Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain

Abstract

Background: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for brain hypoxia and oxidative stress. Methods: Guinea pigs were fed ad libitum (control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1) was injected into pregnant sows. Fetuses were then necropsied and brain tissues were processed for HP-1 (hypoxia marker) and 4HNE, 8-OHdG, and 3-nitrotyrosine (oxidative stress markers) immunoreactivity (IR). Results: FGR-MNR fetal and brain weights were decreased 38 and 12%, respectively, with brain/fetal weights thereby increased 45% as a measure of brain sparing, and more so in males than females. FGR-MNR HP-1 IR was increased in most of the brain regions studied, and more so in males than females, while 4HNE and 8-OHdG IR were increased in select brain regions, but with no sex differences. Conclusions: Chronic hypoxia is likely to be an important signaling mechanism in the FGR brain, but with males showing more hypoxia than females. This may involve sex differences in adaptive decreases in growth and normalizing of oxygen, with implications for sex-specific alterations in brain development and risk for later neuropsychiatric disorder.

Low protein-induced intrauterine growth restriction as a risk factor for schizophrenia phenotype in a rat model: assessing the role of oxidative stress and neuroinflammation interaction

“…Previous studies have already underlined the impact of maternal nutrition on the mental and physical health of the offspring [ 20 , 24 , 55 , 56 ]. Offspring exposed to IUGR show altered neurodevelopment, specifically a delay in synaptogenesis [ 56 ].…”

“…Previous studies have already underlined the impact of maternal nutrition on the mental and physical health of the offspring [ 20 , 24 , 55 , 56 ]. Offspring exposed to IUGR show altered neurodevelopment, specifically a delay in synaptogenesis [ 56 ]. Lack of nutrients during the critical phase of cerebral development provides a hypothesis for the delay in synaptogenesis.…”

“…Indeed, we propose that part of the deleterious effects of IUGR are mediated by oxidative stress and microglia activation occurring during fetal brain development. Previous animal models of maternal nutrient restriction have demonstrated increased 8-oxo-dG but also 4-HNE, a marker of lipid peroxidation, indicating increased oxidative damage in offspring born after IUGR [ 30 , 56 ]. In a model of protein deficiency, increased superoxide production via the NADPH oxidase was observed [ 20 , 31 ], linking the protein availability to ROS generation.…”

“…In a translational application of this thought, pregnant women with growth-restricted fetuses revealed a measurable increase in plasmatic oxidants [ 61 ], a decrease in antioxidant capacities [ 20 , 62 ], as well as the presence of a pro-inflammatory environment [ 17 ], with increased inflammatory cytokines in individuals born after IUGR [ 63 ], changes which are similarly observed in IUGR neonates [ 20 , 26 , 58 ]. Findings of increased biomarkers of oxidative stress in cord blood and placental tissue of infants born after IUGR [ 56 ] as well as the induction of a pro-inflammatory environment [ 17 , 64 , 65 ] suggest the long-term effect of the impaired environment.…”

“…These behavioral alterations may resemble, without being equivalent to, SZ symptoms, and therefore strengthen the link between IUGR and neurodevelopmental psychiatric disorders. A maternal low protein diet seemingly impacts proper neurodevelopment through an increase in oxidative stress and neuroinflammation and thus hinders what is considered to be normal behavior [ 43 , 47 , 56 , 84 ], which may be relevant for SZ. Many adverse events during gestation, such as infection or traumatic events [ 32 , 85 , 86 ], were shown to be risk factors for SZ, and malnutrition, due to famine episodes [ 9 ], were associated with a higher risk of developing SZ in the offspring [ 9 , 15 , 16 ].…”