Maternal Cigarette Smoke Exposure Worsens Neurological Outcomes in Adolescent Offspring with Hypoxic-Ischemic Injury

Yik L Chan,Bryce Vissel,Carol Pollock,Hui Chen,Brian G Oliver,Sonia Saad,Rita Machaalani,Nicole M Jones

doi:10.3389/fnmol.2017.00306

Abstract

Hypoxic-ischemic (HI) encephalopathy occurs in approximately 6 per 1000 term newborns leading to devastating neurological consequences, such as cerebral palsy and seizures. Maternal smoking is one of the prominent risk factors contributing to HI injury. Mitochondrial integrity plays a critical role in neural injury and repair during HI. We previously showed that maternal cigarette smoke exposure (SE) can reduce brain mitochondrial fission and autophagosome markers in male offspring. This was accompanied by increased brain cell apoptosis (active caspase-3) and DNA fragmentation (TUNEL staining). Here, we aimed to investigate whether maternal SE leads to more severe neurological damage after HI brain injury in male offspring. Female BALB/c mice (8 weeks) were exposed to cigarette smoke prior to mating, during gestation, and lactation. At postnatal day 10, half of the pups from each litter underwent left carotid artery occlusion, followed by exposure to 8% oxygen (92% nitrogen). At postnatal day 40–44, maternal SE reduced grip strength in grip traction and foot fault tests, which were also reduced by HI injury to similar levels regardless of the maternal group. Limb coordination was impaired by maternal SE which was not worsened by HI injury. Maternal SE increased anxiety level in the offspring, which was normalized by HI injury. Apoptosis markers were increased in different brain regions by maternal SE, with the cortex having further increased TUNEL by HI injury, along with increased markers of inflammation and mitophagy. We conclude that maternal SE can worsen HI-induced cellular damage in male offspring well into adolescence.

Highlights

Oxygen deprivation before and around the time of birth can result in hypoxic-ischemic (HI) brain damage
Using a mouse model of maternal cigarette smoke exposure (SE), we previously showed that brain markers of mitochondrial fission and autophagy in adult SE offspring, were accompanied by reduced levels of mitochondrial antioxidant manganese superoxide dismutase (MnSOD) suggesting increased oxidative stress (Chan et al, 2017)
We found that maternal SE increased markers of hypoxia, oxidative damage and DNA damage (TUNEL), as well as increased markers of apoptosis in the brains of the SE offspring (Chan et al, 2016b)

Summary

Introduction

Oxygen deprivation before and around the time of birth can result in hypoxic-ischemic (HI) brain damage. In humans, during HI encephalopathy, there is a decrease in blood oxygen saturation and blood flow, interrupting normal fetal brain development (Li et al, 2012a). The cerebral cortex, hippocampus, and sub-ventricular regions are the brain regions most vulnerable to HI damage in Maternal Smoking Worsens Hypoxic-Ischemic Injury rats (Northington et al, 2001). Human studies showed that maternal cigarette smoke exposure (SE) can increase the risk of adverse perinatal outcomes, such as compromised brain development of infants due to maternal anemia and fetal hypoxia (Habek et al, 2002). Cigarette smoking can increase carboxyhemoglobin levels during pregnancy which can reduce the oxygen carrying capacity of both fetal and maternal red blood cells (Cole et al, 1972; Bureau et al, 1983)

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