Navigating redox imbalance: the role of oxidative stress in embryonic development and long-term health outcomes

Abstract

Embryonic development is a complex process of concurrent events comprising cell proliferation, differentiation, morphogenesis, migration, and tissue remodeling. To cope with the demands arising from these developmental processes, cells increase their nutrient uptake, which subsequently increases their metabolic activity. Mitochondria play a key role in the maintenance of metabolism and production of reactive oxygen species (ROS) as a natural byproduct. Regulation of ROS by antioxidants is critical and tightly regulated during embryonic development, as dysregulation results in oxidative stress that damages essential cellular components such as DNA, proteins, and lipids, which are crucial for cellular maintenance and in extension development. However, during development, exposure to certain exogenous factors or damage to cellular components can result in an imbalance between ROS production and its neutralization by antioxidants, leading to detrimental effects on the developmental process. In this review article, we highlight the crucial role of redox homeostasis in normal development and how disruptions in redox balance may result in developmental defects.

Keywords: ADHD; ASD; ROS; antioxidants; embryo; malformations; morphogenesis; oxidative stress.

FIGURE 1

Prominent species of reactive oxygen.

FIGURE 2

Exogenous and endogenous sources of ROS. Sources of oxidative stress can be categorized as exogenous or endogenous. Exogenous sources include external factors such as infections (e.g., Mycobacterium tuberculosis, Pseudomonas aeruginosa, HIV, influenza virus, and Plasmodium falciparum), inflammation, smoking, and alcohol abuse, which contribute to the production of reactive oxygen species (ROS). Endogenous sources arise from internal cellular processes, including mitochondrial activity, disruptions in the nuclear membrane, protein misfolding in the endoplasmic reticulum, and lysosomal dysfunction. Both categories lead to an imbalance in ROS homeostasis, potentially resulting in oxidative damage to biomolecules and cellular structures.

FIGURE 3

Effects of ROS on sperm, oocyte, and developmental competence. Oxidative stress plays a crucial role in reproductive processes, impacting both male and female gametes and embryonic development. In sperm, oxidative stress impairs maturation, motility, and capacitation, key processes essential for successful fertilization. In oocytes, oxidative stress influences calcium regulation, ATP synthesis, and the stability of the spindle and chromosomes, all of which are critical for ensuring developmental competence. During embryonic development, oxidative stress affects embryonic programming, increases the risk of disease, and may have transgenerational effects, potentially influencing the health of future generations.

FIGURE 4

Regulation of Nrf2 under both normal conditions and in the presence of excessive reactive oxygen species (ROS). Under normal conditions, Nrf2 is bound to its cytoplasmic inhibitor, Keap1 (Kelch-like ECH-associated protein 1). This interaction promotes the ubiquitination (Ub) of Nrf2, marking it for proteasomal degradation through the ubiquitin–proteasome pathway, thereby maintaining low intracellular levels of Nrf2. During oxidative stress, characterized by elevated ROS, the interaction between Nrf2 and Keap1 is disrupted. This results in the release of Nrf2, which then translocates into the nucleus. Once in the nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of target genes, initiating the transcription of antioxidant and cytoprotective genes that help mitigate oxidative damage.

FIGURE 5

Effect of oxidative stress on embryonic development.