Neuroscience of Nicotine: Mechanisms and Treatment

Kingdom

Chapter 1

Understanding Tobacco Use in Different Countries

Fabrizio Ferretti    School of Social Sciences, Department of Communication and Economics (DCE), University of Modena and Reggio Emilia (UNIMORE), Reggio Emilia, Italy

Abstract

Understanding the economic determinants of tobacco consumption and measuring tobacco use across countries are essential to design and implement effective tobacco prevention programs. This chapter is a brief guide to some basic concepts of tobacco epidemiology and economics. Firstly, we introduce the main indicators usually employed to assess tobacco consumption in a given population. Secondly, we develop a simple demand model to illustrate how prices, consumers’ income and tastes, and tobacco control measures interact in determining the quantity consumed and the number of smokers. Finally, we use the latest estimations available to provide an overview of tobacco use worldwide.

Keywords

Cigarettes consumption; Price elasticity; Smoking intensity; Smoking prevalence; Tobacco demand

Abbreviations

CDC 

Centers for Disease Control and Prevention, United States

NIH 

National Institutes of Health, United States

OECD 

Organisation for Economic Co-operation and Development

WBG 

The World Bank Group

WHO 

World Health Organization

GBD 

Global Burden of Diseases

IARC 

International Agency for Research on Cancer

1.1 Introduction

There is a good variety of tobacco-based products that allow people around the world to consume tobacco in many different forms, according to local preferences and customs. For instance, tobacco products may be combusted (e.g., cigarettes and bidis), heated (e.g., water pipes and hookah), or even taken orally or nasally (e.g., snuff, betel quid, and chewing tobacco). Each population has its own cultural traditions—for example, bidis in India or hookah and snuff in the Middle East and South Asian countries, respectively (Hammond, 2009, p. 3).

However, along with industrialization, urbanization, and globalization, the consumption of manufactured cigarettes has grown sharply and spread across virtually all countries over the last century. As a result, cigarettes nowadays have become the predominant form of tobacco use worldwide, accounting for about 92% of total tobacco product sales globally. This is why in tobacco epidemiology, looking at current public health challenges, the terms tobacco use and cigarette smoking are often used as synonyms (NIH, 2016, chap. 2).

1.2 Basic Concepts of Tobacco Epidemiology

In each population, the magnitude and pattern of tobacco consumption result from the interplay between various individual and collective influences (Warner & MacKay, 2006). An adapted epidemiological triangle model of agent, host, vector, and environment, as depicted in Fig. 1.1, provides a useful framework to describe and conceptualize these complex relationships (Penn State, 2016; Slade, 1993, chap. 1). Tobacco—in the form, for instance, of cigarette smoking—acts as the agent (i.e., the necessary factor that is required for a disease to occur, although it may not inevitably lead to disease). All habitual smokers are hosts who, at least potentially, due to cigarette consumption, may develop one or more tobacco-related diseases (that usually result in disability and death). The tobacco companies play the role of vectors (i.e., anything that transports and disseminates the agent to susceptible individuals) by producing cigarettes and promoting their use within the population to expand the size of the market (i.e., the number of smokers and the number of cigarettes consumed per smoker). Finally, hosts and vectors operate and interact in a social environment determined by the interplay of a wide range of psychological, cultural, legal, and economic factors (Giovino, 2002).

Fig. 1.1 Interactions between agent, hosts, vectors, and environment in tobacco epidemic. From: Penn State. (2016). Epidemiologic Triad. Department of Statistics. Pennsylvania State University. Available at: https://onlinecourses.science.psu.edu/stat507/node/25. Originally adapted from Egger, G., Swinburn, B., & Rossner, S. (2003). Dusting off the epidemiological triad: could it work with obesity? Obesity Reviews 4(2), 115–119.

Given the outstanding role of tobacco as a major risk factor for several chronic noncommunicable diseases (such as cardiovascular and respiratory diseases and many types of cancer), measuring the distribution and intensity of tobacco use across the world is crucial for (1) better understanding the determinants of smoking behavior, (2) developing effective public health programs, and (3) monitoring countries’ progress (GBD, 2015). Overall, to study the pattern of tobacco use and to simulate the impact of tobacco control policies in specific populations, epidemiologists rely today on aggregate (i.e., compartmental) and individual (i.e., agent-based) comprehensive and sophisticated models (CDC, 2014, chap. 15). However, the bread and butter of monitoring tobacco use at country level and over time still consists of measuring (or better estimating) two key health policy variables—the prevalence of smoking and the intensity of smoking—by using either a direct and an indirect approach or both (IARC, 2008, chap. 3).

The prevalence of smoking in a given population is usually assessed using a direct approach—that is, by asking a sample of representative subjects their smoking status and behavior (Bonnie, Stratton, & Wallace, 2007). These surveys provide information about the identity of smokers (e.g., age, gender, ethnicity, educational attainment, and income levels) and about each smoker's habits and attitudes. Specifically, according to self-reported information, respondents are classified, as shown in Fig. 1.2, into three main categories: never, current, and former smokers (CDC, 2014, chap. 15). The number of people in each group is a stock variable (i.e., a quantity measured at a given point in time). Monitoring of the population under study over time gives the number of smoking initiations, cessations, and relapses. These are flow variables (i.e., quantities measured over a period of time) that represent the amount of change in each stock during a given time lapse (for instance, a year).

Fig. 1.2 Stock and flow variables in tobacco epidemiology.

Data on stock and flow variables are more meaningful if converted into rates by dividing the number of cases in a given category (e.g., the number of smokers) by the corresponding number of people in the population at risk (the sum of never, current, and former smokers), where both the numerator and denominator may refer to the entire sample under study (usually composed of the population aged 15 and over) or to a specific subset, disaggregated by sex, gender, age, and so on (Bonita, Beaglehole, & Kjellstrom, 2006, chap. 2). Advanced statistical techniques are usually applied to gather results from different surveys of a given population to obtain country-level estimates of the prevalence of smoking. Within this framework, the prevalence rate of smoking among the general population provides information on the proportion of current tobacco users in a given country. Finally, these national simple (crude) rates are age-standardized to allow fair comparisons across countries with populations of different age structures (WHO, 2015).

Tobacco use surveys also register self-reported data on the number of cigarettes consumed per day by each smoker. These figures, combined with prevalence data, yield estimates of the total number of cigarettes consumed in the population under study over a given period of time (usually a year). Total cigarette consumption is a basic indicator of the size of the tobacco market in a given economy. Dividing aggregate consumption by the country's number of smokers gives the average number of cigarettes consumed by each smoker. This is a useful country measure of the intensity of smoking, typically expressed as mean daily consumption—that is, the number of cigarettes consumed by the average smoker per day (Guindon & Boisclair, 2003). Total and average cigarette consumption, however, are also assessed at country level by using an indirect approach. Indirect estimates are mainly based on national commodity balance-sheet statistics. In fact, the algebraic sum of cigarette production, net exports (i.e., import minus export), and change in inventories provides a measure of apparent tobacco consumption, being the quantity of cigarettes theoretically available for domestic consumption. In developed countries, these estimates are often integrated with data from tobacco tax revenue statistics. The ratio between the total annual apparent consumption and the population aged 15 or older measures the country's cigarette consumption per capita (WHO, 2017).

Overall, both the direct and the indirect approach have strengths and weaknesses. The indirect approach is a relatively easy way to generate basic statistics that give an overview of tobacco consumption in different countries, whereas the direct approach, although more challenging, provides information on the identity (e.g., sex, age, and gender) of smokers and distinguishes between the prevalence and the intensity of smoking (i.e., between the number of smokers and the consumption per smoker) by allowing in-depth epidemiological investigations into the pattern and evolution of tobacco use within and between countries (Lopez, Neil, & Tapani, 1994).

1.3 The Demand for Tobacco Products: A Brief Introduction

In a market-oriented economy, cigarettes and other tobacco-related products, like any manufactured product, are typically available to current and potential consumers for a price. Price, however, is only one of the many variables affecting consumers’ willingness to buy. Consumers’ incomes and tastes, the prices of related goods (complements and substitutes, such as alcohol and electronic cigarettes), and tobacco control policies are among the main factors that influence how many cigarettes (or tobacco-related products) consumers buy in a given market and period of time (Gallus, Schiaffino, LaVecchia, Townsend, & Fernandez, 2006). With so many interrelated factors influencing the demand, some abstraction is needed to understand the determinants of tobacco consumption in different countries. In economics, this problem is mainly approached by first analyzing the effect of price changes on quantity demanded—holding constant all other factors that may influence purchases—and then by examining the impact on consumption of changes in any variables other than price (for instance, disposable income or mandatory health warnings), considered one at a time (Mankiw, 2012, chap. 4).

The result of this thought experiment is a fundamental tool in economic analysis: the demand-curve model. Broadly speaking, a demand curve describes the relationship between the quantity of a good that consumers are willing to buy and the good's price, holding constant everything else that influences how much of the good consumers want to buy. This relationship can be written as an equation, such as Q = D(P; Z), where Q and P denote quantity and price, respectively; Z is a vector (i.e., a list of variables) used to account for all factors other than price that affect the demand; and D( ) is the function expressing how the variables in parentheses determine the quantity demanded (Allen, Doherty, Weigelt, & Mansfield, 2005, chap. 3). The relationship can also be graphically depicted, as in Fig. 1.3A, which shows a simplified demand-curve model for cigarettes.

Fig. 1.3 (A and B) The market demand for cigarettes.

P, market price; Q, quantity demanded; PRD, reservation price; PT, market price plus tax (t); PH, market price plus tax (t) and health costs (H).

Specifically, in Fig. 1.3A, the horizontal axis measures Q, the quantity of cigarettes demanded in the market under study during a specified period, while the vertical axis measures P, the country's average price of cigarettes. The blue curve labeled D1 shows the quantity demanded at different prices, under the assumption that there is no change in any other factors—listed in Z—that might also influence Q. For instance, if the price is P1, then the quantity demanded will be equal to Q1. By dividing this total quantity of cigarettes consumed in the market under study by the corresponding population at risk (i.e., the population aged 15 or older) or by the estimated number of smokers, we obtain the two main country-level indicators of the intensity of smoking described in the previous section—that is, the average cigarette consumption per capita or per smoker, respectively.

1.3.1 Price Elasticity and Changes in Quantity Demanded

Numerous studies have established that the demand for cigarettes is generally downward sloping—that is, it follows the law of demand (Perucic, 2015). In other words, a lower price tends to encourage current smokers—who are already buying cigarettes—to consume larger quantities, and it may also allow potential smokers, who were previously unable to afford cigarettes, to start smoking. This means that, other things being equal, a lower price (for instance, P2, in Fig. 1.3A) leads to an increase in either the intensity of smoking or the prevalence of smoking or both (consumption increases from Q1 to Q2). The shape and position of the demand curve reflect the degree to which changes in cigarette price affect the number of smokers and the number of cigarettes consumed per smoker. To measure the responsiveness of the quantity demanded to changes in price, economists usually compute the price elasticity of demand, being the ratio between the percentage change in quantity demanded and the percentage change in price (Allen et al., 2005, chap. 3).

For example, if the total number of cigarettes demanded, other things being equal, decreases by 6% in response to an increase in the average market price of 8%, then the price elasticity of demand is (− 6%)/(8%) = − 0.75. The demand for cigarettes is typically relatively inelastic—that is, a price increase causes a less than proportionate fall in the quantity demanded. According to recent estimates, the average price elasticity of cigarettes ranges from − 0.3 to − 0.5 so that a price rise of 10% reduces the quantity demanded, on average, by 4% (Chaloupka & Warner, 2000).

1.3.2 Changes in Demand and Income Elasticity

A change in price, other things being equal, leads to a change in the quantity demanded—that is, a movement along a given demand curve (for instance, from point F to point E along the D1 curve in Fig. 1.3A). Conversely, a change in any factor other than price causes a change in the demand—that is, a shift of the entire demand curve (for instance, a rightward shift in the demand from D1 to D2, as shown in Fig. 1.3A). The latter is a change in the market conditions. The new demand curve D2, depicted in red, implies a greater quantity of cigarettes demanded by consumers at any given price.

The distinction between a movement along the demand curve (due to a change in price) and a shift of the demand curve (due to a change in any other variable, such as income and taste) is also crucial for a better understanding of the impact of tobacco control policies on cigarette consumption. A tax on cigarettes, for example, by raising the market price, discourages cigarette consumption but affects only the quantity demanded, whereas better education about smoking's adverse health effects reduces consumption by structurally decreasing the demand for cigarettes (this is shown in Fig. 1.3A by the leftward shift of the demand curve from D2 to D1). A strategy of price reduction by tobacco companies may completely offset the effects of a tax on cigarettes but not those of an education program, because, if successful, the program will lower the quantity demanded at any given price.

Besides taste, regulation, and the price of related goods, populations’ smoking habits and behaviors are mainly affected by the level and distribution of consumers’ income. As with changes in any factor other than price, changes in disposable income affect consumption by shifting the demand curve. However, an increasing income per capita might shift the demand curve right or left (i.e., from D1 to D2 or vice versa, in Fig. 1.3A) and therefore increase or decrease the consumption of cigarettes.

The income elasticity of demand—computed as the ratio of the percentage change in quantity demanded to the percentage change in income—is a measure of how and to what extent the quantity consumed responds to a change in consumers’ income, other factors being equal. This coefficient is important in determining differences in cigarette consumption between countries. If the income elasticity is positive, cigarettes are a normal good (i.e., a good for which the quantity demanded rises when income rises). In such a context, economic development tends to increase the number of smokers and the consumption per smoker, exacerbating the incidence of tobacco health-related problems. Otherwise, negative income elasticity indicates that cigarettes are an inferior good (i.e., a good whose quantity demanded falls as income rises). In the majority of developed countries, over the last decades, cigarettes have generally moved from being a normal good (with an income elasticity less than 1—around 0.5) to being an inferior good. In many developing countries, however, manufactured cigarettes, as opposed to the traditional forms of tobacco consumption, still have a positive and large income elasticity (Wilkins, Yurekli, & Hu, 2007, chap. 3).

1.3.3 Using the Demand Model to Understand Smoking Prevalence

This basic demand model can be further developed to take into account other specific features of tobacco consumption (Phillips, 2016). To this aim, in Fig. 1.3B, the x-axis measures the number of actual and potential smokers, S, and the y-axis measures the reservation price, PRD (i.e., the highest price that each consumer will accept to pay). Along the downward-sloping demand curve (the D curve, depicted in blue), consumers are placed in descending order according to their willingness to pay. In other words, the height of each point on the D curve indicates the reservation price of a given consumer. This demand curve for cigarettes intersects the x-axis at point R, beyond which it becomes horizontal. The difference between ST (the population at risk) and S4 gives the number of consumers whose reservation price is zero (i.e., those individuals who would not choose to smoke even if cigarettes were available for free). Conversely, the behavior of the remainder of consumers (those to the left of S4) is the function of the total cost of smoking: the sum of cigarettes’ free-market price, taxes, and smoking health-related costs.

If there were no information (or education) about the health risks of smoking and the government did not undertake any tobacco control policies, the total cost of smoking would simply be P, the cigarettes’ free-market price. In such a society, all consumers whose willingness to pay is greater than (or equal to) P would choose to smoke (S3 in Fig. 1.3B). The ratio between the number of smokers and the population at risk (in this case, S3/ST) indicates the rate of prevalence of smoking (as described in the previous section). An increase in the price of cigarettes (up to PT = P + t) due to an excise tax (t) leads to a lower prevalence rate by decreasing the number of smokers to S2. However, the sum of the free-market price and taxes represents only a small fraction of the total cost of smoking. A sharp reduction in smoking prevalence is mainly the result of a widespread awareness of the serious health effects of tobacco use. This is shown in Fig. 1.3B by the decline in the number of smokers until S1, when consumers take into account the full cost of smoking, PH = P + t + H (where H denotes the health-related costs).

A positive and significant prevalence rate of smoking (measured here by the ratio S1/ST), despite the well-known harmful effects of cigarette consumption, highlights one of the main features of tobacco use: addictiveness. From an economic standpoint, the addiction to tobacco is quite similar to other drug addictions, being based on the same three key dimensions: tolerance, reinforcement, and withdrawal. Specifically, tolerance implies a gradual adaptation—that is, current consumption tends to become less satisfying as cumulative past consumption increases. Reinforcement reflects the key role of smoking habits in current smokers’ behavior, whereas withdrawal means some degree of irreversibility of tobacco consumption (i.e., quitting smoking is normally not easy or costless). As a result, consumption in the current period becomes a function of past consumption choices.

A way to capture addiction in a basic model is by writing the equation of the demand curve as Q = D(P; Q⁎, Z), where Q⁎ measures the cumulative sum of cigarettes consumed in previous periods. The concept of addiction may help in explaining some specific properties of the demand for cigarettes, such as (1) the irreducible high level of long-standing smokers’ willingness to pay; (2) the greater responsiveness of long-term demand to changes in price and income (i.e., both price and income elasticity tend to increase the longer the time available to consumers to modify their health-related habits is); and (3) the rise of various alternative tobacco products, like electronic cigarettes (IARC, 2011, chap. 4).

Finally, given the high tangible (medical expenditure) and intangible (the loss of quality of life and loss of life) costs that tobacco use imposes on individuals and societies, even a number of smokers equal to S1 are likely to result in a market failure (i.e., an inefficiency condition that occurs when the individual pursuit of self-interest leads to bad results for society as a whole). Tobacco markets are indeed characterized by two main sources of inefficiency: (1) There is an information failure about both the health risks of smoking and the addictive nature of tobacco consumption, and (2) smoking imposes costs on nonsmokers and on health systems. There is thus an economic rationale for tobacco control measures (besides taxes) that aim to decrease not only the quantity demanded but also and foremost the demand for cigarettes (i.e., measures that shift leftward the D curve), such as a smoking ban in public places, mandatory health warnings on packages, and the prohibition of cigarette advertising (Nguyen, Rosenqvist, & Pekurinen, 2012).

1.4 An Overview of Tobacco Use in Different Countries

According to recent comprehensive estimations and projections (Ng et al., 2014; NIH, 2016, chap. 2), at the time of writing, there are about 1.11 billion smokers (aged 15 or older) worldwide. Around half of them live in the Western Pacific and South East Asia regions, especially in three countries—China, India, and Indonesia—that together account for nearly 45% of the global number of smokers. Gender plays a key role in determining smoking habits. About 85% (938 million) of all smokers are males who live in developing countries. Conversely, female smokers are 175 million, and around 46% are inhabitants of high-income OECD countries.

The total number of smokers has remained quite stable during the last decade, but it is projected to rise to 1.15 billion in 2025. This increase is mainly due to the population growth expected to occur in developing countries. The prevalence of smoking, in contrast, is declining in the vast majority of the world's regions, except for the male population in the Eastern Mediterranean and African WHO regions (where the prevalence rates are around 36% and 26% and are predicted to reach 45% and 34%, respectively, over the next 10 years). Globally, the prevalence of smoking was around 26% 17 years ago; this has declined gradually to about 20% in 2015. The Russian Federation, China, and several European countries (Fig. 1.4) still have prevalence rates well above the world average. For example, in Eastern Europe and Russia, nearly one-third of the adult population (both sexes combined) currently smoke (Ng et al., 2014; NIH, 2016, chap. 2).

Fig. 1.4 Smoking prevalence (age-standardized rate, both sex), 2015.

SMOPRE, smoking prevalence. Source: Author's calculation on Ng et al. (2014).

An estimation of the number of cigarettes consumed indicates that about 5.8 trillion cigarettes were smoked worldwide in 2014. The first six countries for the total number of cigarettes consumed (i.e., China, Russian Federation, India, United States, Indonesia, and Japan) account for around 60% of the total world consumption. There has been an increase in the global number of cigarettes consumed since 2000, mainly due to the increasing consumption registered in several Western Pacific and Eastern Mediterranean countries. The intensity of smoking—measured by the annual per capita cigarette consumption among adults (people aged 15 and older)—has globally declined during the last 10 years, from about 1200 to 1000 cigarettes per person and per year. This basic indicator of tobacco addictiveness is especially declining in OECD countries, where the average consumption was substantially higher than the world average in 2000 (around 2200 cigarettes per capita) and has fallen sharply to about 1400 in 2015. Mean annual consumption is over 2500 cigarettes per capita in some Balkan and Eastern European countries (Fig. 1.5), such as Croatia (2771), Belarus (2896), and the Russian Federation (2838). Furthermore, consumption per capita is around 2000 cigarettes not only in small Mediterranean countries (Greece, Lebanon, and Cyprus) but also in large population countries—for example, Saudi Arabia, South Korea, and especially China (Eriksen, Mackay, Schluger, Gomeshtapeh, & Drope, 2016; Ferretti, 2015; Ng et al., 2014; NIH, 2016, chap. 2).

Fig. 1.5 Number of cigarettes smoked: mean annual consumption per capita, 2015.

CIGPC, cigarettes per capita. Source: Author's calculation on Ng et al. (2014).

Finally, one key driver of cigarette consumption is affordability—usually measured as the ratio between the price of a pack of cigarettes and the daily average disposable income (both expressed in a common currency to account for cross-country differences in cost of living)—that captures the amount of resources (money or labor time) that the country's average consumer has to give up to smoking. Recent evidence suggests that cigarettes are becoming more affordable in developing countries than in developed ones, mainly as a result of the rapid increase in income per capita in emerging economies and the growing burden of excise tax on the price of cigarettes in almost all high-income countries (Blecher & van Walbeek, 2008).

Mini-Dictionary of Terms

Cigarette affordability A measure of the quantity of resources (in terms of money or time) required to buy a pack of cigarettes.

Demand curve for cigarettes The relationship between the quantity that consumers demand and the price of cigarettes, holding constant the other factors that influence purchase such as consumers’ income and tastes, the price of related goods, and government regulation.

Normal (inferior) good A good for which quantity demanded increases (decreases) when income rises.

Price elasticity of cigarettes The percentage change in quantity demanded resulting from a 1% change in the price of cigarettes (other things being equal).

Smoking intensity The ratio between the total number of cigarettes consumed and the number of smokers in a given country and year.

Smoking prevalence The ratio between the number of smokers and the population at risk in a given country and year.

Key Facts on Tobacco Use

•Tobacco may be consumed in different forms. Nowadays, however, manufactured cigarettes account for more than 90% of the total world sales of tobacco products.

•There are around 1.11 billion smokers worldwide. About half of them live in the Western Pacific and South East Asia regions and especially in three countries: China, India, and Indonesia. The total number of smokers is increasing slowly due to the population growth in developing countries.

•Gender matters in global smoking habits. About four-fifths of the world smokers are males who live mostly in developing countries. Conversely, female smokers number around 175 million, and more than 40% of them are inhabitants of developed countries.

•The global prevalence of smoking is around 21%, and it has been declining over the last decade, especially in highly developed OECD countries. However, the prevalence of smoking is predicted to rise during the coming years in African and Eastern Mediterranean countries. The rate of prevalence is particularly high (on average above 25%) in the Russian Federation, China, and several Eastern European countries.

•During recent years, cigarettes have become much less affordable in advance economies due to excise tax and generally more affordable in emerging economies, where smokers’ income is rising more than the average price of cigarettes.

•The intensity of smoking has declined steadily since 2000. A major reduction in cigarette consumption per capita has been registered in OECD countries (from 2240 cigarettes per person in 2000 to 1450 cigarettes per person in 2013). However, mean annual consumption is above 2500 cigarettes per capita in some Balkan and Eastern European countries such as Croatia (2771), Belarus (2896), and the Russian Federation (2838).

Summary Points

•This chapter is a brief guide to some essential concepts of tobacco economics and epidemiology.

•A triangle model of agent (smoke), hosts (smokers), vectors (tobacco companies), and social environment is used to describe the interaction between smoking determinants in a given population.

•There are two fundamental measures of tobacco use in a given country: smoking prevalence and smoking intensity.

•Changes in the price of cigarettes—due, for instance, to excise tax—lead to changes in the quantity demanded (i.e., movements along a given demand curve), whereas changes in consumers’ income and tastes or in tobacco regulation policies lead to changes in demand (i.e., shifts of the entire demand curve).

•The demand for cigarettes tends to be relatively inelastic to changes in price, especially in the short run. Cigarettes often behave as an inferior good in developed countries and as a normal good in developing ones.

References

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Chapter 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

Abstract

Although it is well known that maternal cigarette smoke exposure is detrimental to the health of children, more than 20% of women continue to smoke during pregnancy. Children exposed to maternal smoking in utero have changes in their brain structure and size, often accompanied by cognitive defects. This may be due to increased brain oxidative stress and inflammatory response in the neonatal period, leading to neuron damage in adulthood. The mitochondria, a major source of cellular oxidative stress, are particularly vulnerable to the damage caused by the free radicals they produce. Interestingly, the female offspring seem to be protected by such adverse impact of maternal smoking. This chapter will specifically review the changes in brain inflammation and oxidative stress and the mechanism of mitophagy machinery. Potential therapeutic strategies will be suggested to mitigate the impact of maternal smoking.

Keywords:

Oxidative stress; Mitophagy; Oxidative phosphorylation; Antioxidants

Abbreviations

Drp 

dynamin-related protein

Fis 

fission protein

HI 

hypoxic-ischemic

LC 

microtubule-associated protein light chain

MnSOD 

manganese superoxide dismutase

NO 

nitric oxide

Opa-1 

optic atrophy 1 protein

OXPHOS 

oxidative phosphorylation

Pink 

PTEN-induced putative kinase

ROS 

reactive oxygen species

SE 

cigarette smoke exposure

TLR 

Toll-like receptor

TOM 

translocase of mitochondrial outer membrane

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.

2.2 Maternal Smoking and Brain Development

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.

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 dose-dependent 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).

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.

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 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.

2.5.2.2 Antioxidant Defense System

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 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).

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.

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).

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.

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).

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, 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, Acaz-Fonseca, 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 (Santos-Galindo 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.

Table 2.1

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.

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 (Gülçin, 2006). l-Carnitine acts as an energy carrier in the mitochondrial inner membrane to control acetyl-CoA supply and support OXPHOS complex activities (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 (Gülçin, 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-stress-induced mitochondrial dysfunction in the offspring of smokers.

Table 2.2

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.

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.

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 hypoxic-ischemic 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.

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