Maternal Smoking and Fetal Brain Outcome: Mechanisms and Possible Solutions

C H A P T E R

2 Maternal Smoking and Fetal Brain Outcome: Mechanisms and Possible Solutions Hui Chen*, Yik Lung Chan†, Brian G. Oliver*,†, Carol A. Pollock‡, Sonia Saad‡ *School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, The University of Sydney, Glebe, NSW, Australia ‡ Renal Group, Department of Medicine, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia †

2.2 MATERNAL SMOKING AND BRAIN DEVELOPMENT

Abbreviations Drp Fis HI LC MnSOD NO Opa-1 OXPHOS Pink ROS SE TLR TOM

dynamin-related protein fission protein hypoxic-ischemic microtubule-associated protein light chain manganese superoxide dismutase nitric oxide optic atrophy 1 protein oxidative phosphorylation PTEN-induced putative kinase reactive oxygen species cigarette smoke exposure Toll-like receptor translocase of mitochondrial outer membrane

Despite the general education on the risks of smoking during pregnancy, it is estimated that approximately 20%–45% of women still smoke during pregnancy in some countries, while the rate is even higher in certain indigenous communities. Additionally, 82% of the world’s population is not protected from secondhand smoking, including pregnant women. Maternal smoking/cigarette smoke exposure (SE) is a major contributor to intrauterine growth restriction, low birth weight, perinatal morbidity and mortality, and long-term consequences in the offspring, including behavioral problems (Chen & Morris, 2007). The vasoconstriction effect of nicotine reduces placental blood flow resulting in intrauterine shortage of nutrients and oxygen that restricts fetal growth and subsequently permanently changes the physiological functions. Although the brain receives priority nutrition delivery, smoking during pregnancy is closely linked to small brain weight, frontal lobe, and cerebellar volumes (Fig. 2.1). Maternal nicotine administration alone does not seem to change brain size in the offspring (Grove et al., 2001), whereas maternal SE reduced brain size at birth (Chan, Saad, Pollock, et al., 2016). Clearly, other chemicals in cigarette smoke play a critical role in fetal brain underdevelopment. Due to the complex nature of more than 5000 chemicals in tobacco smoke, it is unlikely that one single component will cause all pathologies.

2.1 INTRODUCTION There has been a rapid advancement in the understanding of fetal programming of diseases in adulthood. Changes in certain gene expression at birth can persist until adulthood, which significantly increase the susceptibility to certain diseases. This highlights the critical role of the ideal intrauterine environment to optimize fetal health outcomes. Maternal smoking can disturb the stability of the intrauterine environment, leading to brain inflammatory response and oxidative stress in the offspring. This can result in neonatal hypoxic-ischemic (HI) injury and adulthood cognitive change, such as depression and anxiety.

Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00002-2

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2. MATERNAL SMOKING AND FETAL BRAIN OUTCOME: MECHANISMS AND POSSIBLE SOLUTIONS

FIG. 2.1 Birth outcome of maternal smoking. Maternal smoking reduces the birth weight and brain size in the newborn offspring.

2.3 MATERNAL SMOKING AND NEUROCOGNITIVE OUTCOME Maternal smoking causes long-lasting adverse effects on the structural and functional development of the fetal brain leading to cognitive disorders (Bublitz & Stroud, 2012). Small brain volume significantly correlates with lower intelligent quotient (Haier, Jung, Yeo, Head, & Alkire, 2004), while verbal ability positively correlates with cerebral volume (Witelson, Beresh, & Kigar, 2006). In humans, 13–16-year-old offspring from the smoking mothers had lower verbal and visual memory abilities than those from nonsmokers (Fried, Watkinson, & Gray, 2003). Heavy smoking (>20 cigarettes/day) during pregnancy can increase the risk of internalizing behaviors such as fear and anxiety in young children (Moylan et al., 2015). In addition, maternal smoking increases the risk of attention deficit hyperactivity disorder in a dosedependent manner (Altink et al., 2009). Hence, smoking during pregnancy is a significant public health issue. However, some confounding factors, such as socioeconomic status of the parents, alcohol consumption, and paternal smoking, can result in inconsistent findings in humans studies (Moylan et al., 2015). Therefore, animal models have the advantage of removing these confounding factors to determine the impact of maternal smoking alone. There are a limited number of studies on the direct impact of SE, whereas most studies adopted nicotine, limiting the data interpretation. This chapter will focus on the animal models using direct SE.

2.4 MATERNAL SMOKING AND HI ENCEPHALOPATHY Oxygen deprivation before and around birth can result in HI brain damage in newborns ( Johnston & Hoon Jr., 2006). Nicotine reduces blood flow to the placenta. Smoking also increases carboxyhemoglobin levels that can

reduce the oxygen-carrying capacity of both fetal and maternal red blood cells. Thus, maternal smoking has been shown to cause hypoxia in the fetus in animal study (Socol, Manning, Murata, & Druzin, 1982). HI itself can cause cerebral palsy and associated disabilities in children ( Johnston & Hoon Jr., 2006), whereas smoking 10 cigarettes/day during pregnancy has been shown to increase the risk of cerebral palsy (Streja et al., 2013). During HI encephalopathy, blood oxygen saturation and blood flow are decreased, interrupting normal fetal brain development (Li, Gonzalez, & Zhang, 2012). Microglia responds rapidly to hypoxia and accumulates in injured tissues, where excessive amounts of inflammatory cytokines such as TNF-α and IL-1β along with reactive oxygen species (ROS) are produced, leading to inflammation and oxidative stress. In mice, increased brain inflammation and oxidative stress are already present in the offspring from the SE mothers even without injury (Chan, Saad, Pollock, et al., 2016). As such, more cell death occurs when such offspring suffer from HI encephalopathy (Chan et al., 2017). Cerebral cortex, hippocampus, and subventricular regions are the most vulnerable to HI damage. Infarct size is increased in male pups with HI encephalopathy, but not in the females (Li, Xiao, et al., 2012), indicating a gender difference with males more seriously affected.

2.5 POTENTIAL MECHANISMS 2.5.1 Brain Inflammatory Response ROS produced by burning tobacco are not removed by the cigarette filters, leading to the activation of inflammatory pathways in various myeloid and lymphoid cells (Qiu et al., 2017). ROS can also activate macrophages, which further produce more ROS (Rahman & Adcock, 2006). Prolonged systemic inflammation in pregnant smokers also affects the offspring. In adult male offspring of SE mothers, brain pro-inflammatory cytokine IL-6, IL-1α receptor, and Toll-like receptor (TLR) 4 expression are increased (Fig. 2.2) (Chan, Saad, Pollock, et al., 2016). The activation of TLRs stimulates the production of IL-1β and IL-6 in monocytes (Fig. 2.2), which in turn enhances TLR expression via a positive feedback loop. The female offspring had similar changes persistent from weaning to adulthood (Chan, Saad, Al-Odat, et al., 2016). Neuroinflammation plays a crucial role in the development of neurodegeneration. Increased levels of TLR4 and IL-1 can both lead to an elevation of β-amyloid, linking to the development of Alzheimer’s disease. Increased brain IL-6 level is also associated with increased anxiety, autism-like behavior, and the progression of neurodegenerative diseases (Wei et al., 2012). Indeed, increased severity of schizophrenia or autism has been found in

2.5 POTENTIAL MECHANISMS

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2.5.2.2 Antioxidant Defense System

FIG. 2.2 Mechanism of maternal-smoking-induced brain disorder in the offspring. Maternal smoking increases brain inflammation and oxidative stress in the offspring’s brain, while both lead to mitochondrial damage and result in neurological dysfunction.

offspring of smoking mothers who have high blood level of inflammatory cytokines (Ashwood et al., 2011; Potvin et al., 2008).

2.5.2 Brain Oxidative Stress 2.5.2.1 ROS When the cellular production of oxidative molecules overwhelms endogenous antioxidant defense systems, oxidative stress occurs. Brain tissue is especially susceptible to ROS damage since it is a major organ to metabolize oxygen (20% of the body consumption). The increase in ROS has been linked to the increase in permeability of mitochondrial membrane and eventually cell death (Popa-Wagner, Mitran, Sivanesan, Chang, & Buga, 2013). Long-term SE itself can increase oxidative stress and cellular damage in the mother’s brain (Chan, Saad, Pollock, et al., 2016). Breast milk is rich in antioxidants, which can temporarily protect the newborn. However, once the pups gradually wean from the breastfeeding, male offspring start to display increased brain oxidative stress persisting until adulthood, with significant cellular damage in the adult brain (Chan, Saad, Pollock, et al., 2016). Certain toxic chemicals in the cigarette smoke may induce oxidative stress in both mothers and offspring, as maternal antioxidant supplementation can reverse such effects (Chan et al., 2017). Interestingly, female offspring seem to be protected from such adverse impact of maternal smoking (Chan, Saad, Al-Odat, et al., 2016). The potential mechanisms will be discussed in Section 2.6.

There is a complex antioxidant defense system to scavenge excess ROS. This is especially important in the brain as the neurons are vulnerable to oxidative stress. The most crucial antioxidant in the brain is manganese superoxide dismutase (MnSOD), which is present at a higher concentration in the mitochondria than the other intracellular components. Mitochondrial oxidative phosphorylation (OXPHOS) complexes I and III produce ROS during normal energy metabolism; therefore, mitochondrial MnSOD is important for removing excessive ROS. Interestingly, there is an MnSOD surge during late gestation and newborn periods, which is subsequently reduced as mice reach postnatal day 4 (Khan & Black, 2003). Several studies have shown that MnSOD is crucial for neuroprotection, which prevents neuronal apoptosis and reduces ischemic brain injury through preventing mitochondrial dysfunction (Keller et al., 1998). MnSOD levels are increased in peripheral tissues such as esophagus and lung, in order to scavenge overproduced ROS by long-term smoking. To date, only two studies reported brain MnSOD change in response to maternal SE (Chan, Saad, Al-Odat, et al., 2016; Chan, Saad, Pollock, et al., 2016). In the brains from both mothers and adult male offspring, MnSOD levels are reduced (Chan, Saad, Pollock, et al., 2016). An exhaustion of MnSOD can cause mitochondrial and DNA damage due to ROS overproduction in the long term (Chan et al., 2017).

2.5.3 Mitochondrial Function and Integrity Mitochondria are the major site for ATP production. In the brain, there is a high density of mitochondria in neurons due to their high metabolic and energy requirement. Mitochondrial dysfunction has been discovered in a number of neurological disorders such as amyotrophic lateral sclerosis and Alzheimer’s disease, suggesting that healthy mitochondria are critical to maintain nervous health ( Jiang, Wang, Perry, Zhu, & Wang, 2015). 2.5.3.1 Mitochondrial Membrane Functional Units ATP is produced through OXPHOS at mitochondrial cristae facilitated by OXPHOS complexes I–V (Fig. 2.3). Complexes I and II act as the first and second entry points of electrons in the respiratory chain, respectively. Complex III facilitates electron transfer to complex IV, which is a crucial regulator for ATP production. Protons from complexes I, III, and IV drive the conversion of ADP to ATP. Brain levels of all five OXPHOS complexes are increased by long-term SE, suggesting increased demand for energy supply (Chan, Saad, Pollock, et al., 2016). Indeed, brain ATPase activities are reduced by SE (Vani, Anbarasi, & Shyamaladevi, 2015). Although brain

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2. MATERNAL SMOKING AND FETAL BRAIN OUTCOME: MECHANISMS AND POSSIBLE SOLUTIONS

FIG. 2.3 Mitochondrial energy metabolic units. Reactive oxygen species (ROS) is generated by oxidative phosphorylation (OXPHOS) complexes (CI–CV). The proteins enter mitochondria through Tom20 and Tom40. ROS combines with nitric oxide (NO) to form peroxynitrite (RNS), which interacts with nitroxylate to form nitrotyrosine. MnSOD suppresses this process.

complex I and V levels are reduced at weaning, all complexes I–V are increased in adulthood by maternal SE, similar as their mothers, suggesting mitochondrial function may be inheritable from the mother (Chan, Saad, Al-Odat, et al., 2016; Chan, Saad, Pollock, et al., 2016). During the OXPHOS process, 90% of ROS are generated as a by-product in complexes I and III (Fig. 2.3). ROS can form peroxynitrate with nitric oxide (NO), which further causes protein tyrosine nitration to form 3-nitrotyrosine to damage mitochondria (Beal, 1998). MnSOD competes with NO to react with superoxide that prevents the generation of peroxynitrate and 3-nitrotyrosine. Nitration itself can also inactivate MnSOD (Surmeli, Litterman, Miller, & Groves, 2010). When MnSOD is reduced and nitrotyrosine levels are high, mitochondria are less protected from oxidative stress, such as during smoking and maternal SE (Chan, Saad, Pollock, et al., 2016). The translocase of mitochondrial outer membrane (TOM) protein complex is the main entry portal for most mitochondrial protein precursors synthesized in the cytoplasm. Tom40 forms ion channels in lipid bilayers during transportation (Rapaport, Neupert, & Lill, 1997). TOM20 (a peripheral subunit of the TOM40 complex) recognizes and imports the protein precursors, by facilitating protein insertion at the outer mitochondrial membrane. TOM20 can be degraded under oxidative stress. While brain TOM20 is unchanged by SE, in the male offspring, its level is reduced in at weaning but increased in the adulthood by maternal smoking (Chan, Saad, Pollock, et al., 2016). 2.5.3.2 Mitochondrial Integrity Mitochondrial structure is highly dynamic and maintained through “mitophagy.” Phagy means to eat; autophagy means “self-eating,” which is to degrade cellular

constituents to maintain intercellular homeostasis. “Mitophagy” is the removal of mitochondria by autophagy. During autophagy, microtubule-associated protein light chain (LC) forms autophagosome to engulf intracellular components. The conversion of LC3A/B-I to LC3A/ B-II is used as an indicator of autophagic activity, and LC3A/B-II level correlates with autophagosome formation. Maternal SE decreases brain LC3A/B-II levels in both weaning and adult male offspring but increases LC3A/B-II levels in the female offspring at the same ages (Chan et al., 2017). This suggests reduced autophagy capacity in the male versus female offspring. Mitophagy is facilitated by fission and fusion (steps 1 and 2 in Fig. 2.4, respectively). Fission separates damaged mitochondrial portion from the healthy fragment, while fusion combines two healthy fragments to form a new mitochondrion. These two processes are balanced to maintain the overall morphology of the mitochondria. High fusion-to-fission ratio leads to less mitochondria, with an elongated and more interconnected shape; low fusion-to-fission ratio leads to small spheres and short rods of mitochondria, often referred as “fragmented mitochondria.” Failure to trigger mitophagy in the brain can lead to neurodegenerative diseases (Cheung & Ip, 2009). 2.5.3.2.1 FISSION MACHINERY

Dynamin-related protein (Drp)-1 presents at sites of mitochondrial division to separate the damaged mitochondrial fragment (Fig. 2.4, step 1). Fission protein (Fis)-1 anchored at the outer membrane of mitochondrion, which serves as a platform to adapt Drp-1. Following the segregation, PTEN-induced putative kinase (Pink)-1 accumulates on the outer membrane of damaged mitochondrion leading to the recruitment of Parkin (Fig. 2.4, step 3).

2.6 GENDER DIFFERENCE IN THE RESPONSE TO MATERNAL SMOKING

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FIG. 2.4 Mitophagy and autophagy machinery. Mitophagy and autophagy. Damaged mitochondrial fragments are separated from the healthy part facilitated by dynamin-related protein (Drp)-1 and fission protein (Fis)-1. Damaged mitochondria attract PTEN-induced putative kinase (Pink)-1 and Parkin. This complex is then engulfed by microtubule-associated protein light chain (LC3) A/B-I/II to form autophagosome for degradation. The healthy part of a mitochondrion can bind to the healthy part of another mitochondrion through optic atrophy 1 protein (Opa)-1.

Mitochondrial Drp-1 is increased at postnatal day 1 but reduced in adult male offspring by maternal smoking (Chan et al., 2017). Mitochondrial Fis-1 is not increased until postnatal day 20 (weaning age), which is also reduced in the adult male offspring, suggesting reduced fission capacity by maternal smoking. This may be related to reduced brain mitochondrial density due to increased neural apoptosis. On the contrary, Drp-1 is reduced at postnatal day 1 but increased in adult female offspring (Chan et al., 2017). Parkin is also reduced in female offspring at postnatal day 1 and 20, but Pink-1 is somewhat increased in adult female offspring. Such increase is associated with increased mitochondrial MnSOD and reduced apoptotic marker levels. This suggests that increased fission activity can prevent the brain from increased apoptosis induced by maternal smoking in the female offspring. 2.5.3.2.2 FUSION MACHINERY

Optic atrophy 1 protein (Opa-1) regulates fusion process (Fig. 2.4, step 2). Opa-1 knockout mice die at embryonic day 9; thus, Opa-1 is essential for embryonic development (Rahn, Stackley, & Chan, 2013). Mitochondrial fusion appears to protect cells from apoptosis and prolongation of lifespan, although the mechanism is unknown. In response to maternal smoking, brain Opa-1 is significantly reduced in the male offspring at adulthood with increased brain apoptosis, suggesting less healthy

mitochondrial fragments are available for recycling (Chan et al., 2017). A reduction of brain mitochondrial fusion was observed in Alzheimer’s disease (Zhang et al., 2016). Although it has been well studied that smoking itself is closely linked to Alzheimer’s disease and dementia (Anstey, von Sanden, Salim, & O’Kearney, 2007), such risks in the offspring are yet to be investigated in humans. On the other hand, Opa-1 level is increased in the female offspring at postnatal day 1 but unchanged in the adulthood (Chan et al., 2017). This suggests that unknown mechanism promotes mitochondrial fusion machinery to prevent excess brain apoptosis in the female offspring. Similar observation in mitochondrial protection has been found in young women (Azarashvili, Stricker, & Reiser, 2010).

2.6 GENDER DIFFERENCE IN THE RESPONSE TO MATERNAL SMOKING Although the brain structures in men and women are similar, they have different susceptibility to specific neural diseases. Males are more vulnerable to mental illness, such as autism and attention deficit and hyperactivity disorders (Davies, 2014). When females suffer from these brain disorders, they start at an older age than men (Zagni, Simoni, & Colombo, 2016). The male offspring are also more vulnerable to maternal-smoking-induced inflammatory response,

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2. MATERNAL SMOKING AND FETAL BRAIN OUTCOME: MECHANISMS AND POSSIBLE SOLUTIONS

TABLE 2.1 Impact of Maternal SE on Brain Mitophagy in the Offspring

TABLE 2.2 Impact of Maternal L-Carnitine Supplementation on Mitophagy in the Offspring

Gender

Gender

Male offspring

Female offspring

Male offspring

Female offspring

Mitophagy—fission

Mitophagy—fission

No change

Mitophagy—fusion

Mitophagy—fusion

No change

Autophagy

No change

Autophagy

No change

Maternal smoking reduced mitochondrial fission and fusion activities in the male offspring’s brain with no impact on autophagy activity; however, it increased fission, fusion, and autophagy.

Maternal L-carnitine supplementation during pregnancy can improve brain mitochondrial fission and fusion activities in the male offspring from the smoking mothers, while it reduces autophagy in the female offspring.

oxidative stress, mitochondrial injury, and brain apoptosis compared to female offspring. This gender difference is speculated to be driven by estrogen, which has been considered neuroprotective and antiinflammatory and thus protects the female’s brain (Brann, Dhandapani, Wakade, Mahesh, & Khan, 2007). Another role of estrogen is to act as an antioxidant to prevent lipid peroxidation, protein oxidation, and DNA damage (Escalante, Mora, & Bolaños, 2017). Estrogen has also been shown to maintain mitochondrial membrane potential during mitochondrial toxin exposure (Wang, Green, & Simpkins, 2001). In the male and female brains, glial cells react to the environmental insults differently. The astrocytes are the most abundant glial cells, which support nutrition homeostasis and neural transmission of electric impulses. The astrocytes obtained from the males express higher levels of IL-1β mRNA that can result in worse outcomes following neuronal injury (Santos-Galindo, AcazFonseca, Bellini, & Garcia-Segura, 2011). The astrocytes from the females are more resistant to stressors, such as oxidant-induced cell death, than those from the males (Liu, Oyarzabal, Yang, Murphy, & Hurn, 2008). Lipopolysaccharide found in cigarette smoke (Hasday, Bascom, Costa, Fitzgerald, & Dubin, 1999) can increase IL-6, TNF-α, and IL1β mRNA expression in the astrocytes from the males compared to those from the females (SantosGalindo et al., 2011). Similarly, maternal smoking SE increased brain IL-6 in the adult male offspring, but not the females (Chan, Saad, Al-Odat, et al., 2016; Chan, Saad, Pollock, et al., 2016). The gender difference in mitophagy response to maternal smoking has been described in Section 2.5.3 and summarized in Table 2.1.

(Virmani & Binienda, 2004). L-Carnitine also acts as a ROS scavenger that protects MnSOD from oxidative damage, suggesting that it may be useful for improving mitochondrial function (G€ ulc¸in, 2006). L-Carnitine is also neuroprotective. Pretreatment with L-carnitine before mitochondrial toxin exposure can increase the activities of endogenous ROS scavengers to protect against oxidative stress (Virmani & Binienda, 2004). In SE mice mothers, L-carnitine supplementation during gestation and lactation can increase brain MnSOD and TOM20 levels in newborn male offspring, leading to a marked improvement in mitophagy markers in adulthood (summarized in Table 2.2) (Chan et al., 2017). Brain apoptosis and cellular DNA damage are also reduced, suggesting sustained neural protection of L-carnitine against maternal smoking. Similar improvement in brain mitophagy markers has also been observed in the female offspring’s brain. Thus, L-carnitine supplementation might be a good candidate to mitigate oxidative-stressinduced mitochondrial dysfunction in the offspring of smokers.

2.7 L-CARNITINE AS A THERAPEUTIC STRATEGY L-Carnitine is an endogenous natural quaternary ammonium compound found in all mammalian species. It is a vital component for mitochondrial fatty acid oxidation (G€ ulc¸in, 2006). L-Carnitine acts as an energy carrier in the mitochondrial inner membrane to control acetylCoA supply and support OXPHOS complex activities

2.8 CONCLUSION Maternal smoking during gestation and lactation can induce significant inflammatory response and oxidative stress in male offspring’s brain, which impairs mitochondrial integrity leading to cell death. Female offspring seems to be protected from such impact by maternal smoking. Maternal supplementation of L-carnitine has shown promising neural protective effect in the offspring of the smoking mothers.

MINI-DICTIONARY OF TERMS Acetyl-CoA A produce from glycolysis, which is a metabolic intermediate that can convert into carbohydrate, protein, and fat. Apoptosis A programmed cell death in response to stress, such as environmental pollution exposure and smoking. Autophagy Means “self-eating,” which is a strategy for cells to remove damaged proteins by self-digesting. Encephalopathy Brain disease or brain disorders. Hypoxic-ischemic A condition due to reduced oxygen and blood supply, commonly occurs when an artery is blocked.

REFERENCES

Mitochondrion A cellular “powerhouse,” where the energy substance ATP is produced from energy substrate acetyl-CoA and oxygen. Mitophagy Damaged mitochondrial self-eating or self-renewal process to maintain the healthy mitochondrial population in the body. Oxidative phosphorylation When the electrons produced through the citric acid cycle are deposited in the electron transport chain in the inner mitochondrial membrane, they are captured by enzymes to generate ATP. Oxidative stress The production of free radicals, mainly during the process of ATP synthesis, is over the capacity of endogenous antioxidant to clear them from the cell. Reactive oxygen species Chemically reactive chemical species containing additional oxygen molecule that can oxidize other cellular components.

Key Facts of Maternal Smoking • Offspring from smoking mother have brain underdevelopment resulting in impaired learning and memory functions. • Offspring from smoking mother are more likely to have oxygen-shortage- and blood-shortage-induced brain damage. • Male offspring from smoking mother have more brain cell death than the female offspring. • Brain cellular powerhouse mitochondrial function is damaged by maternal smoking. • Female offspring’s brain is more protected from maternal smoking than the male offspring. Summary Points • Maternal smoking delays brain development in the offspring. • Maternal smoking impairs cognitive function in the offspring. • Maternal smoking is linked to high risk of hypoxicischemic encephalopathy. • Maternal smoking increases brain apoptosis in the male offspring. • Maternal smoking increases oxidative stress and impairs brain mitochondrial function in the male offspring. • Female offspring’s brain is more protected from the detrimental impact of maternal smoking than the male offspring.

References Altink, M. E., Slaats-Willemse, D. I. E., Rommelse, N. N. J., Buschgens, C. J. M., Fliers, E. A., Arias-Vásquez, A., et al. (2009). Effects of maternal and paternal smoking on attentional control in children with and without ADHD. European Child & Adolescent Psychiatry, 18(8), 465–475. Anstey, K. J., von Sanden, C., Salim, A., & O’Kearney, R. (2007). Smoking as a risk factor for dementia and cognitive decline: a metaanalysis of prospective studies. American Journal of Epidemiology, 166(4), 367–378.

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Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I., & Van de Water, J. (2011). Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain, Behavior, and Immunity, 25(1), 40–45. Azarashvili, T., Stricker, R., & Reiser, G. (2010). The mitochondria permeability transition pore complex in the brain with interacting proteins - promising targets for protection in neurodegenerative diseases. Biological Chemistry, 391(6), 619–629. Beal, M. F. (1998). Mitochondrial dysfunction in neurodegenerative diseases. Biochimica et Biophysica Acta (BBA): Bioenergetics, 1366(1–2), 211–223. Brann, D. W., Dhandapani, K., Wakade, C., Mahesh, V. B., & Khan, M. M. (2007). Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids, 72(5), 381–405. Bublitz, M. H., & Stroud, L. R. (2012). Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research. Nicotine & Tobacco Research, 14(4), 388–397. Chan, Y. L., Saad, S., Al-Odat, I., Oliver, B. G., Pollock, C., Jones, N. M., et al. (2017). Maternal L-carnitine supplementation improves brain health in offspring from cigarette smoke exposed mothers. Frontiers in Molecular Neuroscience, 10(33). Chan, Y. L., Saad, S., Al-Odat, I., Zaky, A. A., Oliver, B., Pollock, C., et al. (2016). Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring. Clinical and Experimental Pharmacology & Physiology, 43(12), 1168–1176. Chan, Y. L., Saad, S., Pollock, C., Oliver, B., Al-Odat, I., Zaky, A. A., et al. (2016). Impact of maternal cigarette smoke exposure on brain inflammation and oxidative stress in male mice offspring. Scientific Reports, 6, 25881. Chen, H., & Morris, M. J. (2007). Maternal smoking—a contributor to the obesity epidemic? Obesity Research & Clinical Practice, 1, 155–163. Cheung, Z. H., & Ip, N. Y. (2009). The emerging role of autophagy in Parkinson’s disease. Molecular Brain, 2, 29. Davies, W. (2014). Sex differences in attention deficit hyperactivity disorder: candidate genetic and endocrine mechanisms. Frontiers in Neuroendocrinology, 35(3), 331–346. Escalante, C. G., Mora, S. Q., & Bolaños, L. N. (2017). Hormone replacement therapy reduces lipid oxidation directly at the arterial wall: a possible link to estrogens’ cardioprotective effect through atherosclerosis prevention. Journal of Mid-Life Health, 8(1), 11–16. Fried, P. A., Watkinson, B., & Gray, R. (2003). Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology, 25(4), 427–436. Grove, K. L., Sekhon, H. S., Brogan, R. S., Keller, J. A., Smith, M. S., & Spindel, E. R. (2001). Chronic maternal nicotine exposure alters neuronal systems in the arcuate nucleus that regulate feeding behavior in the newborn rhesus macaque. The Journal of Clinical Endocrinology & Metabolism, 86(11), 5420–5426. PMID:11701716. _ (2006). Antioxidant and antiradical activities of l-carnitine. Life G€ ulc¸in, I. Sciences, 78(8), 803–811. Haier, R. J., Jung, R. E., Yeo, R. A., Head, K., & Alkire, M. T. (2004). Structural brain variation and general intelligence. NeuroImage, 23(1), 425–433. Hasday, J. D., Bascom, R., Costa, J. J., Fitzgerald, T., & Dubin, W. (1999). Bacterial endotoxin is an active component of cigarette smoke. Chest, 115(3), 829–835. Jiang, Z., Wang, W., Perry, G., Zhu, X., & Wang, X. (2015). Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis. Translational Neurodegeneration, 4, 14. Johnston, M. V., & Hoon, A. H., Jr. (2006). Cerebral palsy. Neuromolecular Medicine, 8(4), 435–450. Keller, J. N., Kindy, M. S., Holtsberg, F. W., St. Clair, D. K., Yen, H.-C., Germeyer, A., et al. (1998). Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation,

16

2. MATERNAL SMOKING AND FETAL BRAIN OUTCOME: MECHANISMS AND POSSIBLE SOLUTIONS

and mitochondrial dysfunction. The Journal of Neuroscience, 18(2), 687–697. Khan, J. Y., & Black, S. M. (2003). Developmental changes in murine brain antioxidant enzymes. Pediatric Research, 54(1), 77–82. Li, Y., Gonzalez, P., & Zhang, L. (2012). Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions. Progress in Neurobiology, 98(2), 145–165. Li, Y., Xiao, D., Dasgupta, C., Xiong, F., Tong, W., Yang, S., et al. (2012). Perinatal nicotine exposure increases vulnerability of hypoxicischemic brain injury in neonatal rats: role of angiotensin II receptors. Stroke 43(9), 2483–2490. Liu, M., Oyarzabal, E. A., Yang, R., Murphy, S. J., & Hurn, P. D. (2008). A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture. Journal of Neuroscience Methods, 171(2), 214–217. Moylan, S., Gustavson, K., Øverland, S., Karevold, E. B., Jacka, F. N., Pasco, J. A., et al. (2015). The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian mother and child cohort study. BMC Medicine, 13(1), 24. Popa-Wagner, A., Mitran, S., Sivanesan, S., Chang, E., & Buga, A. M. (2013). ROS and brain diseases: the good, the bad, and the ugly. Oxidative Medicine and Cellular Longevity, 2013, 963520. Potvin, S., Stip, E., Sepehry, A. A., Gendron, A., Bah, R., & Kouassi, E. (2008). Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biological Psychiatry, 63(8), 801–808. Qiu, F., Liang, C.-L., Liu, H., Zeng, Y.-Q., Hou, S., Huang, S., et al. (2017). Impacts of cigarette smoking on immune responsiveness: up and down or upside down? Oncotarget, 8(1), 268–284. Rahman, I., & Adcock, I. M. (2006). Oxidative stress and redox regulation of lung inflammation in COPD. The European Respiratory Journal, 28(1), 219–242. Rahn, J. J., Stackley, K. D., & Chan, S. S. (2013). Opa1 is required for proper mitochondrial metabolism in early development. PLoS ONE, 8(3)e59218. Rapaport, D., Neupert, W., & Lill, R. (1997). Mitochondrial protein import. Tom40 plays a major role in targeting and translocation of preproteins by forming a specific binding site for the presequence. The Journal of Biological Chemistry, 272(30), 18725–18731.

Santos-Galindo, M., Acaz-Fonseca, E., Bellini, M. J., & Garcia-Segura, L. M. (2011). Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide. Biology of Sex Differences, 2, 7. Socol, M. L., Manning, F. A., Murata, Y., & Druzin, M. L. (1982). Maternal smoking causes fetal hypoxia: experimental evidence. American Journal of Obstetrics and Gynecology, 142(2), 214–218. Streja, E., Miller, J. E., Bech, B. H., Greene, N., Pedersen, L. H., Yeargin-Allsopp, M., et al. (2013). Congenital cerebral palsy and prenatal exposure to self-reported maternal infections, fever, or smoking. American Journal of Obstetrics and Gynecology, 209(4), 332.e1–332.e10. Surmeli, N. B., Litterman, N. K., Miller, A. F., & Groves, J. T. (2010). Peroxynitrite mediates active site tyrosine nitration in manganese superoxide dismutase. Evidence of a role for the carbonate radical anion. Journal of the American Chemical Society, 132(48), 17174–17185. Vani, G., Anbarasi, K., & Shyamaladevi, C. S. (2015). Bacoside A: role in cigarette smoking induced changes in brain. Evidence-based Complementary and Alternative Medicine: eCAM, 2015, 286137. Virmani, A., & Binienda, Z. (2004). Role of carnitine esters in brain neuropathology. Molecular Aspects of Medicine, 25(5–6), 533–549. Wang, J., Green, P. S., & Simpkins, J. W. (2001). Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. Journal of Neurochemistry, 77(3), 804–811. Wei, H., Chadman, K. K., McCloskey, D. P., Sheikh, A. M., Malik, M., Brown, W. T., et al. (2012). Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochimica et Biophysica Acta (BBA): Molecular Basis of Disease, 1822(6), 831–842. Witelson, S. F., Beresh, H., & Kigar, D. L. (2006). Intelligence and brain size in 100 postmortem brains: sex, lateralization and age factors. Brain, 129(2), 386–398. Zagni, E., Simoni, L., & Colombo, D. (2016). Sex and gender differences in central nervous system-related disorders. Neuroscience Journal, 2016, 2827090. Zhang, L., Trushin, S., Christensen, T. A., Bachmeier, B. V., Gateno, B., Schroeder, A., et al. (2016). Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s disease. Scientific Reports, 6, 18725.