The effects of the drug BGP-15 on metabolic processes altered by advancing age and oxidative stress on murine fertility

Abstract

Current clinical assisted reproductive technologies (ARTs) have a limited capacity to address the decline of gamete quality (oocytes and sperm) that occurs with advanced age. This age-associated decline has been linked to a compromised gamete metabolism and the promotion of oxidative stress. Pharmacological agent BGP-15 has demonstrated both a capacity to address the negative effects associated with advanced age in somatic tissue and has improved ART outcomes in response to maternal obesity in a murine model and therefore BGP-15 may improve clinical ART outcomes for older patients. This study investigated the use of BGP-15 to improve gamete quality in response to advanced age and oxidative stress, a hallmark of advanced age. The focuses of this thesis are reproductive biology, mitochondrial activity and redistribution that were assessed by confocal microscopy and 3D modelling. The activity of BGP-15 on the oocyte mitochondria was found to be dynamic and changed dependent on oocyte maturity and the presence or absence of H2O2 induced oxidative stress. BGP-15 could act under these circumstances as either an oxidant or an antioxidant but consistently reduced the negative effects of H2O2 induced oxidative stress. In addition, mitochondria redistribution was assessed with a novel 3D modelling procedure that determine that an exposure to BGP-15 reduced mitochondrial membrane potential but prevented H2O2 induced changes to mitochondrial redistribution. From this study, BGP-15 improved ovulation rates in response to advanced maternal age and early embryo development but the effect of BGP-15 on later development was not determined. Additionally, transzonal projections are a unique but understudied aspect of oocyte morphology that connects the oocyte to the cumulus cells of the ovarian follicle. These filamentous structures were assessed by a novel 3D assessment procedure. A BGP-15 treatment in young mice prevented H2O2 induced damage upon the oocyte’s transzonal projections but a BGP-15 exposure reduced the transzonal projection density observed in the oocytes from old mice. The results of this study act as a proof of concept that BGP-15 may represent a therapeutic treatment against the reduced ART success observed with advanced maternal and paternal age.