Prenatal Hypoxia and Placental Oxidative Stress: Insights from Animal Models to Clinical Evidences

Abstract

Hypoxia is a common form of intrauterine stress characterized by exposure to low oxygen concentrations. Gestational hypoxia is associated with the generation of reactive oxygen species. Increase in oxidative stress is responsible for damage to proteins, lipids and DNA with consequent impairment of normal cellular functions. The purpose of this review is to propose a summary of preclinical and clinical evidences designed to outline the correlation between fetal hypoxia and oxidative stress. The results of the studies described show that increases of oxidative stress in the placenta is responsible for changes in fetal development. Specifically, oxidative stress plays a key role in vascular, cardiac and neurological disease and reproductive function dysfunctions. Moreover, the different finding suggests that the prenatal hypoxia-induced oxidative stress is associated with pregnancy complications, responsible for changes in fetal programming. In this way, fetal hypoxia predisposes the offspring to congenital anomalies and chronic diseases in future life. Several antioxidant agents, such as melatonin, erythropoietin, vitamin C, resveratrol and hydrogen, shown potential protective effects in prenatal hypoxia. However, future investigations will be needed to allow the implementation of these antioxidants in clinical practice for the promotion of health in early intrauterine life, in fetuses and children.

Maternal Western diet exposure increases periportal fibrosis beginning in utero in nonhuman primate offspring

“…Here, we demonstrated that supplementation of WSD-fed mothers with resveratrol reduced fetal hepatic oxidative stress, decreased periportal collagen deposition, and decreased ACTA2 + and ACTA2 and TIMP1 double-positive portal triad HSCs/myofibroblasts to levels comparable to CD fetuses. Activation of oxidative stress in WSD-exposed fetuses may result from decreased umbilical artery oxygenation ( 22 ) and impaired placental function ( 22 , 62 , 63 ). Importantly, we found that SHG area correlated positively with markers of fetal hypoxemia, suggesting that fetal stress and hypoxemia might be drivers of liver fibrosis in utero.…”

Hypoxia and Mitochondrial Dysfunction in Pregnancy Complications

“…Hypoxia is a common feature of preeclampsia and FGR [ 17 , 174 ]. Placental hypoxia is long believed to induce oxidative stress by stimulating ROS generation in mitochondria and other compartments of uteroplacental cells, leading to placental dysfunction and subsequent development of preeclampsia and FGR [ 17 , 18 , 174 ]. The placenta is a metabolically active organ and has a high nutrient and energy demand.…”

“…It is now recognized that both preeclampsia and FGR originate from the placenta due to uteroplacental dysfunction conferred by gestational hypoxia [ 1 , 12 , 13 , 14 , 15 ]. Gestational hypoxia is associated with overproduction in reactive oxygen species (ROS) in the placenta, leading to oxidative stress [ 12 , 16 , 17 , 18 ]. ROS can be beneficial or deleterious, depending on their levels in cells.…”

“…Oxidative stress has been implicated in many human diseases including hypertension [ 20 , 21 ]. Not surprisingly, uteroplacental tissues/cells of preeclampsia and FGR display a heightened level of oxidative stress [ 22 ], which plays a central role in the pathogenesis of both complications [ 18 , 23 ]. Mitochondria consume most cellular oxygen (O 2 ) to produce ATP to sustain cellular functions and a significant portion of ROS is also generated during the oxidation-phosphorylation coupling.…”

Effects of Prenatal Hypoxia on Nervous System Development and Related Diseases

“…Prenatal hypoxia also leads to increased placental oxidative stress and decreased mitochondrial respiration and mitochondrial fusion, which may lead to disorders of placental function and fetal development ( Ganguly et al, 2021 ). Increased oxidative stress also leads to damage to proteins, lipids and DNA, which disrupts normal cellular function ( Silvestro et al, 2020 ). Rapid re-oxygenation after hypoxia can disrupt the fetal blood-brain barrier by producing ROS, thereby amplifying the effects of molecules in fetal blood on the brain ( Piesova and Mach, 2020 ).…”