Abstract
An increase in intraovarian reactive oxygen species (ROS) has long been implicated in the decline in oocyte quality associated with maternal ageing. Oxidative stress (OS)-induced lipid peroxidation and the consequent generation of highly electrophilic aldehydes, such as 4-hydroxynonenal (4-HNE), represents a potential mechanism by which ROS can inflict damage in the ageing oocyte. In this study, we have established that aged oocytes are vulnerable to damage by 4-HNE resulting from increased cytosolic ROS production within the oocyte itself. 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. Importantly, 4-HNE-tubulin adduction, as well as increased aneuploidy rates, were resolved by co-treatment with the antioxidant penicillamine, demonstrating a possible therapeutic mechanism to improve oocyte quality in older females.
Highlights
In humans, a finite number of female germ cells enter meiosis during embryonic life, only to become meiotically arrested in an extended prophase I, until recruitment into the growing follicle pool for ovulation decades later[1]
The lipid-aldehyde, 4-HNE, represents one of the primary by-products of lipid peroxidation cascades and is a major contributor to pathologies generated under conditions of OS63, 64
To investigate the possibility of 4-HNE as a causative intermediate of the age-related decline in oocyte quality, our initial experiments sought to establish whether this aldehyde is generated within ovarian oocytes and their follicular environment
Summary
Received: 1 February 2017 Accepted: 12 June 2017 Published online: 24 July 2017 deterioration of the ageing oocyte. A ‘free radical theory’ has long been postulated as a leading causative agent underpinning the deterioration of oocyte quality with increasing maternal age[15, 16] This hypothesis centres on the proposal that oocytes experience an accumulation of oxidative damage during the decades they spend in extended meiotic arrest while remaining metabolically active[15,16,17,18]. Elevated levels of ROS have been associated with a decrease in meiotic completion[34, 35] and age-associated phenotypes including altered spindle microtubules, chromosome misalignment[36,37,38], aneuploidy[15, 39] and diminishing embryo developmental potential[32, 40,41,42,43,44] These combined effects culminate in reduced pregnancy rates. By improving our understanding of the mechanisms by which oocyte quality declines with age such studies should help inform the development of therapeutic interventions for women choosing to delay child bearing until their later reproductive years
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