The effects of maternal cigarette smoke exposure on brain health in offspring

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There are approximately 1 billion smokers worldwide with three million in Australia. Cigarette smoking contributes to a number of chronic diseases such as cardiovascular and cerebrovascular diseases. Although it is well known that maternal cigarette smoke exposure (SE) is detrimental to the health of offspring, more than 20% of women still smoke when they are pregnant. Previous studies only focused on brain structure, sizes and aetiology of the offspring from the smokers. However, none have investigated the impact of maternal smoking on the markers of inflammation, oxidative stress and mitochondrial wellbeing in the offspring’s brain, whereas maternal smoking during pregnancy is linked to brain hypoxia-ischemic injury in the neonates and resulting cerebral palsy and associated disabilities in children. Mitochondrial integrity may play a key role, as they are the major powerhouse of the cells and vulnerable to increased oxidative stress. Mitophagy is a selective removal of damaged mitochondria by autophagy facilitated by fission and fusion. The former divides mitochondrion into healthy and damaged fragments; while the latter combines the healthy fragments to regenerate new mitochondria. Abnormal level of mitophagy markers have been observed in neurological conditions, such as stroke. Thus, this thesis aimed to study (1) the impact of maternal cigarette smoke exposure on brain markers of inflammation, oxidative stress, and mitophagy in both dams and offspring at different ages; (2) the gender differences in response to maternal SE; (3) the impact of maternal L-Carnitine (antioxidant) supplementation during pregnancy and lactation on brain mitophagy and autophagy markers in offspring, and; (4) the impact of maternal SE on hypoxic ischemic (HI) injury in male offspring. Virgin female Balb/c mice (6 weeks) were exposed to cigarette smoke (SE) or air (SHAM) 6 weeks prior to mating, during gestation and lactation. They were mated with male Balb/c mice (8 weeks). The pups were sacrificed at postnatal day (P) 1, P20 and 13 weeks for Aims 1-3 and P45 for Aim 4. In aim 4, hypoxic ischemic injury was induced in half of the litters via left carotid artery occlusion. Behaviour tests (novel objective recognition test, error ladder, grip test, and elevated plus maze test) were carried out in offspring with HI injury at P40 to assess motor and cognitive functions. The dams were sacrificed when the pups weaned. The brains of both dams and offspring were analysed by western blotting, immunohistochemistry, and real-time PCR for markers of inflammation, oxidative stress and mitochondrial wellbeing. It was found that brain inflammatory markers were increased in adult male SE offspring at 13 weeks, but not changed in female offspring by maternal SE. Brain endogenous antioxidant was reduced in male offspring, which was increased in female offspring by maternal SE. Mitochondrial oxidative phosphorylation (OXPHOS) complexes I, III and V were increased by maternal SE in male offspring but all OXPHOS complexes (I-V) were increased in female SE offspring. Brain cell damage was increased in male offspring but not in female offspring by maternal SE. Maternal L-Carnitine supplementation partially reversed the above-mentioned impacts of maternal SE in offspring’s brain, including brain cell injury. HI injury reduced motor and cognitive functional outcomes in both SHAM and SE offspring but maternal SE did not worsen it. However, HI injury increased brain inflammatory markers in SE offspring, as well as mitochondrial fission markers. Autophagy and mitochondrial fusion markers were reduced by HI injury in male SE offspring. Apoptotic markers were also increased in SE offspring with HI injury. In conclusion, maternal SE had adverse impact on the brain health in offspring with more impact on male offspring than females. Maternal L-Carnitine supplementation seems to partially reverse such maternal impact. Maternal SE can worsen the cellular outcome in the offspring’s brain. Interventions to improve mitochondrial function may be plausible to mitigate the adverse impact of maternal SE.
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