TOBACCO INDUCED DISEASES Vol. 3, No. 2:5-16 (2006) © PTID Society

Exposure to Smoke During Development: Fetal Programming of Adult Disease

Hugo T. Bergen

Dept. of Human Anatomy & Cell Science, University of Manitoba,

ABSTRACT: It is well established that smoking has potent effects on a number of parameters including food intake, body weight, metabolism, and blood pressure. For example, it is well documented that 1) there is an inverse relationship between smoking and body weight, and 2) smoking cessation is associated with weight gain. However, there is increasing evidence that smoking can exert deleterious effects on energy balance through maternal exposure during fetal development. Specifically, there appears to be an increased incidence of metabolic disease (including ), and cardiovascular disease in children and adults that were exposed to smoke during fetal development. The present review will examine the relationship between maternal smoke and adult disease in offspring. The epidemiological studies highlighting this relationship will be reviewed as well as the experimental animal models that point to potential mechanisms underlying this relationship. A better understanding of how smoking effects changes in energy balance may lead to treatments to ameliorate the long-lasting effects of perinatal exposure to smoke as well as increasing the health benefits associated with smoking cessation.

Smoking And The Fetal Origins Of and newborn growth and the subsequent Disease development of obesity is a commonly cited example of this phenomenon (7; 8). I. Introduction - Fetal Programming of The epidemiological studies that reported Adult Disease this association led to the formulation of the “thrifty phenotype hypothesis” (9). Recently there has been increased This hypothesis stated that a poor attention paid to the hypothesis that some nutritional environment for the fetus, diseases that have been considered to be brought on by either malnutrition or diseases of adulthood (e.g., obesity, type II placental dysfunction, can induce an , cardiovascular disease, adaptive response that will optimize hypertension, and some cancers) may have growth and development later in life. The their origins in fetal development. This is adaptive response (which may include most commonly referred to as either the changes in circulating hormones, receptor “developmental origins of disease” or the sensitivity, regulatory enzymes, central “fetal origins of disease” (1-7). The nervous system changes), would lead to hypothesis states that the susceptibility to potential increased survival of the adult develop some diseases is determined in individual under conditions of marginal part by the intrauterine and early postnatal nutritional supply. However, under environment, i.e., perturbations to the conditions of nutritional abundance the early environment (e.g., nutritional result will be maladaptive with increased deficits) can significantly increase incidence of obesity, hyperlipidemia, susceptibility to develop disease later in hypertension and type II diabetes in life. The association between poor fetal adulthood. 6 Bergen H

One of the first and best documented One of the first epidemiological studies examples of this phenomenon was the that examined the effect of maternal development of obesity in individuals 20 smoking on the subsequent development years after they were born during the of obesity was a birth cohort study of over Dutch famine of 1944-1945. Individuals 17,000 births and these individuals were were at greater risk of developing obesity tracked at 16 and 33 years of age (20). following exposure to under-nutrition This study identified a significant effect of during late gestation and early post-natal maternal smoking on the subsequent periods (10). The last 30 years has seen development of non-diabetic obesity, as numerous epidemiological studies well as an effect on diabetes (see below). outlining a relationship between In the offspring of mothers that smoked gestational nutrition together with birth during pregnancy, there was significant weight (as a marker of impaired fetal increase in the incidence of obesity (at 33 growth) and subsequent diseases such as years of age) and the magnitude of the obesity, type II diabetes, hypertension and effect was greater in the offspring of heavy cardiovascular disease to name a few (1; 5; smokers than the offspring of medium 11-15) Epidemiological studies have now smokers. Similar results were obtained in been bolstered by an increasing number of a study of over 6,000 children (21). experimental studies demonstrating a Specifically, there was a dose dependent relationship between perinatal nutrition association between maternal smoking and/or birth weight, and adult disease (2; during pregnancy and childhood obesity 7; 16-19). The mechanism(s) responsible (5-7 yrs. of age) that was independent of a for translating fetal effects into adult variety of lifestyle confounders or other disease are not well understood but several risk factors for obesity. However, it is candidates include imprinting through also known that maternal smoking can epigenetic programming. significantly impair fetal growth (22; 23) and that low birth weight is itself Most of the research, with respect to early associated with increased incidence of programming of adult disease, has focused obesity later in life (24). In this clinical on nutritional challenges (under- and over- scenario, i.e., obesity in individuals born nutrition) on the subsequent development small for gestational age, the post-natal of adult diseases. However, there is and early developmental period is increasing evidence that long-lived effects characterized by a phenomenon referred to of perinatal perturbations may not be as “catch-up growth”(22; 24-26). limited to nutritional influences but may Therefore, obesity due to maternal also include other influences such as smoking may be secondary to the effects maternal smoking. The present review of maternal smoking on fetal growth; i.e., will focus on the effects of maternal maternal smoking produces smaller babies smoking on the subsequent development and smaller babies are more susceptible to of diseases in the offspring. It should be develop a variety of adult diseases. noted that cigarette smoke contains However, it should be noted that the numerous components that are relationship between maternal smoking biologically active. Although nicotine is a during pregnancy and overweight in dominant factor in this regard, other children is a complex one. Specifically, a components of smoke may also be more recent epidemiological study involved in mediating the detrimental reported that the likelihood of being effects of smoke on fetal development and overweight at 4.5 years was almost the subsequent promotion of disease into doubled as a result of maternal smoking adulthood. during pregnancy. Interestingly, the effect of maternal smoking on overweight was II. Smoking and Obesity seen in normal birth weight children that Exposure To Smoke During Development: Fetal Programming Of Adult Disease 7 had the greatest weight gain in the first note that the effect was independent of few months of life as well as in high birth birth weight (and mother’s pre-pregnancy weight children that had the least amount weight). Given that smoking has also of weight gain after birth (27). This been linked to low birth weight and that suggests that maternal smoking may low birth weight has been linked to increase susceptibility to develop obesity; the dissociation between these overweight and this can occur in normal two variables in this study indicates that birth weight as well as high birth weight the effect of smoking is not simply children. through an effect on birth weight (32; 33).

However, although catch-up growth may An important issue regarding the effect of be a factor in the subsequent development maternal smoke on fetal development and of obesity, studies also suggest that the subsequent health effects is determining effect of maternal smoking on obesity in the sensitivity of the fetus to the offspring can occur independently of detrimental effects of smoke. From a catch-up growth (21). It was reported that public health perspective, it is vital to infants exposed to maternal smoke had know whether smoking is harmful to the lighter birth weights but as they grew into fetus in the first trimester when women adolescence they tended to have greater who smoke and do not know that they are and this tendency pregnant, will be unintentionally exposing increased with age (28). Importantly, their fetuses to the harmful effects of studies have reported that the association smoke. In a recent study it was reported between maternal smoking on obesity that there was no difference in the effect of remains even when adjusted for birth maternal smoking between mothers that weight; i.e, maternal smoking exerts an smoked throughout pregnancy and those influence independent of its effects on that smoked only during the first trimester fetal growth (21; 28; 29). In a subsequent on subsequent development of obesity study it was also reported that the effects (34). These results could not be explained of maternal smoke on development of by other potentially confounding factors obesity was observed in children 5-7 years such as breastfeeding, watching television, of age and that if mothers that otherwise playing video games, and parental obesity. smoked, abstained during pregnancy and This suggests that during the first three then resumed smoking after childbirth, the months of pregnancy the fetus is association was no longer observed (30). particularly sensitive to the detrimental This clearly suggests that intrauterine effects of exposure to maternal smoke. In exposure to maternal smoke, rather than a recent prospective study, maternal other family or lifestyle factors, can exert smoking during early pregnancy was profound influences on regulation of associated with overweight at three years energy balance that can be detected as of age (35). Furthermore, the effect was early as 3 to 5 years of age (30; 31). For observed even when adjusted for other example, the size of the effect of maternal factors such as ethnicity, income, smoking on childhood obesity was as great education and childhood diet. In contrast, as that observed in studies linking obesity an increased incidence of obesity was not with frequent television viewing and observed in children of mothers who quit playing video games (21). smoking prior to conception (as compared to never smokers). These studies suggest In a study that examined the relationship that the detrimental effects of maternal of maternal smoking to obesity in smoking on fetal development may occur American Indian children there was a in the first trimester. Therefore, it seems significant effect of maternal smoking prudent that women should be encouraged during pregnancy on overweight at three to quit smoking before conception; as is years of age (31). It is also of interest to 8 Bergen H the case with alcohol consumption. hypertension could occur indirectly through effects on birth weight. In a III. Smoking and Diabetes prospective cohort study with over 1700 pregnant women, a significant effect of One of the first epidemiological studies maternal smoking during pregnancy on that identified a link between the effect of blood pressure at six years of age was maternal smoking and the subsequent found and interestingly, this was not development of diabetes was a birth cohort entirely due to the effect of smoking on study of over 17,000 births. In addition to birth weight (38). In a second prospective identifying maternal smoking as a risk study of over 3,800 children, a relationship factor for obesity, this study identified a between smoking during pregnancy and significant effect of maternal smoking on increased blood pressure at 5 years of age the subsequent development of early adult was reported and the effect was onset diabetes (20). For example, if a independent of birth weight (39). mother smoked more than 10 cigarettes a day while pregnant, there was a four-fold While the above studies highlight the greater chance that the offspring would detrimental effects of maternal smoking on develop diabetes, as compared to offspring the subsequent susceptibility to develop that were not exposed to smoke. obesity, diabetes, and hypertension, the Moreover in a more recent study aimed at mechanism underlying this effect is not examining the effects of smoking in well understood and a number of association with other drugs (alcohol and possibilities have been proposed. Clearly, illicit drugs), prenatal exposure to nicotine, a better understanding of how maternal but not alcohol, had a significant effect on smoking, and/or nicotine, effects changes subsequent BMI and similar to other in energy balance, metabolism, and blood studies, a dose response relationship was pressure, may lead to treatments to detected (36). Taken together, these ameliorate the long-lasting effects of epidemiological studies suggest that perinatal exposure to smoke as well as prenatal exposure to smoke has a long- increasing the health benefits associated lasting effect on body weight. with smoking cessation. In any case, Specifically, there is a greater incidence of recommendations to stop smoking are overweight and obesity in those exposed particularly relevant in women that are to maternal smoke and that there is a planning or attempting to become significant dose-response relationship. pregnant. The mechanism for the effect is not known however the authors speculated that it may V. Smoking and Fetal Origins of be related to either fetal malnutrition or the Disease: Potential Mechanisms toxicity of smoke on the fetus. A. Decreased fetal growth – As IV. Smoking and Hypertension mentioned above, a number of studies have found evidence of a link between low In addition to nicotine’s effect on the birth weight and subsequent development subsequent development of obesity, of obesity (Reviewed in (2; 7; 40; 41)). maternal smoking also appears to have an Since maternal smoking is associated with effect on the subsequent development of decreased fetal growth, the increased cardiovascular disease; specifically incidence of obesity may be a secondary hypertension. A number of studies have result of being born small for gestational provided evidence that low birth weight is age. However it should be noted that associated with hypertension later in life while low birth weight may play a role in (37). Therefore, since smoking during subsequent disease processes, there is pregnancy acts to decrease birth weight, evidence that the detrimental effects of the effects of smoking on subsequent smoking may occur independently of low Exposure To Smoke During Development: Fetal Programming Of Adult Disease 9 birth weight (see above). In any case, the decreased fetal growth observed produced mechanism(s) underlying the effect of in the smoking pregnant woman (50; 52; nicotine on birth weight is (are) not well 53). There are also a number of studies understood and a number of possibilities that have reported that smoking is clearly exist. The possibilities highlighted associated with marked changes in below are neither exhaustive nor mutually placental structure and function. For exclusive. example, smoking is associated with a significant increase in the thickness of the 1. Low birth weight is due to smoking- villous membrane which could predictably derived nicotine effects on maternal lead to a decrease in gas and nutrient appetite and energy expenditure. exchange across the placenta and impaired Nicotine is considered to have an fetal growth (54; 55). Smoking also exerts inhibitory effect on body weight gain. detrimental effects on the trophoblast This is supported by the association that component of the placenta as well as smokers weigh less than non-smokers and decreasing the area for diffusion between cessation of smoking is accompanied by the maternal blood and fetal blood (56- significant weight gain (42). There is 59). For example, trophoblast cell evidence to suggest that the mechanism differentiation is impaired with maternal for nicotine’s effect on body weight may smoking and this effect can occur early in involve both an increase in energy the development of the placenta (58; 59). expenditure and a decrease in food intake Structural changes of the placenta may act (43-48). Therefore, during pregnancy the to decrease gas exchange, as well as combination of nicotine-induced nutrient exchange (e.g., amino acid suppression of maternal food intake and transport) across the placenta (60) Taken increased energy expenditure may together it is clear that smoking during collaborate to be sufficient to produce pregnancy has significant effects on poor or under nutrition which then leads to placental development that leads to decreased fetal growth. The effect of significant changes in structure and smoking appears to be an effect of intra- function that may result in detrimental uterine growth retardation and not an effects on fetal growth and well-being effect on pre-term delivery (32). 3. Low birth weight is due to 2. Low birth weight is due to detrimental effects of nicotine on fetal detrimental effects of nicotine on metabolism. A third possibility is that placental structure and function. A nicotine or other constituents of smoke second possible mechanism responsible may have detrimental or toxic effects on for smoking’s effect on decreased fetal fetal metabolism that impair growth of the growth may be at the level of the placenta; fetus. Nicotine readily crosses the i.e., through impaired delivery of oxygen placenta and therefore it could potentially and/or nutrients to the fetus. Nicotine via exert direct effects on fetal tissues (49). activation of nicotinic acetylcholine For example, it is becoming increasingly receptors, can exert a vasoconstrictive evident that the endocrine status of the effect on placental arterial supply leading fetus is altered significantly in response to to attenuation of oxygen delivery to the maternal smoking (61; 62). In particular, fetus which in turn could lead to decreased , growth hormone and insulin-like fetal growth (49-51). Smoking is also growth factor (IGF) levels in the fetal associated with increased carbon compartment are altered in response to monoxide in maternal blood which in turn maternal smoke (61). It was suggested reduces oxygen delivery to the fetus that decreased IGF levels detected in cord leading to decreased fetal growth. blood associated with maternal smoking Smoking decreases uterine blood flow to may play a role in limiting fetal growth the placenta which could play a role in 10 Bergen H

(62). Of particular interest is the effect of that maternal nicotine exposure had a maternal smoke and/or nicotine on leptin significant effect on gene expression of levels present in cord blood. As discussed neuropeptides (neuropeptide Y and below, leptin may exert profound proopiomelanocortin) in the hypothalamus influences on development of the neural (74).. It is well established that these systems underlying regulation of appetite hypothalamic neuropeptides can exert and metabolism. Taken together, it is potent effects on the regulation of energy clear that maternal smoking may exert balance and it was proposed that altered potent and detrimental effects on fetal regulation of these neuropeptides may play growth via a number of mechanisms. a role in decreased body weight associated with maternal smoking. Interestingly, it was also reported that circulating leptin B. Perturbations in Central Regulatory levels were reduced following nicotine Circuits – Most of the studies exploring treatment, similar to the situation that potential mechanisms underlying smoking occurs in humans (61; 74). Decreased and disease later in life have focused on leptin levels in response to nicotine is of obesity. It is well established from animal particular interest since a number of recent studies that nicotine can act within the studies have suggested that leptin may central nervous system to decrease food play a critical role in the development of intake and body weight (63-66). Although brain circuits that regulate energy balance most studies examining nicotine’s effect (80-83). In genetically obese mice that on energy balance are acute studies lack leptin (i.e., ob/ob mice), exogenous performed in adult animals, there is an administration of leptin had marked effects increasing evidence that exposure to on synaptic contacts between excitatory nicotine during development can produce and inhibitory hypothalamic neurons that long lasting perturbations in brain regulate energy balance (82). The neurochemistry including dopamine, importance of leptin in development is serotonin, acetylcholine, and a variety of further bolstered by recent studies neuropeptides, as well as leptin receptors demonstrating that treatment with leptin (67-77). These changes could potentially during the perinatal period can offset lead to long term changes in the neural developmental programming that occurs regulation of energy balance, i.e., nicotine as a result of maternal undernourishment either directly or indirectly may alter (84). Clearly, the role of leptin as a appetite or self regulation of food intake in hormone that regulates neuronal infants exposed to maternal smoke. It has development is a topic of increasing been proposed that smoking acts by means interest and if nicotine alters circulating of metabolic imprinting on the system leptin during development, this could have controlling food intake and satiety. A long-term consequences (85). In this number of rodent studies have provided regard it is also interesting to note that evidence in support of the hypothesis that under-nutrition of mouse dams (which maternal nicotine has long-lasting effects decreases circulating leptin) was on neurotransmitter systems that are associated with obesity in the pups when implicated in the regulation of energy they were subsequently fed a high-fat diet balance. In addition there is recent (86). This may be a mechanism by which evidence suggesting that programming of nutritional perturbations in the perinatal the neural circuits that regulate energy period, for example brought on by balance occurs in the perinatal period and maternal smoking, may have long-lasting that metabolic or nutritional deficits result effects. Taken together these results in altered regulation of energy balance, suggest that smoking may have long including appetite (78; 79). For example, lasting effects on the neural circuits a study in Rhesus monkeys demonstrated responsible for regulating food intake and Exposure To Smoke During Development: Fetal Programming Of Adult Disease 11 metabolism. epigenetic mechanisms and prevention of perinatally acquired VI. Conclusion lasting health risks. J Perinat Med 2004;32:297-305. It is becoming increasingly clear that fetal 7. 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