Impact of Oxidative Stress on Development

Abstract

The developing embryo and fetus, collectively termed the conceptus, are highly susceptible to the adverse effects of oxidative stress initiated by endogenous processes and by xenobiotics that enhance the formation of reactive oxygen species (ROS). This susceptibility is due in part to the high conceptal rates of cellular division and differentiation, and the complex processes involved in the formation of organ structures and development of functional systems, including brain activity. Alterations in these processes can result in in utero or perinatal death, or structural and functional birth defects, termed “teratogenesis.” The instability of ROS, and particularly hydroxyl radicals, means that proximate formation of ROS within the conceptus, rather than distal maternal formation, plays a critical role in teratogenesis. Susceptibility is compounded by relatively high levels of embryonic and fetal enzymes involved in ROS formation and xenobiotic bioactivation to free radical intermediates and conversely low levels of protective antioxidative enzymes. Enhanced ROS levels can adversely affect development by altering signal transduction and/or by oxidatively damaging conceptal cellular macromolecules such as lipids, proteins, and DNA, the latter of which may be mitigated by DNA repair enzymes. The risk of teratogenesis is therefore largely determined at the conceptal level, wherein mouse models littermates with an unfavorable imbalance among pathways of ROS formation and detoxification, and DNA repair, exhibit greater structural and/or functional birth defects than littermates with a favorable balance.