- Title
- Regulation of sperm function and oxidative stress by lipoxygenase enzymes
- Creator
- Walters, Jessica
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Male infertility accounts for half of all reproductive complications, yet is a poorly characterised aspect of human health. As a result, a large proportion of infertility cases are categorised as idiopathic with a commensurate lack of treatment options for male infertility. Without a molecular understanding of the underlying cause of infertility, there is very limited scope for providing therapeutic options to these patients. Importantly, in recent years there has been a heightened focus on understanding key differences between the oxidative stress cascades that naturally drive the maturation of sperm cells and processes that lead to the overproduction of reactive oxygen species (ROS) that occurs in the spermatozoa of many individuals with idiopathic infertility. Oxidative stress stimulates several pathways that contribute to sperm dysfunction, one of the most damaging being membrane lipid peroxidation. Membrane lipid peroxidation results in the degradation of lipids within cell membranes, forming several cytotoxic products including lipid aldehydes. These aldehydes cause an impairment to cellular homeostasis by damaging both DNA and proteins and can ultimately causes cell death. Critically, lipid peroxidation, and its deleterious products, are key factors underpinning both male infertility, and inefficiencies in assisted reproductive technologies applied within the agricultural industry. The work described within this thesis provides an enhanced understanding of lipid peroxidation processes in human and equine spermatozoa, providing data that challenges the long-held paradigm that the generation of cytotoxic lipid peroxidation products occur solely in the absence of a central enzyme catalysed reaction. This thesis robustly demonstrates the importance of the lipoxygenase enzyme arachidonate 15-lipoxygenase (ALOX15) in the catalysis of lipid oxidation processes that result in the production of reactive aldehyde byproducts, such as 4-hydroxynonenal (4HNE) in human spermatozoa. The pharmacological inhibition of ALOX15 within human spermatozoa alongside oxidative challenges not only 8 dramatically reduced lipid peroxidation levels but also significantly protected the functional competence of sperm cells. Moreover, for the first time, this work has provided a positive link between the expression levels of ALOX15 and the abundance of 4HNE in the spermatozoa of infertile men. Thus, the work within this thesis provides the foundation for a novel strategy to prevent oxidative stress-induced male infertility through the inactivation of ALOX15. Radiating from this mechanistic basis, this work provides a clear impetus to assess the safety and efficacy of ALOX15 inhibitors in vivo for future clinical use. In the context of animal breeding, my work also provides preliminary evidence that this technology may find important applications in artificial breeding practices for both domesticated and wildlife animal species by virtue of its ability to preserve equine sperm function during extended storage. To this end, we have examined the utility of ALOX15 inhibition in equine spermatozoa and demonstrated the maintenance of sperm motility and viability after 24 hours of chilled storage in the presence of ALOX15 inhibitors. This series of studies ultimately provides an important platform for the improvement of assisted reproduction practices in both humans and animals. Through the characterisation of ALOX15 function in both human and equine spermatozoa, the results within this thesis provide a novel application for ALOX15 inhibitors to improve the resilience of sperm cells to oxidative damage and hold the potential to direct clinical practice towards new strategies to prevent oxidative stress-induced male infertility.
- Subject
- sperm function; oxidative stress; lipoxygenase enzymes; male infertility; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1489125
- Identifier
- uon:52622
- Rights
- Copyright 2021 Jessica Walters
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 508 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 230 KB | Adobe Acrobat PDF | View Details Download |