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

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.

Prenatal electronic cigarette exposure decreases brain glucose utilization and worsens outcome in offspring hypoxic–ischemic brain injury

“…In the foot fault test, we have found that prenatal e‐Cig exposure impairs motor coordination in both sham and HI adolescent offspring. Chan et al showed that prenatal TS exposure impairs limb coordination in adolescent male offspring with HI brain injury which supports our findings (Chan, Saad, Machaalani, et al, ). Our results indicate that maternal e‐Cig exposure combined with HI brain injury could be a significant insult to affect offspring cognitive and motor functions.…”

“…TS has been shown to increase the risk of fetal hypoxia (Habek, Habek, Ivanisevic, & Djelmis, ) and reduce the oxygen carrying capacity of both fetal and maternal red blood cells (Bureau et al, ). Perinatal nicotine and TS exposure have been demonstrated as a significant insult which can also exacerbate the sensitivity of neonatal brain to HI injury (Chan, Saad, Machaalani, et al, ; Froen, Amerio, Stray‐Pedersen, & Saugstad, ; Li, Xiao, et al, ). During neonatal HI brain injury, alterations of brain glucose and energy metabolism occur (Vannucci, Seaman, & Vannucci, ), which can play a crucial role in the short‐ and long‐term outcome of this injury in animals.…”

What lessons have we learnt about the impact of maternal cigarette smoking from animal models?

“…ROS will firstly damage the mitochondria and DNA. Maternal SE is indeed linked to reduced mitochondrial density in multiple brain regions in the male offspring …”

“…The outcomes of HI are a diminished exchange of oxygen and carbon dioxide, and severe lactic acidosis, increasing the risk of cerebral palsy after birth . Studies in rodents using both maternal nicotine administration and SE showed an increase in the vulnerability of the neonatal brain to HI encephalopathy, leading to more severe neurological functional loss in the offspring from nicotine treated/SE dams than those from the control dams, including the risk of cerebral palsy . Indeed, the risk of cerebral palsy is high in individuals whose mothers are heavy smokers (≥10 cigarettes/day) .…”

“…Maternal smoking has been modelled in rodents either using direct cigarette smoke exposure (SE) or nicotine infusion to the mothers, to investigate the development of various disorders in the offspring, including hypoxia–ischemia (HI) induced brain injury and cognitive changes . Such studies aimed to understand the underlying mechanisms and investigate potential interventional strategies to mitigate the adverse impact of maternal cigarette smoking on the offspring.…”