Download Environmental Causes of Central Nervous System Maldevelopment

Environmental Causes of Central Nervous
System Maldevelopment
Patricia M. Rodier, PhD
ABSTRACT. The central nervous system is the most
vulnerable of all body systems to developmental injury.
This review focuses on developmental processes by
which the nervous system is formed and how those processes are known or suspected to be injured by toxic
agents. The processes discussed are establishment of
neuron numbers; migration of neurons; establishment of
connections, neurotransmitter activity, and receptor
numbers; deposition of myelin; and 2 processes that are
prominent in postnatal development, trimming back of
connections and postnatal neurogenesis. Our knowledge
of the risks of exposure to environmental hazards in
childhood and adolescence is minimal. Most of our information concerns the effects of neurotoxicants in prenatal and early postnatal life. More worrisome than our
lack of data regarding later stages of development is the
minimal effort that we have mounted to protect the public from known neurotoxic agents and that regulations
for testing new drugs and chemicals still do not require
any assessment of neuroteratologic effects. Pediatrics
2004;113:1076 –1083; CNS development, teratology, critical
periods, gene-environment interactions.
ABBREVIATIONS. CNS, central nervous system; MAM, methylazoxymethanol; RA, retinoic acid; VPA, valproic acid; GABA,
␥-aminobutyric acid.
O
f all of the body systems, the central nervous
system (CNS) is the one for which we have
the most information on normal development and developmental injury, yet it is also the
system for which the gaps in our knowledge are
greatest. The assembly of the CNS requires many
more steps than other systems. A myriad of different
cell types must be produced, and some of these must
migrate into their final positions. The differentiation
of neurons is complex and dependent on neuron
activity as well as other influences. The formation of
connections between neurons and the setting of
transmitter types and receptor levels all are developmental processes that are subject to interference from
environmental factors. In addition, the development
of the CNS includes periods of cell death and dying
back of connections— developmental processes that
are rarely seen in other systems and are likely to be
From the Department of OB/GYN, University of Rochester Medical Center,
Rochester, New York.
Received for publication Oct 7, 2003; accepted Oct 20, 2003.
Reprint requests to (P.M.R.) Department of OB/GYN, University of Rochester Medical Center, Rochester, NY 14642. E-mail: patricia_rodier@URMC.
rochester.edu
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.
1076
influenced by exogenous factors. The addition of
myelin to sheath fibers of the central pathways and
peripheral nerves is yet another process that is subject to interference from the outside world. All of this
is made even more complex by the fact that the
sequence of developmental events runs on different
schedules for different neuron types. For example,
migration of human oculomotor neurons is an early
embryonic event, whereas migration of cerebellar
granule cells is still ongoing in postnatal life.
The reader should be forewarned that many questions for which pediatricians need answers cannot be
answered from the existing literature. Most of the
studies in this review are related to prenatal exposure to neurotoxicants. It is well known that prenatal
exposures to agents that seem relatively innocuous
in adults (eg, ethanol, thalidomide, isotretinoin) can
have disastrous effects on the developing brain of the
conceptus that would not be predicted from the effects of the same compounds on adults. By extension,
it is natural to be concerned that postnatal development of the brain is similarly sensitive to environmental exposures. That injuries and infections in
childhood and adolescence can result in many lasting CNS problems, such as mental retardation, hydrocephalus, and epilepsy, increases our concern.
However, almost no research has been done to determine whether neurotoxicants have different impacts in children versus adults. Thus, when parents
inquire, “Are my children at special risk from the
pesticides the exterminator uses?” the answer is,
“We don’t know.”
The importance of detecting teratologic injuries to
the CNS was not recognized in the initial safety
testing guidelines of government agencies, which
focused on somatic birth defects rather than functional defects. This is surprising, because the first
teratogens recognized, rubella infection1 and radiation,2 both have major effects on CNS function. As
more and more CNS teratogens have been identified,
guidelines have been adjusted to provide some limited protection.3 Unfortunately, we still find ourselves in the situation in which most of the known
CNS teratogens have been discovered in human
cases rather than in the laboratory. Even so, teratologic research has given us many ideas about which
kinds of agents are likely to be hazardous to the
developing CNS and how to test for CNS injury. In
the past 10 years, great advances in understanding
the genetic control of normal development of the
CNS have provided clues to newly identified devel-
PEDIATRICS Vol. 113 No. 4 April 2004
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opmental processes that might be subject to environmental interference. This brief review focuses on
early discoveries, to emphasize how long we have
known that CNS teratogenicity should be a concern,
and very recent discoveries, to highlight new research directions in the field.
ESTABLISHMENT OF NEURON NUMBERS
It is obvious that exposure to agents that interfere
with cell proliferation can disrupt development. This
was first demonstrated in studies of radiation exposure in rodents4,5 and later in studies of anticarcinogens.6,7 The earliest studies of CNS teratogenesis focused on these exposures and taught us many
principles that apply to other classes of teratogens.
Whether teratogens prevent cell division or kill proliferating or migrating cells outright, the effect is
similar: only those cells that are actively proliferating
are reduced in number, and which cells will be affected is determined by the exact stage of development when exposure occurs. Because different neuron populations form at different stages, exposure to
the same agent at different times will result in different patterns of morphologic anomalies and different behavioral effects. Morphologic differences with
different exposure periods have been reported in
many studies using methylazoxymethanol (MAM)8;
this agent provides 1 of the best examples of how
exposure time is linked to behavioral outcome.
Balduini et al9 studied spontaneous activity in rats
that were exposed to MAM at 6 different exposure
times between day 14 and day 19. Groups of animals
that were exposed during the mid-fetal period were
hyperactive compared with controls. The group that
was exposed to the same agent on day 19 was hypoactive. There is nothing inconsistent in these disparate results. Rather, if one examines the brain regions
that most actively add neurons during the exposure
periods, it is obvious that hyperactivity results when
exposures injure the cerebral cortex and hippocampus, whereas hypoactivity follows exposures that
injure the cerebellum.10 Typically, injury of those
structures by other means, such as electrolytic lesions, would have the same behavioral effects.
The critical importance of exposure time is only 1
feature of exogenous agents that interfere with neuron production. Another is the way that teratologically reduced neuron numbers are expressed in morphology. Unlike loss of neurons from the mature
CNS, which can be seen in reduced density of cells,
the typical result of failure of neuron production is a
set of neurons with normal density and a reduction
in the volume of the structure that they form. Density
changes are observed only when the reduction of cell
numbers is massive, whereas functional changes can
occur with less extreme losses. Yet another feature
worth noting is that studies of antimitotic agents do
not support the idea that brief insults to proliferation
reduce the numbers of all of the cells formed after the
exposure has ended. Instead, proliferative tissues
seem to rebound from insult and return to producing
normal cell numbers.11 Therefore, whereas populations of neurons that are exposed at the peak of
proliferation may show permanent deficits in num-
ber, those that are formed subsequently are typically
normal in number. The result is that neuron numbers
can be reduced in very specific regions, while many
parts of the brain seem unaffected.
An important characteristic of the functional impact of early neuron loss is that expression of the
deficit may not occur for some time after the injury.
For example, MAM exposure during the prenatal
proliferation of growth hormone–releasing factor
neurons has a dramatic effect on growth but not until
after weaning,8 when growth hormone becomes a
critical determinant of growth. Furthermore, aging
may increase the expression of both anatomic and
behavioral symptoms of developmental injury, as
has been shown in animals that were exposed as
neonates to triethyltin.12
An example of a widespread environmental hazard with antimitotic properties is methylmercury.
Data from environmental disasters in Japan13 and
Iraq14 led to the conclusion that children in utero are
much more sensitive to this neurotoxicant than those
exposed after birth. Furthermore, their symptoms are
different.15 Studies in animals have revealed that
methylmercury exposure arrests mitotic cells in
metaphase by disrupting the microtubules of the
mitotic spindle.16,17 Thus, although the chemical has
many mechanisms of neurotoxicity, it has 1 that is
particularly injurious to the developing brain. Because most neurons form before birth, prenatal exposure to an antimitotic agent would be especially
hazardous to the embryonic or fetal brain.
Environmental exposures need not be antimitotic
to lead to failures of neuron production. The discovery that there are families of genes, such as the HOX
genes and PAX genes, that are critical to early brain
development, along with the discovery that some of
these genes respond to teratogens, has opened a new
avenue of research in teratology. Retinoic acid (RA)
is a potent teratogen because it is the endogenous
signal that sets off the HOX cascade.18,19 If the level
of RA is too high, then genes such as HOXA1 and
HOXB1 produce too much of their protein product. If
the level of RA is too low, then the genes produce too
little of their products. Both situations lead to birth
defects of the CNS.20,21 In the future, we are likely to
find many more examples of teratogens that act by
altering gene expression, and some of the mechanisms will be unexpected. A recent example comes
from human and animal studies of the antiseizure
medication valproic acid (VPA). It has been known
for some time that human offspring who are exposed
to this drug have a significantly increased risk of
neural tube defects22 and an even greater risk of
neurologic symptoms and developmental delays.23
Subsequently, case reports began to suggest an association between exposure to valproate and autism.24,25 A recent study found that 5 of 46 children
who were enrolled in a family support group after in
utero exposure met the diagnostic criteria for autism,
pervasive developmental disorder, or Asperger syndrome.26 It has been reported that VPA is even more
potent than RA in increasing the expression of Hoxa1
and that this seems to be 1 of the drug’s mechanisms
of teratogenicity,27 but which mechanism could ex-
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plain how the drug accomplishes this alteration of
gene expression? A recent series of studies demonstrated that VPA is a direct inhibitor of histone
deacetylase.28 Inhibition of this family of proteins
causes a change in chromatin structure that increases
the availability of some genes for transcription.29
It may be that VPA’s effect of driving expression of
Hox genes is mediated by its inhibition of histone
deacetylase.
Soon after their formation, many neuron populations undergo a period of rapid apoptotic cell death
that cuts their numbers by half. The process coincides with synaptogenesis of the affected neurons
and thus is thought to represent selective retention of
those that have been most successful in forming connections. Researchers have identified several trophic
factors that influence the programmed death of neurons30 as well as some of the genes whose expression
is required.31 Thus far, no environmental agents that
affect programmed cell death have been discovered.
ing that interference with this protein’s role in migration may be 1 of the mechanisms by which hypoand hyperthyroidism are teratogenic to the CNS.
Unlike reelin, which is thought to act as a signal to
migrating neurons, the gene coding for cyclin dependent kinase 5 (cdk5) is expressed in migrating neurons, themselves. It is thought to play a role in the
cytoskeletal processes required for cell movement.
The phenotype of the knockout is complex. For example, Purkinje cells fail to reach their normal positions in the cerebellum, whereas granule cell precursors seem to migrate normally to the cortical surface
of that structure. Subsequently, granule cell progeny
fail to migrate to the internal granule layer. Clearly,
the activity of cdk5 is not required for migration by
all neurons at all stages of their development, but
some neurons require it at some stages.44
MIGRATION OF NEURONS
The discovery that handling of neonatal rodents
has a lasting effect on the nervous system, modifying
the animals’ response to stress as an adult,45 brought
attention to the fact that transient changes in the
milieu of developing neurons can have unexpected
effects. Release of corticosterone initiates the handling effect, but how this ultimately alters the brain
remains unclear, because the event has so many effects on so many parts of the CNS (reviewed by
Champagne and Meaney46). However, there are surprising new developments. Maternal behavior toward rat offspring shows individual differences,
which determine the response to stress in the next
generation, and features of an individual mother’s
behavior are seen to recur in the mothering behavior
of her female offspring. Studies in which pups are
raised by their own mothers or reared by unrelated
females demonstrate that this transmission of maternal behavior and stress responses is not genetic but
depends on the maternal behavior experienced by
the pups.47
It is now recognized that the processes by which
neurons establish their connections, begin to release
transmitters, and form receptors for transmitters are
targets for many teratogens. Any exposure that alters
hormone levels or transmitter levels has the potential
to be teratogenic. Furthermore, the chance of human
exposure to agents with these properties is great. For
example, the widespread use of psychoactive drugs
has increased the number of pregnancies in which
exposure to transmitter- or receptor-altering drugs
occurs. Another example is exposure to pesticides. It
should come as no surprise that the most efficient
way to control insects is by disrupting the function of
either the CNS or the reproductive system. Unfortunately, the transmitter systems and hormone systems
of humans are similar to those of insects.
The creation and elimination of synapses is a lifelong process, but the establishment of the basic pathways is essential to later development. Several environmental factors have been shown to reduce the
number of connections formed by neurons during
A number of teratogenic exposures are known to
lead to ectopic neurons, eg, neurons that should appear in gray matter appear in white matter, instead,
as though they failed to reach their normal destination. In most cases, it is not clear whether teratogens
interfere directly with the mechanisms involved in
the actual process of migration, because many agents
that reduce proliferation seem to result in ectopias
(eg, radiation,32 methylmercury,33 toluene,34 ethanol35,36). This suggests that loss of neurons as they
are forming eliminates signals that are needed for the
migration of those that are formed afterward. For
other agents, the mechanism by which migration is
disturbed is unclear.
What is more certain is that the timing of migration is well established for many different brain regions. Thus, migration failures sometimes can be
used to establish the stage of development when
injury occurred. For example, human cerebrocortical
ectopias suggest a disturbance of brain development
between the fifth or sixth week postconception,
when the cortical plate is established,37 and the fifth
month postconception, when virtually all cortical
neurons have assumed their final positions.38
The genetic control of migration is an area of research in which rapid progress has been made in
recent years. As we come to understand more about
what attracts moving cells and what repels them, it is
likely that environmental factors that interfere with
those processes will be identified. For example, it is
now known that the function of Reelin, the gene that
is abnormal in the reeler mutant mouse, is critical for
normal migration in the layered cortical structures of
the cerebral cortex, hippocampus, and cerebellum
(reviewed by Caviness and Rakic39) as well as other
structures that undergo migration, such as the facial
nucleus.40 Humans who lack the normal REELIN
protein exhibit lissencephaly with cerebellar hypoplasia,41 whereas increased REELIN expression has
been reported in cases of polymicrogyria.42 Reelin
expression is thyroid hormone dependent,43 suggest-
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ESTABLISHMENT OF CONNECTIONS,
NEUROTRANSMITTER ACTIVITY, AND
RECEPTOR NUMBERS
ENVIRONMENTAL CAUSES OF CNS MALDEVELOPMENT
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development. For example, protein malnutrition,48
hypothyroidism,49 and lead exposure50 of the postnatal rodent seem to disturb this process in cerebral
cortex.
Studies of the ontogeny of transmitters and their
receptors have yielded many surprising results. First,
the distribution of these elements in developing
brain differs from the distribution seen in adults.51–54
This fact has led to the recognition that the signaling
functions served by transmitter systems may differ at
different stages of development. For example, the
transmitters ␥-aminobutyric acid (GABA) and glutamate seem to act as chemoattractants to migrating
cortical neurons in the rat and the mouse, respectively,55,56 and glutamate serves the same role in the
cerebellum.57 The presence of GABAergic fibers is
thought to promote differentiation of monoaminergic and peptidergic neurons.51 Although GABA is
the major inhibitory transmitter in the mature CNS,
it has been shown to be excitatory to neurons in the
developing hypothalamus.58 Because the firing of
neurons plays a role as they differentiate to assume
their final transmitter characteristics,59 understanding what depolarizes developing neurons is an important field of investigation.
These examples make it clear that environmental
exposures that inhibit or mimic transmitter activity
are likely to disrupt development of the CNS. The
possibility has been confirmed for several psychoactive drugs. A classic case is that of prenatal exposure
to haloperidol. Brief prenatal exposure of rats provokes a decrease of dopamine receptor numbers that
persists after birth. The critical period for the lasting
effect is when dopamine receptor numbers are being
established.60 At the same time, muscarinic cholinergic receptor activity is increased,61 suggesting that
exposure permanently alters the type as well as the
number of receptors expressed by neurons when
they receive abnormal input at certain stages of development. Diazepam is another example of a drug
that affects receptors transiently in the adult but has
lasting effects when the fetal brain is exposed. Adult
norepinephrine levels in the hypothalamus are significantly reduced, and the stress response, as reflected in plasma corticosterone levels, is suppressed
in exposed animals when they reach maturity.62,63 As
with haloperidol, there is a critical period for diazepam’s teratologic effects. It occurs at the time when
benzodiazepine receptors are appearing, and blocking those receptors while diazepam is present eliminates the teratologic outcome.62
Nicotinic receptors are of special concern because
of the possibility of exposure from maternal smoking
and second-hand smoke. Nicotine exposure during
neurulation has been shown to interfere with neuron
survival in cultured rat embryos.64 Behavioral studies suggest that males exposed in utero respond to a
postnatal nicotine challenge with exaggerated locomotor activity, whereas females do not.65
There is no question that adolescence is a period
when the brain is undergoing maturational changes,
so there is good reason to suspect that environmental
factors might have important developmental conse-
quences during this period (reviewed by Adams et
al66). Nicotine is 1 of the few teratogenic agents that
have been studied for teratologic effects in the adolescent rodent. For obvious reasons, researchers are
concerned that nicotine exposure of adolescents may
be more addictive than later exposures. In a recent
series of studies,67,68 adolescent rats that were exposed to nicotine showed less obvious effects on
measures of neuron number and neuron size than
rats that were exposed in utero. However, they did
show long-lasting changes in noradrenergic and dopaminergic function, including aberrant responses to
a nicotine challenge.
Neurotoxicologists use the term “endocrine disrupters” to describe agents that are hormones, mimic
the effects of hormones, or alter hormone status.
Thyroid hormones and corticosterone have been
mentioned in earlier sections of this review. Sex hormones have long been known to have organizing
effects on the developing nervous system that lead to
permanent changes in many sexually dimorphic behaviors, from rough and tumble play to reproductive
behaviors to tolerance for salt and saccharine in
drinking water. The critical period for such changes
in the rodent extends from fetal to neonatal life,
whereas in primates, including humans, the critical
period occurs before birth.
A number of teratogens have been found to alter
sexually dimorphic behaviors. Of these, the ones
most studied in humans are synthetic progestins.
Offspring who were exposed prenatally attained significantly higher scores on a paper-and-pencil test of
potential for aggressive behavior than their unexposed same-sex siblings.69 In addition, tests of offspring indicated lasting effects on such personality
variables as independence and self-assurance.70 In
animal models, also, synthetic progestin exposure
during development affects later behavior. For example, Whalen et al71 found marked changes in sexual
receptivity of adult female rats that were exposed to
progestins in prenatal life.
Examples of teratogens that are not hormones but
alter sexual differentiation of the brain include cocaine, ethanol, and nicotine. The volume of the sexually dimorphic nucleus of the preoptic area72 in
male rats is significantly reduced by perinatal exposure to cocaine.73 Neonatal exposure to ethanol feminizes the preference of male rats for saccharinesweetened water.74 Prenatal exposure to ethanol
alters both saccharine preference and maze learning
in rats, making females behave more like males and
males behave more like females on these sexually
dimorphic measures.75 Studies of prenatal nicotine
exposure demonstrate that it can abolish the testosterone surge characteristic of male rats on the 18th
day of gestation and that exposed males exhibit a
feminized saccharine preference as adults.76
DEPOSITION OF MYELIN
Like other developmental events in the CNS, deposition of myelin runs on different schedules in different regions. A team of investigators has provided
a schedule of postnatal human myelination that
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highlights the status of many regions in the period
when myelination is proceeding most rapidly, from
birth to 24 months.77,78 Their survey of 62 sites in 162
autopsied infants describes both the median age
when myelin is mature and the variability with
which milestones of maturity are reached. As examples of white matter that myelinates early (50% of
cases by 68 weeks or less), the authors cited the optic
tract, the corticospinal tracts of the midbrain and
pons, and the middle cerebellar peduncle among
regions that show ⬎10% myelination at birth.
Among regions that lack myelin at birth, early maturity was observed in the optic and auditory radiations and the body and splenium of the corpus callosum. In the period between 70 and 107 weeks, the
pyramids, the lateral cerebellar hemispheres, and the
radiations to the frontal, parietal, and occipital cortices reached maturity in 50% of cases. Later-maturing
regions include the corticospinal tracts at the cervical, thoracic, and lumbar levels; the globus pallidus;
the frontal and temporal poles; and the mamillothalamic tract. Regions that mature past the period surveyed (after 144 weeks) include the tractus solitarius,
central tegmental tract, and fornix.
The environmental factor best known for interfering with myelin deposition is malnutrition.79 Postnatal undernutrition in rats delays and decreases rapid
myelination in the critical period that begins in the
second week after parturition.80 When rats were returned to a normal diet for 2 weeks, there was partial
recovery of myelin lamellae numbers on small axons
but not on large fibers.81 Other teratogens that are
thought to affect myelination include ethanol82 and
anticonvulsants83 at high doses.
POSTNATAL BRAIN DEVELOPMENT
Development of the CNS does not end at birth but
continues through infancy, childhood, and adolescence. Because developmental processes are vulnerable to disruption by agents that may not be toxic to
mature systems, it is reasonable to expect that the
later stages of brain development present special
risks. That expectation is confirmed by the known
effects of exposure to agents such as lead, which
causes lasting brain damage in children at doses well
below those that produce toxicity in adults.84 Both
prenatal and postnatal lead levels are inversely correlated with IQ.85,86
This pattern is far from universal. For example,
prenatal methylmercury exposure interferes with
brain development at much lower doses than postnatal exposure,14,87 and behavioral effects of polychlorinated biphenyls are related to prenatal exposure levels, although the doses delivered in breast
milk are higher than those received in utero.88 Completion of the blood-brain barrier at approximately 6
months89 protects infants and children from some
exposures, but it does not account for differential
sensitivity in all cases. For example, methylmercury
is transported across the barrier freely at any age.90 A
more likely reason for the apparent sensitivity of the
prenatal CNS is that many vulnerable developmental
processes are completed before birth. In addition, the
rapidity of events in the embryo and fetus makes
1080
them subject to even very brief exposure to hazards,
whereas the slower progress of later development is
likely to be more affected by chronic exposures. Developmental events around the time of puberty
could be an exception, and they are beginning to
receive some attention.
Two processes that might be vulnerable to environmental interference in childhood and beyond
have not been studied by teratologists. The first is
trimming back of connections, often called “pruning.” The number of synapses in the human brain is
thought to peak at approximately age 2 and decrease
by 40% to the adult number during adolescence.91
Unfortunately, because we have not identified any
environmental factors that reduce or increase pruning, it is not clear how to study what happens to
brain function when the process is altered. Increasing
information on the molecular mechanisms by which
pruning occurs may identify manipulations that can
be used to answer this question. In the meantime, at
least 1 developmental disorder—autism— has been
found to have a substantial number of individuals
with above-average head size, which seems to reflect
a large brain.92 Some of the subjects had increased
head size at birth, but in most, the growth trajectory
seemed to shift in childhood. No one knows whether
increased brain size plays a role in the symptoms of
autism, but results such as these make investigators
wonder whether this could be an example of a deficit
in pruning.
Neurobiologists long believed that neurogenesis in
the human ended during the first months of postnatal life, but recent rodent and primate studies demonstrate that there is lifelong neuron production in
some parts of the CNS, particularly the dentate gyrus
of the hippocampus.93,94 The same replacement of
old neurons with new is likely to occur in humans.
What is the role of this process in the normal CNS,
and what would happen to function if the process
were disturbed? Because many agents that disrupt
neuron proliferation are known, scientists are likely
to answer these questions soon.
CONCLUSION
A number of excellent reviews cover parts of the
material discussed in this article and extend to other
areas. Adams et al66 and Rice and Barone95 reported
the findings of a workshop organized to identify
critical periods of teratologic vulnerability in children. Herschkowitz et al96 described neurobiologic
development as it relates to behavior in the first year
of life. A chapter by Jensen and Catalano97 focuses on
brain morphogenesis and developmental injury. For
readers who want to learn more about the times
when different neurons form, there is a comprehensive summary of neuron birthdating studies in rats,
with extrapolation to human neurogenesis.37 A special issue of Neurotoxicology and Teratology was devoted to the question of whether teratologic results
of animal studies parallel the results in humans.98 It
reports the proceedings of a conference held to compare human and animal data on the developmental
neurotoxicity of various teratogens. The evidence
supports comparability across species for both the
ENVIRONMENTAL CAUSES OF CNS MALDEVELOPMENT
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outcome measures affected and the doses at which
effects occur.
Pediatricians know that they receive little or no
training in embryology or teratology of the CNS in
medical school or residency programs, but they may
be surprised to learn that the same lack of training
exists in all specialties, including obstetrics and gynecology. To the credit of the American Academy of
Pediatrics, it now offers an online continuing medical
education course in early brain and child development.
The pediatricians who reviewed this article suggested that it should include a reminder to the reader
that pediatricians have many opportunities to make
a difference in the prenatal development of children.
In fact, no specialty has more contact with women of
childbearing age in the preconceptional period,
which is known to be of paramount importance for
prevention of some birth defects, such as neural tube
defects. Mothers of pediatric patients and adolescent
girls are important target audiences for preconceptional counseling. The March of Dimes has developed a program of slides and notes to train clinicians
in assisting their patients and screening checklists
for evaluation of preconceptional health (www.
modimes.org—search site for “preconception”).
There is a special module for pediatricians.
Most reviews end with a call for more research,
and no one can doubt that there are enormous gaps
in our knowledge of the causes of CNS maldevelopment. However, what is most discouraging in this
field is not the limitations of the information available but the limited use that we have made of that
information in protecting children from environmental factors that cause CNS injury. If a pediatrician
were to read only 1 article from this reference list,
then it should be the article by Kimmel and Makris.3
It reviews the present status of regulations and
guidelines. Using the screening methods now in
place, virtually none of the human teratogens mentioned in this review would be detected as hazardous
to the developing brain of test animals at doses already known to cause lasting impairments of the
human CNS.
ACKNOWLEDGMENTS
Support was provided by U19HD/DC35466, a Collaborative
Program of Excellence in Autism.
I thank Norma Harary, Melanie O’Bara, and Barbara Tisdale for
assistance with the references for this article.
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Environmental Causes of Central Nervous System Maldevelopment
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Environmental Causes of Central Nervous System Maldevelopment
Patricia M. Rodier
Pediatrics 2004;113;1076
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
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