Understanding the biological and environmental factors contributing to poor oocyte quality

<p dir="ltr">Infertility impacts 1 in 6 people globally, with female infertility making up half of all cases. Poor oocyte quality is critical factor that underpins female infertility and cannot be improved using assisted reproductive technologies (ART). Pre-ovulatory oocytes remain paused in meiosis for a period that can span many decades before ovulation. These oocytes are vulnerable to the damaging impacts of cellular stressors over time. This resultant decline in oocyte quality can be attributed to environmental exposures and biological ageing, particularly prevalent once reaching the age of 35. Furthermore, there are currently no clinically implemented methods that can improve or identify a poor-quality oocyte. It is therefore imperative that we continue to investigate the mechanisms that impact oocyte health, to aid the development of methods to identify, improve, or prevent poor oocyte quality. Therefore, in this thesis, I sought to deepen our knowledge of the biological and environmental factors and processes that contribute to the demise of oocyte quality.</p><p dir="ltr">In Chapter one, I examined global ART trends over three decades through the lens of oocyte quality to contextualise female infertility and characterise the current state of ART. This study illustrated vast increases in ART reliance globally, with the performance of oocyte and embryo cryopreservation and frozen cycles following suit, rising to dominate over fresh cycles. Female patients aged 35 and over, the population impacted most by the consequences of poor oocyte quality due to age-related infertility, remained the primary patient demographic over this time. Fresh cycle success rates (live birth rates) in female patients aged 35 and over remained low, whereas frozen cycles increased in success, highlighting the changing nature of the ART industry to overcome the biological limitations of oocyte quality. This study provides valuable information towards the development of strategies to improve ART success and reporting, and emphasises priority areas for prospective studies evaluating oocyte quality.</p><p dir="ltr">Chapter two explores oocyte quality in the context of environmental exposure to Bisphenol A (BPA) and BPA alternatives. These dietary contaminants are a group of endocrine disrupting chemicals that can exert harmful health effects and remain chronically prevalent in populations globally for decades. Through conducting a comprehensive scoping review, this chapter synthesised the findings from the existing body of evidence assessing the effect of bisphenols on oocyte health. Analysis of 107 studies using a framework to assess oocyte health parameters resulted in an overwhelming consensus that BPA and BPA alternatives, at doses deemed safe, are detrimental to oocyte health and female fertility. From this work, key recommendations were designed for future studies to encourage the generation of high-quality, impactful, and consistent evidence to drive change. This chapter highlights the critical need to revise and create current regulations for safe exposure to BPA and BPA alternatives to adequately protect oocyte quality.</p><p dir="ltr">Chapters three and four investigate oocyte quality in the context of biological ageing. Through reviewing the known factors and cellular mechanisms responsible for oocyte quality decline, Chapter three indicates the importance of the protein degradation pathway, autophagy, in cellular health, and highlights the gap in our understanding of how autophagy could play a role in age-related oocyte quality decline. To fill this gap, Chapter four utilises an in vivo mouse model of female reproductive ageing to interrogate the role of macroautophagy in the ageing pre-ovulatory oocyte. This study demonstrated age-related alterations in the characteristics of autophagosomes, lysosomes, and documented the presence and accumulation of large aggregated amphisome-like vesicular structures in the ageing pre-ovulatory oocyte for the first time. These features were indicative of autophagy dysfunction. It also successfully identified a causative mechanism for the accumulation of these large vesicular structures by reproducing this accumulation in young oocytes using an in vitro lysosomal inhibition model. These studies demonstrate an important role for autophagy in maintaining oocyte health and when dysfunctional, potentially contributing to oocyte quality decline in age-related infertility.</p><p dir="ltr">Combined, the studies that comprise this multi-contextual body of work employed a range of novel approaches to exemplify the contribution of biological factors, such as age-related autophagy dysfunction, and environmental factors, such as dietary exposure to bisphenols, to poor oocyte quality and female infertility. The diverse knowledge gained in this thesis has made a valuable and novel contribution to the field of research dedicated to understanding oocyte quality. This enhanced understanding will ultimately assist in the development of methods to improve ART outcomes, preventative strategies to reduce the burden of female infertility, and ensure the health and fertility of offspring and future generations.</p>