a progenitor state. Accordingly, at the next mitotic ision, these SSC transitory are likely to join the progenitor pool and have lost stem cell capacity. This model supports the concept of a linear relationship between spermatogonial chain length and propensity for differentiation, while leaving open the possibility that the SSC transitory (some A single and potentially some A paired spermatogonia), may contribute to the self-renewing pool rather than transition to a progenitor state in response to perturbations of steady-state conditions.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.YDBIO.2016.06.035
Abstract: Double strand breaks (DSBs) are highly damaging DNA lesions that can destabilize the genome and generate a suite of adverse physiological outcomes in the oocyte and early embryo. While it is therefore likely that these cells possess a sophisticated suite of protective mechanisms to ameliorate such damage, the precise nature of these defense systems are yet to be fully elucidated. This study characterizes the sensitivity of the oocyte to etoposide, a chemotherapeutic agent with the ability to elicit DSBs. We demonstrate significant developmental changes in etoposide vulnerability, with fertilization of the oocyte leading to an enhancement of its cellular defense machinery. Using a parthenogenic model we show that this response is mediated, at least in part, by permeability glycoprotein (PGP), an endogenous multidrug efflux transporter that is up-regulated, translocated to the oolemma and phosphorylated upon oocyte activation. Moreover, evidence from dye exclusion assays in the presence of a specific PGP pharmacological inhibitor (PSC833), illustrates that these events effectively increase oocyte efflux activity, thereby enhancing the ability of these cells to exclude genotoxicants capable of eliciting DSB formation.
Publisher: Bioscientifica
Date: 12-2022
DOI: 10.1530/REP-22-0206
Abstract: Post-ovulatory ageing of oocytes leads to poor oocyte and embryo quality as well as abnormalities in offspring. This review provides an update on the contributions of oxidative stress to this process and discusses the current literature surrounding the use of antioxidant media to delay post-ovulatory oocyte ageing. Following ovulation, the metaphase II stage oocyte has a limited functional lifespan before succumbing to a process known as post-ovulatory oocyte ageing. This progressive demise occurs both in vivo and in vitro and is accompanied by a deterioration in oocyte quality, leading to a well-defined sequelae of reduced fertilisation rates, poor embryo quality, post-implantation errors, and abnormalities in the offspring. Although the physiological consequences of post-ovulatory oocyte ageing have largely been characterised, less is known regarding the molecular mechanisms that drive this process. This review presents an update on the established relationships between the biochemical changes exhibited by the ageing oocyte and the myriad of symptoms associated with the ageing phenotype. In doing so, we consider the molecular events that are potentially involved in orchestrating post-ovulatory ageing with a particular focus on the role of oxidative stress. We highlight the mounting evidence that oxidative stress acts as an initiator for a cascade of events that create the aged oocyte phenotype. Specifically, oxidative stress has the capacity to disrupt mitochondrial function and directly damage multiple intracellular components of the oocyte such as lipids, proteins, and DNA. Finally, this review addresses emerging strategies for delaying post-ovulatory oocyte ageing with emphasis placed on the promise afforded by the use of selected antioxidants to guide the development of media tailored for the preservation of oocyte integrity during in vitro fertilisation procedures.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-05-2019
Abstract: Mammals evolved testis-specific Mage-a genes to protect the male germline under starvation stress and are co-opted in cancer.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2021
DOI: 10.1186/S12864-021-07951-1
Abstract: The seminal vesicles synthesise bioactive factors that support gamete function, modulate the female reproductive tract to promote implantation, and influence developmental programming of offspring phenotype. Despite the significance of the seminal vesicles in reproduction, their biology remains poorly defined. Here, to advance understanding of seminal vesicle biology, we analyse the mouse seminal vesicle transcriptome under normal physiological conditions and in response to acute exposure to the reproductive toxicant acrylamide. Mice were administered acrylamide (25 mg/kg bw/day) or vehicle control daily for five consecutive days prior to collecting seminal vesicle tissue 72 h following the final injection. A total of 15,304 genes were identified in the seminal vesicles with those encoding secreted proteins amongst the most abundant. In addition to reproductive hormone pathways, functional annotation of the seminal vesicle transcriptome identified cell proliferation, protein synthesis, and cellular death and survival pathways as prominent biological processes. Administration of acrylamide elicited 70 differentially regulated (fold-change ≥1.5 or ≤ 0.67) genes, several of which were orthogonally validated using quantitative PCR. Pathways that initiate gene and protein synthesis to promote cellular survival were prominent amongst the dysregulated pathways. Inflammation was also a key transcriptomic response to acrylamide, with the cytokine, Colony stimulating factor 2 ( Csf2 ) identified as a top-ranked upstream driver and inflammatory mediator associated with recovery of homeostasis. Early growth response ( Egr1 ), C-C motif chemokine ligand 8 ( Ccl8 ), and Collagen, type V, alpha 1 ( Col5a1 ) were also identified amongst the dysregulated genes. Additionally, acrylamide treatment led to subtle changes in the expression of genes that encode proteins secreted by the seminal vesicle, including the complement regulator, Complement factor b ( Cfb ). These data add to emerging evidence demonstrating that the seminal vesicles, like other male reproductive tract tissues, are sensitive to environmental insults, and respond in a manner with potential to exert impact on fetal development and later offspring health.
Publisher: Wiley
Date: 27-09-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-06-2020
Abstract: Immature testicular germ cells secrete factors that influence sperm maturation in mice
Publisher: Bioscientifica
Date: 12-2013
DOI: 10.1530/REP-13-0111
Abstract: With extended periods of time following ovulation, the metaphase II stage oocyte experiences deterioration in quality referred to as post-ovulatory oocyte ageing. Post-ovulatory ageing occurs both in vivo and in vitro and has been associated with reduced fertilization rates, poor embryo quality, post-implantation errors and abnormalities in the offspring. Although the physiological consequences of post-ovulatory oocyte ageing have largely been established, the molecular mechanisms controlling this process are not well defined. This review analyses the relationships between biochemical changes exhibited by the ageing oocyte and the symptoms associated with the ageing phenotype. We also discuss molecular events that are potentially involved in orchestrating post-ovulatory ageing with a particular focus on the role of oxidative stress. We propose that oxidative stress may act as the initiator for a cascade of events that create the aged oocyte phenotype. Specifically, oxidative stress has the capacity to cause a decline in levels of critical cell cycle factors such as maturation-promoting factor, impair calcium homoeostasis, induce mitochondrial dysfunction and directly damage multiple intracellular components of the oocyte such as lipids, proteins and DNA. Finally, this review addresses current strategies for delaying post-ovulatory oocyte ageing with a particular focus on the potential use of compounds such as caffeine or selected antioxidants in the development of more refined media for the preservation of oocyte integrity during IVF procedures.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 05-2018
Publisher: Elsevier BV
Date: 02-2018
Publisher: Frontiers Media SA
Date: 20-12-2019
Publisher: Oxford University Press (OUP)
Date: 30-01-2019
Abstract: Diabetes is associated with poor oocyte quality and the dysregulation of ovarian function and is thus a leading contributor to the increasing prevalence of female reproductive pathologies. Accordingly, it is well-established that insulin fulfills a key role in the regulation of several facets of female reproduction. What remains less certain is whether proinsulin C-peptide, which has recently been implicated in cellular signaling cascades, holds a functional role in the female germline. In the present study, we examined the expression of insulin, C-peptide, and its purported receptor GPR146, within the mouse ovary and oocyte. Our data establish the presence of abundant C-peptide within follicular fluid and raise the prospect that this bioactive peptide is internalized by oocytes in a G-protein coupled receptor-dependent manner. Further, our data reveal that internalized C-peptide undergoes pronounced subcellular relocalization from the ooplasm to the pronuclei postfertilization. The application of immunoprecipitation analysis and mass spectrometry identified breast cancer type 2 susceptibility protein (BRCA2), the meiotic resumption/DNA repair protein, as a primary binding partner for C-peptide within the oocyte. Collectively, these findings establish a novel accumulation profile for C-peptide in the female germline and provide the first evidence for an interaction between C-peptide and BRCA2. This interaction is particularly intriguing when considering the propensity for oocytes from diabetic women to experience aberrant meiotic resumption and perturbation of traditional DNA repair processes. This therefore provides a clear imperative for further investigation of the implications of dysregulated C-peptide production in these in iduals.
Publisher: Elsevier BV
Date: 11-2012
Publisher: Elsevier
Date: 2018
Publisher: Oxford University Press (OUP)
Date: 03-2013
DOI: 10.1095/BIOLREPROD.112.106450
Abstract: The quality of metaphase II oocytes deteriorates rapidly following ovulation as the result of an aging process associated with impaired fertilizing potential, disrupted developmental competence, and increased likelihood of embryonic resorption. Because oxidative stress accelerates the onset of apoptosis in oocytes and influences their capacity for fertilization, this study aimed to characterize the significance of such stress in the postovulatory aging of mouse oocytes in vitro. We investigated the ability of the potent antioxidant melatonin to arrest the aging process when used to supplement oocyte culture medium. This study demonstrated that oxidative stress may occur in oocytes after as little as 8 h in culture and coincides with the appearance of early apoptotic markers such as phosphatidylserine externalization, followed 16 h later by caspase activation (P < 0.05) and morphological evidence of oocyte senescence. Importantly, supplementation of oocyte culture medium with 1 mM melatonin was able to significantly relieve the time-dependent appearance of oxidative stress in oocytes (P < 0.05) and, as a result, significantly delay the onset of apoptosis (P < 0.05). Furthermore, melatonin supplementation extended the optimal window for fertilization of oocytes aged for 8 and 16 h in vitro (P < 0.05) and significantly improved the quality of the resulting embryos (P < 0.01). We conclude that melatonin may be a useful tool in a clinical setting to prevent the time-dependent deterioration of oocyte quality following prolonged culture in vitro.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.YDBIO.2015.07.024
Abstract: Oxidative DNA damage harbored by both spermatozoa and oocytes at the time of fertilization must be repaired prior to S-phase of the first mitotic ision to reduce the risk of transversion mutations occurring in the zygote and subverting the normal patterns of cell differentiation and development. Of the characterised oxidative DNA lesions, 8-hydroxy-2'-deoxyguanosine (8OHdG) is particularly mutagenic. The current study reveals for the first time a marked acceleration of 8OHdG repair in the mouse oocyte/zygote by the base excision repair (BER) pathway following fertilization. Specifically, fertilization initiates post-translational modification to BER enzymes such as OGG1 and XRCC1, causing nuclear localisation and accelerated 8OHdG excision. Additionally, both the nuclear and mitochondrial genomes appear to benefit from increased protection against further 8OHdG formation by a fertilization-associated increase in glutathione peroxidase activity. The major limitation of the characterised 8OHdG repair system is the relatively low level of OGG1 expression in the oocyte, in contrast to the male germ line where it is the only constituent of the BER pathway. The male and female germ lines therefore collaborate in the repair of oxidative DNA damage, and oocytes are vulnerable to high levels of 8OHdG being carried into the zygote by the fertilizing spermatozoon.
Publisher: Wiley
Date: 13-01-2013
DOI: 10.1111/J.2047-2927.2012.00056.X
Abstract: Oxidative stress is known to have a major impact on human sperm function and, as a result, there is a need to develop sensitive methods for measuring reactive oxygen species (ROS) generation by these cells. A variety of techniques have been developed for this purpose including chemiluminescence (luminol and lucigenin), flow cytometry (MitoSOX Red, dihydroethidium, 4,5-diaminofluorescein diacetate and 2',7'-dichlorodihydrofluorescein diacetate) and spectrophotometry (nitroblue tetrazolium). The relative sensitivity of these assays and their comparative ability to detect ROS generated in different subcellular compartments of human spermatozoa, have not previously been investigated. To address this issue, we have compared the performance of these assays when ROS generation was triggered with a variety of reagents including 2-hydroxyestradiol, menadione, 4-hydroxynonenal and arachidonic acid. The results revealed that menadione predominantly induced release of ROS into the extracellular space where these metabolites could be readily detected by luminol-peroxidase and, to a lesser extent, 2',7'-dichlorodihydrofluorescein. However, such sensitivity to extracellular ROS meant that these assays were particularly vulnerable to interference by leucocytes. The remaining reagents predominantly elicited ROS generation by the sperm mitochondria and could be optimally detected by MitoSOX Red and DHE. Examination of spontaneous ROS generation by defective human spermatozoa revealed that MitoSOX Red was the most effective indicator of oxidative stress, thereby emphasizing the general importance of mitochondrial dysregulation in the aetiology of defective sperm function.
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/RD19449
Abstract: The 2019 meeting of the Society for Reproductive Biology (SRB) provided a platform for the dissemination of new knowledge and innovations to improve reproductive health in humans, enhance animal breeding efficiency and understand the effect of the environment on reproductive processes. The effects of environment and lifestyle on fertility and animal behaviour are emerging as the most important modern issues facing reproductive health. Here, we summarise key highlights from recent work on endocrine-disrupting chemicals and diet- and lifestyle-induced metabolic changes and how these factors affect reproduction. This is particularly important to discuss in the context of potential effects on the reproductive potential that may be imparted to future generations of humans and animals. In addition to key summaries of new work in the male and female reproductive tract and on the health of the placenta, for the first time the SRB meeting included a workshop on endometriosis. This was an important opportunity for researchers, healthcare professionals and patient advocates to unite and provide critical updates on efforts to reduce the effect of this chronic disease and to improve the welfare of the women it affects. These new findings and directions are captured in this review.
Publisher: Frontiers Media SA
Date: 04-2022
DOI: 10.3389/FCELL.2022.782996
Abstract: Spermatogonial stem cell (SSC) function is essential for male fertility, and these cells hold potential therapeutic value spanning from human infertility treatments to wildlife conservation. As in vitro culture is likely to be an integral component of many therapeutic pipelines, we have elected to explore changes in gene expression occurring in undifferentiated spermatogonia in culture that may be intertwined with the temporal reduction in regenerative capacity that they experience. Single cell RNA-sequencing analysis was conducted, comparing undifferentiated spermatogonia retrieved from the adult mouse testis with those that had been subjected to 10 weeks of in vitro culture. Although the majority of SSC signature genes were conserved between the two populations, a suite of differentially expressed genes were also identified. Gene ontology analysis revealed upregulated expression of genes involved in oxidative phosphorylation in cultured spermatogonia, along with downregulation of integral processes such as DNA repair and ubiquitin-mediated proteolysis. Indeed, our follow-up analyses have provided the first depiction of a significant accumulation of ubiquitinated proteins in cultured spermatogonia, when compared to those residing in the testis. The data produced in this manuscript will provide a valuable platform for future studies looking to improve SSC culture approaches and assess their safety for utilisation in therapeutic pipelines.
Publisher: Bioscientifica
Date: 09-2013
DOI: 10.1530/REP-13-0186
Abstract: The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence-accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in the Ogg1 gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2′-deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue ( P .05) as well as in mature spermatozoa ( P .001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age ( P .05). When challenged with Fenton reagents (H 2 O 2 and Fe 2 + ), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls ( P .001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2018
DOI: 10.1038/S41598-018-27892-2
Abstract: The unique biology of the oocyte means that accepted paradigms for DNA repair and protection are not of direct relevance to the female gamete. Instead, preservation of the integrity of the maternal genome depends on endogenous protein stores and/or mRNA transcripts accumulated during oogenesis. The aim of this study was to determine whether mature (MII) oocytes have the capacity to detect DNA damage and subsequently mount effective repair. For this purpose, DNA double strand breaks (DSB) were elicited using the topoisomerase II inhibitor, etoposide (ETP). ETP challenge led to a rapid and significant increase in DSB (P = 0.0002) and the consequential incidence of metaphase plate abnormalities (P = 0.0031). Despite this, ETP-treated MII oocytes retained their ability to participate in in vitro fertilisation, though displayed reduced developmental competence beyond the 2-cell stage (P = 0.02). To account for these findings, we analysed the efficacy of DSB resolution, revealing a significant reduction in DSB lesions 4 h post-ETP treatment. Notably, this response was completely abrogated by pharmacological inhibition of key elements (DNA-PKcs and DNA ligase IV) of the canonical non-homologous end joining DNA repair pathway, thus providing the first evidence implicating this reparative cascade in the protection of the maternal genome.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Frontiers Media SA
Date: 22-02-2023
DOI: 10.3389/FENDO.2023.1145533
Abstract: Male infertility is a commonly encountered pathology that is estimated to be a contributory factor in approximately 50% of couples seeking recourse to assisted reproductive technologies. Upon clinical presentation, such males are commonly subjected to conventional diagnostic andrological practices that rely on descriptive criteria to define their fertility based on the number of morphologically normal, motile spermatozoa encountered within their ejaculate. Despite the virtual ubiquitous adoption of such diagnostic practices, they are not without their limitations and accordingly, there is now increasing awareness of the importance of assessing sperm quality in order to more accurately predict a male’s fertility status. This realization raises the important question of which characteristics signify a high-quality, fertilization competent sperm cell. In this review, we reflect on recent advances in our mechanistic understanding of sperm biology and function, which are contributing to a growing armory of innovative approaches to diagnose and treat male infertility. In particular we review progress toward the implementation of precision medicine the robust clinical adoption of which in the setting of fertility, currently lags well behind that of other fields of medicine. Despite this, research shows that the application of advanced technology platforms such as whole exome sequencing and proteomic analyses hold considerable promise in optimizing outcomes for the management of male infertility by uncovering and expanding our inventory of candidate infertility biomarkers, as well as those associated with recurrent pregnancy loss. Similarly, the development of advanced imaging technologies in tandem with machine learning artificial intelligence are poised to disrupt the fertility care paradigm by advancing our understanding of the molecular and biological causes of infertility to provide novel avenues for future diagnostics and treatments.
Start Date: 2022
End Date: 12-2024
Amount: $379,264.00
Funder: Australian Research Council
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