Running Head: PNE and CNS Development

Nicotines Effect on Prenatal Central Nervous System Development

Lindsay A. Birchall
University of Calgary

Neurobiological and Developmental Bases of Learning and Behaviour EDPS 654

Dr. Stephanie Griffiths
November 18, 2013

Pre-Natal Nicotine Exposure

Pre-natal nicotine exposure (PNE) is associated with cognitive and behavioural problems
in both children and laboratory animals. Specifically, deficits in executive attention, learning and
memory, conduct problems, lower IQ and hyperactivity has been linked to PNE in children
(Brent & Weitzman, 2004; DiFranza, Aligne, & Weitzman, 2004; Fried, 2002; Fried, Watkinson,
& Gray, 2003; Herrmann, King, & Weitzman, 2008; Wakschlag, Leventhal, Pine, Pickett, &
Carter, 2006; Weitzman, Byrd, Aligne, & Moss, 2002; Williams, et al., 1998). Child
psychopathology such as ADHD, ODD and Specific LDs have been correlated with PNE (APA,
2013; Masch & Barkley, 2003). In addition, sleep problems, low birth weight, asthma and
Sudden Infant Death Syndrome have also been documented to occur in children that have been
prenatally exposed to nicotine (Bluestein et. al., 2013; Kelmanson, 2009; Slotkin, 1998). It is
hypothesized that PNE is a contributing factor in specific neurological dysfunctions, resulting in
symptoms such as limited cognitive control and learning. And, although research has not been
able support specific structural dysfunction as a result of PNE in children, researchers have made
some evidential gain in the areas of cellular dysfunction in animals. However, it is important to
note that the link between animal structural dysfunction and childhood psychopathology is
speculative at best.
Cigarette smoke contains approximately 4, 700 ingredients (Zeidler, Alberman & Lang,
2007). Nicotine and carbon monoxide have been at the forefront of research. Because nicotine
easily crosses the placental and bloodbrain barriers and presents in amniotic fluid, fetal blood
and breast milk (Mychasiuk, Muhamad & Kolb, 2012; Luck, Nau, Hansen & Steldinger, 1985)
the fetus is exposed to nicotine through a multitude of channels when a mother smokes.
Additionally, the fetus experiences considerably higher concentrations of nicotine then the

mother and nicotine remains in the fetuss body longer (Guan et. al., 2009). Slotkin, 2008
cautions the use of smoking cessation aides, which he states are used freely, without
regard to critical developmental periods or pharmacokinetic issues.
Cessation aides and second hand smoke and have both shown to produce adverse
effects in animals prenatally exposed to nicotine (Guan et. al., 2009; Dwyer, McQuown & Leslie,
2009).

Specific CNS Deficits

Exposure to nicotine during any critical periods in Central Nervous System (CNS)
development likely has adverse effects, with potential to dramatically change structure and
function within the brain (Dwyer et al., 2009). Because physical brain growth and maximal brain
plasticity occur during the prenatal period, it is imperative that this experience is healthy
(Huttenlocher & Dabholkar, 1997; Knickmeyer, et al., 2008; Matsuzawa, et al., 2001; Webb,
Monk, & Nelson, 2001). Exposure to other toxins, such as cocaine and alcohol, during this time
of multiple preprogrammed critical and sensitive periods disrupts CNS development (Peadon,
Jones-Rhys, Bower & Elliott, 2009; Slotkin, 1998). It is hypothesized that nicotine would do the
same.
Muhammad et. al., 2012 describes the prenatal period as characterized by extreme
neuroplasticity, which provides psychostimulant drugs such as nicotine, the ability to
dramatically perturb neuroanatomical organization of the brain. A multitude of effects have
been shown in animal populations with PNE. Even models that delivered low doses of nicotine,
simulating second hand smoke and smoke cessation, have consistently proven that structural
dysfunction can occur with minimal exposure (Guan et. al., 2009; Yolton et. al., 2009). In

addition, although low birth weight is a common symptom in animals and children, CNS
dysfunction can still occur in the absence of this biological marker to nicotine exposure in
animals.
Research identifies many developmental differences in the CNS, a result of PNE in
animals and children. Specifically, low birth weight and reduced brain weight have been reported
(Blutstein et. al., 2013; Muhammad et. al., 2012; Mychasiuk et. al., 2012; Guan et. al., 2009).
Evidence for reduction in cell numbers, alterations in synapses, and early apoptosis have been
identified in animals (Mychasiuk et. al., 2012, Zeidler et. al., 2007; Slotkin, 1998, 2004).
Differences in cerebral cortex thickness and hippocampal structures are fairly new areas of
research (Blutstein et. al., 2013; Muhammad et. al., 2012; Myschasiuk et. al., 2012). Altered
reactivity of cholinergic receptors and increased fetal hypoxia has been vastly researched in
prenatal nicotine exposure (Blutstein et. al., 2013; Muhammad et. al., 2012; Guan et. al., 2009;
Slotkin, 2004; Slotkin, 1998). Lastly, neural tube deficits (Suarez et al., 2010), dendritic
morphology and spine density differences (Mychasiuk et. al., 2012; Muhammad et. al., 2012),
pre-disposure to hydrocephaly (To & Tang, 1999) and differences in right prefrontal white matter
(Hudkins, ONeill, Tobias, Bartzokis & London, 2012) have also been linked to PNE in animals.
Most heavily researched areas within laboratory animals surround the effects of prenatal
hypoxia, cholinergic receptor dysfunctions and alterations in cellular functions such as apoptosis.
As such, these three areas will be discussed with reference to specific alterations in structure and
function.
Hypoxia. Children that have endured hypoxic episodes often present with significant
cognitive difficulties in multiple domains. Hypoxia is an environmental factor that occurs when
the fetus is deprived of oxygen. When oxygen in the blood is reduced, Ischemia results in the

oxygen deprived brain. A range of CNS structural damage such as Hypoxic Ischemic
Encephalopathy (i.e. the swelling of the brain) can result from hypoxia. Gunn & Bennet, 2009
identify several factors that influence the risk and outcome of fetal hypoxic injury, including
depth/severity, duration, and repetition of the insult, the maturity, and condition of the fetus, preexisting hypoxia, and exposure to pyrexia and infection/inflammation. When a mother smokes
throughout pregnancy the fetus experiences highly concentrated, repeated exposures to nicotine
throughout fetal maturity. It is also likely that pre-existing hypoxia occur, increasing risk and
negative outcomes for the fetus.
When a mother smokes, carbon monoxide leads to formation of carboxyhemoglobin. This
results in diminished oxygen carrying capacity of maternal and fetal blood (Slotkin, 1998) and
vasoconstriction in the placenta (Guan et. al., 2009). This interferes with the circulatory systems
ability to deliver oxygen to the fetal brain and other organs. Because the fetus is exposed to
higher concentrations of nicotine then the mother, and those concentrations remain at peak for
longer, it is likely that a hypoxic episode could occur, significantly impacting fetal development.
In animals, researchers have observed rising fetal blood pressure and slowing fetal heart rates
during times of maternal nicotine administration (Blutstein et. al., 2013; Guan et. al., 2009).
In research conducted by Guan et. al., 2009, they found low doses of nicotine in
maternal sheep induced fetal hypoxia, elevated fetal blood pressure, and increased the expression
of Fos protein in the fetal central nervous system. Even low levels of nicotine, intended to
mimic second hand smoke and cessation aides, could significantly impact fetal cardiovascular
and central nervous systems, as well as oxygen status (Guan et. al., 2009). Guan et. al., 2009,
concluded that there is a toxic risk for hypoxia in fetuses exposed to low levels of nicotine.

In 1995, Slotkin, Lappi, McCook, Lorber, & Seidler, examined the possibility of hypoxia
as a result of prenatal nicotine exposure, and observed the same decreased pattern in heart rate
and increase in blood pressure in rats. In addition, Slotkin, 1998 found that during hypoxic
episodes, rats did not secrete catecholamine, a substance involved in cardiac regulation that the
adrenal gland releases upon a hypoxia event. Normal rats were observed to secrete 40% of their
total catecholamine, whereas nicotine exposed fetal rats secreted almost none (Slotkin, 1998).
The heart rates of these PNE rats continued to steadily decrease in the low-oxygen environment
causing some subject mortality. Slotkin, 1998 states The absence of an adrenomedullary
response to hypoxia is likely to be the most important deficiency in autonomic function after
nicotine exposure.which leaves a window of vulnerability where there is no protection from
hypoxia for PNE rats. Although the reduced pronunciation of catecholamine is an interesting
finding, replication of these results were not found in more recent research.
More recently, Blutstein et. al.s, 2013 found hypoxia to alter synaptic patterning during
fetal development. And, Berro et. al, 2008, found PNE to have a negative impact on airway
hyperresponsiveness and increased asthma in offspring using a mouse model. Both provide
evidence of life-long implications as a result of hypoxic events created by parental nicotine
exposure. Blutstein et. al., 2013 states, depending on the severity and time of the exposure and
likely hypoxic environment, permanent effects in the adult brain are likely.
Neurotransmitters. Neurotransmitters are responsible for sending messages from one
neuron to another. Vesicles are released from the transmitting neuron into the synaptic gap in
order to bind to receptor sites of the receiving neuron. Specific receptor sites are available for
specific neurotransmitters. Within fetal development activation of a given set of
receptors may: (1) promote neural cell replication, (2) initiate the switch

from replication to differentiation, (3) enhance or retard axonogenesis or

synaptogenesis, (4) evoke or prevent apoptosis, or (5) enable the
appropriate migration and localization of specific cell populations within each
brain region (Slotkin, 2004). In addition, the developmental context in which
neurotransmitter stimulation occurs, effects of the fate of each cell. Neurons are exceptionally
sensitive to environmental stimuli during the process of experience dependent and experience
expectant synapse development. Toxins can be detrimental to cellular neurodevelopmental
processes during these critical periods (Dwyer et. al., 2009).
Nicotinic acetylcholine receptors (nAChRs) regulate critical aspects of brain maturation
during the prenatal period, play a key role in early brain plasticity and possess a diverse range of
flexibility when modulating multiple events (Dwyer et. al., 2009). According to Mychasiuk et.
al., 2012, during the period of experience dependent synaptic development, over-activation of
these receptors may alter normal responses in the brain. As such, children and animals
parentally exposed to nicotine during this critical period of synaptic development may
experience structural alterations. Interestingly, Mansvelder & McGehee, 2002 found
that nAChR activates synaptic mechanisms in reward systems of the CNS,
which ultimately leads to reinforcement and addiction. This affirms the wellknown correlation between children that have been prenatally exposed to
nicotine later becoming smokers as adults (Agrawal et. al., 2010).
When the fetus is exposed to nicotine, the nicotine stimulates a specific population of
cholinergic target sites, called the nicotinic cholinergic receptors (nAChR). Nicotine effectively
recapitulates many of the roles of acetylcholine (Slotkin, 1998). This causes increased
stimulation of those receptor sites, uniquely communicating with the genes that

control cells fate (Zeidler et. al., 2007; Slotkin, 1998). Specifically, as seen in rats,
processes such as cell migration, differentiation, apoptosis, synaptogenesis, angiogenesis and
cell-mediated immunity are deregulated during this nicotine stimulation (Zeidler et. al., 2007;
Dwyer et. al, 2009; Slotkin, 1998). Because of the many critical and sensitive periods in fetal
CNS development, nicotine produces effects that are unique to the period of exposure
impact(ing) the developing structures regulated by acetylcholine at that time (Dwyer et. al.,
2009). Slotkin, 2004, supports this by saying environmental toxicants that promote or interfere
with neurotransmitter function evoke neurodevelopmental abnormalities by disrupting the timing
or intensity of neurotrophic actions. As such, depending on the time of exposure, different
neurodevelopmental processes have shown to be adversely effected in fetal rats.
Researchers have identified some consistent results through the examination of rats
neurodevelopment. Slotkin et. al., 1998, identified two distinct errors in cell development that
occur as a result of nicotines effects on neurotransmitters in rats: a premature change from cell
replication to differentiation and, after a delay, initiation of apoptosis. In addition Slotkin et.
al.s 1998 research found outright cell loss, cell damage, reduced cell number and
impaired synaptic activity. In 2004, Slotkin found further evidence of
cellular damage including adverse effects on specific processes involved in brain cell
replication and differentiation, synaptic development and function. This cellular damage was
traced to cellular events surrounding the trophic role of acetylcholine acting on its specific
cellular receptors and associated signaling cascades (Slotkin, 2004), which further supports
adverse effect of nicotine on neurotransmitters and receptor sites. A common dysfunction found
in the above research, as a result of neurotransmitter function, is cell death, or Apoptosis (Dwyer
et. al., 2009; Zeidler et. al., 2007; Slotkin, 1998, 2004). As such, this will be discussed.

Apoptosis. Slotkin, 1998, 2004 and Dwyer et. al., 2009 both found supporting evidence
of premature apoptosis in the neurodevelopment of animals with PNE. Ziedler et. al, 2007,
reviewed current research on the apoptosis effect nicotine may have on developing fetal cells in
animals. They found evidence of both pro-apoptotic, in poorly differentiated cells and antiapoptotic, in differentiated cells (Ziedler et.al., 2007). One would conclude that poorly
differentiated cells are likely experience dependent and therefore have more plasticity then cells
that are experience expectant and have already differentiated. However, it is important to note
that both types of cells can be modified through experience and have the potential for abnormal
development. Slotkin, 2004, explains that because many phases of brain development are
dependent on trophic responses to acetylcholine, promotion or prevention of apoptosis could
happen based on the timing of the exposure of nicotine. This increases the likelihood that both
experience dependent and experience expectant cells could undergo premature apoptosis. More
specifically Because of the close regulatory association of cholinergic and catecholaminergic
systems, adverse effects of nicotine involve multiple transmitter pathways and influence not only
the immediate developmental events in fetal brain, but also the eventual programming of
synaptic competence (Slotkin, 1998). One could hypothesize altered CNS development based
on these observed changes in the pre-programmed apoptosis process. Myschasiuk et. al., 2012,
predicts that PNE may block experience-dependent plasticity in adulthood which would in turn
impact cognition and produce significant behavioral effects if neurons are rendered less plastic
by the early exposure.

Making the Connection Cognitive Deficits in Laboratory Animals and Humans

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So, how do we make the connection between specific structural abnormalities in

laboratory animals, such as neurotransmitter dysfunction, and symptom presentation of children
PNE? Further, how do structural abnormalities relate to specific cognitive deficits in PNE
children? First, we must examine research on specific neuropsychological features common to
children with PNE.
In Mezzacappa, Buckner & Earls research in 2011, they found that found that PNE
impaired the speed of executive attention, which is a process highly involved in self-regulation
and cognitive-control. Fried, Watkinson & Gray, (1992, 1998, 2003) found that PNE children
aged 6-16 years had significantly lower verbal IQ, impaired performance on tasks of sustained
attention and poorer performance on response inhibition tasks. Jacobsen, et. al., (2006, 2007)
found evidence that maternal smoking is associated with deficits in visual-spatial memory and
auditory and visual attention in children. Even sex dependent differences have been found in
Jacobsen et. al.s 2007, research, where a larger effect on auditory and visual attention occurred
in females. In 2009, Toro et. al. also found gender related differences with regard to the cerebral
cortex presentation. Orbitofrontal, middle frontal, and parahippocampal cortices were thinner in
exposed, as compared with non-exposed, individuals; these differences were more pronounced in
female adolescents (Toro et. al., 2009). In addition, Bennett et. al.s, 2013 preliminary research
shows that PNE children used different brain regions and approaches to succeed in working
memory tasks then unexposed children. Taking all of the above into consideration, one could
hypothesize differences in pre-frontal cortex functioning in children with PNE.
Because most structural CNS research is based on animals, not children, it is important to
identify similar cognitive deficits and symptomology in animals if we are to hypothesize a
connection between the two. There is consistent evidence that shows cognitive, attention and

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learning deficits in rats that have experienced PNE. Cognitive maze tasks using rats showed
negative effects on choice accuracy and response duration performance within Levin, Briggs,
Christopher & Roses 1993, research. In 1991, Sorenson, Raskin & Suh found significant
impairment in rats ability to learn an 8-arm-maze cognitive task. They hypothesized that
attention mechanisms may be disrupted by PNE sincethe radial arm maze places substantial
demands on attention processes (Sorenson et. al., 1991). To further confirm PNEs effects on
cognition, Schneider et. al., 2011 conducted a 5-choice serial reaction time task to assess
continuous attention in a learning and memory task in PNE adult rats. Schneider et. al., 2011
found adult rats showed an increase in anticipatory responses, increased omissions errors, more
variable response times, and lower accuracy (received fewer rewards) supporting a direct effect
of prenatal nicotine exposure on important aspects of attention, inhibitory control and learning
later in life. Lastly, and most interesting, Kolb et. al., 2012 placed PNE animals in complex
environments, where one would expect experience dependent neurons to change, however, there
was no experience-dependent change in either parietal or prefrontal cortex. This alteration in
neuronal activity is highly intriguing with reference to previous information on apoptosis and
synaptic development differences.

Prenatal Nicotine Exposure - Connections to Childs Psychopathology

Maternal nicotine use and fetal exposure to nicotine has been linked to a number of
impairments in functioning such as growth, intelligence, academic achievement, executive
functioning and behavioural regulation (Lambert & Bauer, 2012). Specific child
psychopathology has also been associated to children prenatally exposed to nicotine such as:
Conduct Disorder, Attention Deficit Hyperactivity Disorder, Oppositional Defiant Disorder and

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Specific Learning Disabilities (APA, 2013 p.62; Mash & Barkley, 2003 p.95,173,540; Cornelius
& Day, 2009; Gatzke-Kopp & Beauchaine, 2007). In addition, medical challenges have been
connected to children and animals with PNE such as, increased fetal heart rate and blood
pressure, fetal hypoxia, Sudden Infant Death Syndrome, mortality, low birth weight, asthma,
prematurity, sleep difficulties and reduced head circumference (Rehan et. al., 2012; Guan et. al.,
2009; Berro et. al., 2008; Slotkin, 2004; Slotkin, 1998, DiFranza & Lew, 1995; Lambers &
Clark, 1996). Environmental factors such as parental education, genetic variability, SES,
substance abuse, poorer quality of care (malnutrition), etc. are shown to correlate with prenatal
exposure to nicotine (Mezzacapa et. al., 2011; Gatzke-Kopp & Beauchaine, 2007;Wakshlag &
Hans, 2002,). With the multitude of psychological, environmental and medical correlates it is
impossible to determine effects of individual variables for children with PNE.
It has been extensively proven that PNE in rats and other animals affects their ability to
efficiently complete tasks involving sustained attention, learning and memory. PNE children
present with similar symptomology, and even correlated psychopathology, such as ADHD. As
Mychasiuk et. al., 2012 identifies, one consistent pattern of behavioral and anatomical changes
is that there are abnormalities in tasks related to prefrontal functioning in both humans and
rodents prenatally exposed to nicotine.

Conclusion
Many studies have been conducted within laboratory animals showing multiple adverse
effects of PNE on CNS development. However, most research stresses the importance of the
stage of fetal development at the time of PNE exposure. With high vulnerability and plasticity of
the fetal brain, nicotine exposure at any time constitutes the possibility for a multitude of

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dysfunctional effects. Pregnant women are likely to use cessation aides to help them quit
smoking cigarettes, however, there are adverse fetal effects that result from this type of nicotine
exposure. In addition, specific timing of cessation aides are recommended, ideally within the first
trimester and not thereafter, based on fetal CNS developmental periods (Slotkin, 2008). Nicotine
has shown to effect prefrontal cortex functions such as cognitive process involved in attention
and learning in animals and is linked to similar symptomology in PNE children. In addition
differences in cell development, differentiation and cell death occurs in laboratory animals,
which prompts one to consider the same neurological development in children PNE. Lastly,
hypoxia does result in animals and could result in children, with a plethora of detrimental lifelong implications for cognition and learning.
Correlation does not prove causation, and the jump in assumption between structural
abnormalities in animals to children is a far one. However, one can cautiously hypothesize the
potential of a causal relationship between nicotine and structural dysfunction. Ultimately, this
hypothetical relationship between structural abnormalities in animals and similar symptomology
between animals and humans could be used to motivate mothers to cease smoking when
pregnant. Mychasiuk et. al., 2012 stresses a footprint that is left in the fetal brain that
potentially could affect individuals well into adulthood and may only become evident with later
experiences. It is public knowledge that women who are pregnant should not smoke cigarettes,
however, 17% of women do continue to smoke throughout their pregnancy (Statistics Canada,
Nov 18, 2013). Providing women with potential, but specific neurodevelopmental risks, may
further reduce the likelihood of prenatal nicotine exposure.

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