Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

The lipid peroxidation product 4-hydroxynonenal contributes to oxidative stress-mediated deterioration of the ageing oocyte (#95)

Bettina P Mihalas 1 , Geoffry N De Iuliis 1 , Kate A Redgrove 1 , Eileen A McLaughlin 1 2 , Brett Nixon 1
  1. University of Newcastle, Callaghan, NSW, Australia
  2. Biological Sciences, The University of Auckland, Auckland, New Zealand

An increase in intraovarian reactive oxygen species (ROS) has long been implicated in the decline in oocyte quality associated with maternal ageing. Despite evidence suggesting that elevated levels of ROS in the ovary correlates with reduced oocyte quality, diminished embryo development and a reduction in live births, the mechanism(s) by which ROS elicits damage to oocytes remain largely unexplored. We propose that oxidative stress (OS)-induced lipid peroxidation and the consequent generation of electrophilic aldehydes, such as 4-hydroxynonenal (4-HNE), represents a potential mechanism by which ROS can inflict damage in the ageing oocyte. In support of this hypothesis, we have established that aged oocytes are vulnerable to damage from elevated 4-HNE exposure generated from increased cytosolic ROS production. Further, we demonstrated that the age-related induction of OS can be recapitulated by exposure of germinal vesicle (GV) oocytes to exogenous H2O2. Such treatments stimulated an increase in 4-HNE generation, which remained elevated during in vitro oocyte maturation to metaphase II. Additionally, exposure of GV oocytes to either H2O2 or 4-HNE resulted in decreased meiotic completion, increased spindle abnormalities, chromosome misalignments and aneuploidy. In seeking to account for these data, we revealed that proteins essential for oocyte health and meiotic development, namely α-, β-, and γ-tubulin are vulnerable to adduction via 4-HNE in a manner that would likely to render them dysfunctional. Furthermore, the tubulin of aged oocytes presented with a higher susceptibility to adduction via 4-HNE. This observation suggests that elevated levels of ROS-induced 4-HNE production can disrupt spindle assembly by interfering with the function of tubulin proteins and thus provides novel insight into causative factors that may contribute to age-related decline in oocyte quality. Importantly, 4-HNE-tubulin adduction and increased aneuploidy rates were resolved by co-treatment with the antioxidant penicillamine, demonstrating a possible therapeutic mechanism to improve oocyte quality in older females.