Poster Presentation ESA-SRB-APEG-NZSE 2022

Lysosomal inhibition of mouse oocytes as a model of age-related oocyte quality decline (#387)

Alexandra E Peters 1 2 , Eileen A McLaughlin 1 2 3 4 , Shaun D Roman 5 , Kirsty G Pringle 1 2 , Elizabeth G Bromfield 6 7 , Brett Nixon 6 7 , Jessie M Sutherland 1 2
  1. School of Biomedical Science and Pharmacy, College of Health, Medicine, and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
  2. Mothers and Babies Research Program, Hunter Medical Research Institute , New Lambton Heights, NSW, Australia
  3. Faculty of Science, Medicine, and Health, University of Wollongong, Wollongong, NSW, Australia
  4. School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand
  5. Unaffiliated, Newcastle
  6. School of Environmental and Life Sciences, College of Engineering, Science, and Environment, University of Newcastle, Callaghan, NSW, Australia
  7. Infertility and Reproduction Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

Oocyte quality is imperative in determining embryo health and subsequent pregnancy success. Advancing maternal age is a key factor that contributes to the decline of oocyte quality. In this study we aimed to model this decline using an in vitro acute treatment regimen targeting the autophagy pathway; a protein degradation pathway necessary for maintaining cell health. We have previously used advanced quantitative image analysis techniques to demonstrate that autophagy is impaired in aged mouse oocytes. These aged mouse oocytes harbour reduced numbers of key pathway components including autophagosomes (LC3B, P = 0.01) and lysosomes (LAMP1, P = 0.01), alongside an accumulation of amphisomes (LC3B and EEA1, P < 0.01) compared to young oocytes. To model these changes, we exposed pre-ovulatory oocytes collected from 4-6 week old C57BL/6 x CBA F1 mice with a lysosomal inhibitor, chloroquine (200 µM), for 6 hours. Oocytes were either assessed immediately after treatment at the GV stage for autophagy pathway markers (LC3B, EEA1, and LAMP1), or incubated overnight and matured in vitro to assess functional impacts on meiosis and equivalent pathway markers at subsequent meiotic stages. Chloroquine treatment of young oocytes led to a significant accumulation of amphisomes (staining for LC3B and EEA1) compared with controls (P < 0.05), thus mimicking the response seen in aged oocytes. Preliminary assessment of lysosomal inhibition on GV oocytes prior to in vitro maturation revealed a marked reduction in polar body extrusion rates, a phenotype indicative of impaired meiosis. Together, these data implicate lysosomal dysfunction as a potential key player in oocyte quality control. These findings highlight the enhancement of autophagy as a prospective target pathway to improve oocyte quality, particularly in an in vitro setting.