Hypoxia: its short- and long-term effects on the developing fetus
In addition to traditional risks, such as smoking and obesity, the quality of our prenatal development plays a role in determining whether we suffer disease. In turn, the quality of the intrauterine environment is largely determined by the available nutrient and oxygen supply to the growing young. As such, the association between poor conditions in utero and increased risk of disease in adulthood has exploded a number of studies investigating the effects of changes in materno-fetal nutrition on programming of disease. In contrast to this international research effort, the contribution of fetal hypoxia, of the type that can occur during pre-eclampsia or placental insufficiency, to developmental programming has been comparatively ignored. Further, the mechanisms underlying the early programming of disease in complicated pregnancy remain unknown, preventing the identification of potential therapeutic targets for clinical intervention. Here, we put forward the hypothesis that oxidative stress in the fetus underlies the molecular basis via which prenatal hypoxia alters fetal growth and contributes to the developmental programming of disease. Observations in human pregnancy at high altitude and experiments in chick and rat embryos show that developmental hypoxia independent of changes in maternal nutrition not only alters the trajectory of fetal growth, but it also induces changes in the cardiovascular, metabolic and endocrine systems, which are normally associated with disease states in later life. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, the fetal cardiovascular, metabolic and endocrine remodelling, and the increased oxidative stress. Combined, the human and experimental data support the hypothesis tested and the work offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of disease in risky pregnancy.