In the first trimester the extravillous cytotrophoblast cells occlude the uterine spiral arterioles creating a low oxygen environment early in pregnancy, which is essential for pregnancy success. Paradoxically, shallow trophoblast invasion and defective vascular remodelling of the uterine spiral arteries in the first trimester may result in impaired placental perfusion and chronic placental ischemia and hypoxia later in gestation leading to adverse pregnancy outcomes. The hypoxia inducible factors (HIFs) are key mediators of the response to low oxygen. We aimed to elucidate mechanisms of regulation of HIFs and the role these may play in the control of placental differentiation, growth and function in both normal and pathological pregnancies. The Pubmed database was consulted for identification of the most relevant published articles. Search terms used were oxygen, placenta, trophoblast, pregnancy, HIF and hypoxia. The HIFs are able to function throughout all aspects of normal and abnormal placental differentiation, growth and function; during the first trimester (physiologically low oxygen), during mid-late gestation (where there is adequate supply of blood and oxygen to the placenta) and in pathological pregnancies complicated by placental hypoxia/ischemia. During normal pregnancy HIFs may respond to complex alterations in oxygen, hormones, cytokines and growth factors to regulate placental invasion, differentiation, transport and vascularization. In the ever-changing environment created during pregnancy, the HIFs appear to act as key mediators of placental development and function and thereby are likely to be important contributors to both normal and adverse pregnancy outcomes.

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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Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.