Exposure to Smoke During Development: Fetal Programming of Adult Disease
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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 obesity),
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
diabetes, 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 thatExposure 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
body mass index 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 to8 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 lowExposure 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 leptin, 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 in10 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 andExposure To Smoke During Development: Fetal Programming Of Adult Disease 11
metabolism. epigenetic mechanisms and
prevention of perinatally acquired
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