REDOX regulation of early embryo development

Abstract

Early embryo development requires energy (that is, the formation of adenosine triphosphate, ATP), which is produced through two possible mechanisms: glycolysis, using glucose as a substrate, and oxidative phosphorylation, using pyruvate or oxaloacetate as a substrate. The pioneering work of Brinster, Biggers, Whitten, Whittingham and Wales from the late 1950s to the early 1970s revealed that for mouse embryo development to the blastocyst stage, pyruvate or oxaloacetate are essential for early cleavage, but that glucose is an effective substrate from the eight-cell stage (Bavister, 1995; Wales, 1975). These studies were the first to reveal that a change in metabolic state is involved in the control of early development and led many other workers to examine the concentrations of exogenous energy substrates required for optimal ex vivo embryo development (Bavister, 1995).Another key energy substrate (although usually not considered as such) is oxygen (Fig. 1). Oxygen is essential for the conversion of ADP to ATP in oxidative phosphorylation through its role as an electron acceptor in the electron transport chain. However, the use of oxygen as an energy substrate also results in the production of reactive oxygen species (ROS), particularly the superoxide anion (O 2 -• ) and the hydroxyl radical (OH • ). ROS are highly active electron acceptors, able to strip electrons from other molecules that, in turn, become free radicals. Hydrogen peroxide (H 2 O 2 ) is not a radical per se, but is a product of O 2 -• and metal ion catalysis. However, both H 2 O 2 and O 2 -• can form the extremely reactive OH • . The over-generation of intracellular ROS during culture of mammalian embryos in vitro is generally thought to be detrimental to embryo development (reviewed by Johnson and Nasr-Esfahani, 1994; Guerin et al., 2001). The consensus view is that 'over-production' of ROS is unfavourable for embryo development, coincident with perturbed metabolic activity. We believe this to be an overly simplistic view and prefer to think in terms of altered reduction-oxidation (REDOX) states, in which a prolonged oxidized state within the embryo, especially after early cleavage, is not favourable for embryo development. Other in vitro culture conditions may also shift the REDOX state unfavourably. Furthermore, there are some specific events in development that appear to be associated with a change in the REDOX state, indicating that REDOX state has a causative role. These events include sperm-mediated oocyte activation, embryonic genome activation and embryonic hatching from the zona pellucida. Intracellular reduction-oxidation statesThe intracellular REDOX state describes a complex interaction of the relative concentrations of reduced and oxidized forms of a variety of molecules, including the nicotinamide adenine nucleotides (NAD(P) + /NAD(P)H), flavins (FAD + /FADH), ubiquinones, peroxides and thiols-disulphides (for example, glutathione (GSH/GSSG)), and others (Fig. 1) REDOX state is also significantly influenced by factors that stimul...

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