Abstract
ObjectiveHypoxic-ischemic encephalopathy affects ∼6 in 1,000 preterm neonates, leading to significant neurological sequela (e.g., cognitive deficits and cerebral palsy). Maternal smoke exposure (SE) is one of the common causes of neurological disorders; however, female offspring seems to be less affected than males in our previous study. We also showed that maternal SE exaggerated neurological disorders caused by neonatal hypoxic-ischemic brain injury in adolescent male offspring. Here, we aimed to examine whether female littermates of these males are protected from such insult.MethodsBALB/c dams were exposed to cigarette smoke generated from 2 cigarettes twice daily for 6 weeks before mating, during gestation and lactation. To induce hypoxic-ischemic brain injury, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen) at postnatal day (P) 10. Behavioral tests were performed at P40–44, and brain tissues were collected at P45.ResultsMaternal SE worsened the defects in short-term memory and motor function in females with hypoxic-ischemic injury; however, reduced anxiety due to injury was observed in the control offspring, but not the SE offspring. Both hypoxic-ischemic injury and maternal SE caused significant loss of neuronal cells and synaptic proteins, along with increased oxidative stress and inflammatory responses.ConclusionOxidative stress and inflammatory response due to maternal SE may be the mechanism of worsened neurological outcomes by hypoxic-ischemic brain injury in females, which was similar to their male littermates shown in our previous study.
Highlights
Neonatal Hypoxia-ischemic (HI) encephalopathy (HIE) is a common brain injury of neonates, which occurs in 3 per 1,000 term newborns and 6 per 1,000 preterm newborns (≤36 weeks of gestation) (Hagberg et al, 2015; Herrera et al, 2018)
During the occurrence of hypoxic-ischemic injury, there is a significant decrease in blood oxygen delivery and blood flow to the affected brain areas, interrupting neonatal brain development which is the likely cause of neurological disorders associated with HI brain damage (Yong et al, 2012)
HI increased the levels of both 4-HNE and SOD-1 in offspring from both control and smoke exposure (SE) dams, with SOD-1 increasing even higher in SE offspring in both cerebral cortex and hippocampal regions. These results suggest an adaptive increase in the antioxidant SOD-1 due to oxidative stress reflected by 4-HNE level, which was, unsuccessful in protecting affected brain regions regardless of maternal status
Summary
Neonatal Hypoxia-ischemic (HI) encephalopathy (HIE) is a common brain injury of neonates, which occurs in 3 per 1,000 term newborns and 6 per 1,000 preterm newborns (≤36 weeks of gestation) (Hagberg et al, 2015; Herrera et al, 2018). During the occurrence of hypoxic-ischemic injury, there is a significant decrease in blood oxygen delivery and blood flow to the affected brain areas, interrupting neonatal brain development which is the likely cause of neurological disorders associated with HI brain damage (Yong et al, 2012). Maternal cigarette smoke exposure (SE) is a well-accepted risk factor for fetal hypoxia, by decreasing the blood flow to the placenta due to the vasoconstriction effects of nicotine and reducing oxygen carrying capacity of both fetal and maternal red blood cells due to increased caroxyhemoglobin (Bureau et al, 1983; Philipp et al, 1984; Habek et al, 2002; Sen et al, 2010). Another study in an Australian cohort failed to find any sex difference in such susceptibility (Silva et al, 2014)
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