Cord blood genomic analysis highlights the role of redox balance

Abstract

Neonates are exposed to elevated levels of reactive oxygen species as they transition from a hypoxic intrauterine to a normoxic extrauterine environment at birth. This increased oxidative stress is associated with neonatal morbidity. Current antioxidant supplementation treatment strategies have yet to translate into improved neonatal outcomes. Our understanding of a newborn's intricate redox balance, particularly at the genomic level, remains limited. Here, we performed genomic microarray analyses (approximately 14,500 genes) on extracted mRNA from umbilical cord whole blood at term gestation (n=10). Bioinformatic analyses identified 282 genes (2.0%) that were consistently present within the highest quintile of expressed genes. These genes were highly associated with oxidant stress and included superoxide dismutase 1, catalase, peroxiredoxins, and uncoupling proteins. Pathway analyses identified statistically significantly overrepresented functional pathways including "oxidative stress," "oxidative stress response mediated by nuclear factor-erythroid 2-related factor," "hypoxia-inducible factor signaling," and "mitochondrial dysfunction" (p<0.05). These results suggest that neonates require high levels of antioxidants and an intricate cellular redox balance to ensure a successful transition to the extrauterine environment. Understanding the genes necessary to maintain this delicate redox balance may lead to the development of alternative treatment strategies.

Figure 1. Neonatal Defensive Cellular Response Mechanisms to Oxidative Stress at Birth

Schematic figure highlighting the complex cellular redox pathways involved in successful neonatal transitioning at birth.

1. Free Radical Scavenging: Superoxide dismutase 1 (SOD1) scavenges oxygen free radicals while catalase (CAT) converts hydrogen peroxide to water and oxygen.

2. Thioredoxin System: Peroxidredoxins reduce hydrogen peroxide by transferring electrons from thioredoxin (TRX) via PRDX2 or another donor such as glutathione via PRDX6 [25]

3. Nrf2 Signaling Pathway: Increased levels of ROS within the cellular milieu lead to an uncoupling and subsequent activation of Nrf2. Nrf2 then translocates to the nucleus, binds to ARE, and causes the upregulation of antioxidant genes such as glutathione transferase (GST), thioredoxin 1 (TR1), and NADPH:quinone oxidoreducatse-1 (NQO1) [23].

4. Mitochondrial Dysfunction: Activation of UCP2 in the inner mitochondrial membrane diminishes the protonmotive force, attenuates mitochondrial ROS production, and reduces cellular oxidative stress damage [28].