Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Developing Brain as a Target of Toxicity
Patricia M. Rodier
Department of Obstetrics/Gynecology, University of Rochester Medical
Center, Rochester, New York
Abstract
The human brain forms over an unusually long period compared to other
organs. While most of the basic structure is laid down before birth, neuron
proliferation and migration continue in the postnatal period. The blood-brain
barrier is not fully developed until the middle of the first year of life.
The number of synaptic connections between neurons reaches a peak around
age two and is then trimmed back by about half. Similarly, there is great
postnatal activity in the development of receptors and transmitter systems
as well as in the production of myelin. Many of the toxic agents known to
damage the developing brain interfere with one or more of these developmental
processes. Those with antimitotic action, such as X-ray and methyl mercury,
have distinctly different effects on structure depending on which neurons
are forming at the time of exposure. Vulnerability to agents that interfere
with cell production decreases rapidly over the early postnatal period.
Other toxic substances, such as psychoactive drugs and agents that alter
hormone levels, are expecially hazardous during synaptogenesis and the development
of transmitter systems, and thus continue to be damaging for years after
birth. Still other toxic substances such as lead, seem to have their greatest
effects during even later stages of brain development, perhaps by interfering
with the trimming back of connections. Guidelines designed to protect human
populations from developmental neurotoxicity need to take into account the
changing sensitivity of the brain as it passes through different developmental
stages, as well as the fundamental differences in the effects of toxicants
on the mature and the developing brain. -- Environ Health Perspect
103(Suppl 6):73-76 (1995)
Key words: toxicants, lead poisoning, brain development, synapse,
neurotransmitter, neurons, teratology
This article was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
Dr. Rodier's research is supported by NIH grants AA08666
and NS24287.
Address correspondence to Dr. Patricia M. Rodier, Department
of OB/GYN, Box 668, Medical Center, University of Rochester, 601 Elmwood
Avenue, Rochester, NY 14642. Telephone (716) 275-2582. Fax (716) 244-2209.
The nervous system in the adult is often described as one of the best-protected
systems of the body. It is physically protected by being encased in bone
and chemically protected by the blood-brain barrier, which prevents the
random passage of many toxic agents into the brain. It is common for adults
to experience toxic effects in the body systems most exposed to the outside
world: the gastrointestinal system, respiratory system, and skin; and in
the internal organs most exposed to blood-born toxic agents: the liver and
kidneys. Brain effects are relatively rare.
Unfortunately, the developing central nervous system (CNS) is much more
vulnerable to injury from toxic agents than the adult CNS. In fact, if we
consider congenital defects, we see the brain as the major target of toxicity.
If you try to list all the causes of birth defects that you know, you will
find that virtually all damage the nervous system, while most do relatively
little damage to other organs. For example, consider rubella (1),
metals like lead (2) and methylmercury (3), alcohol (4),
retinoids (5), and thalidomide (6). Among these, rubella can
cause heart defects, alcohol causes changes in facial features, retinoids
cause abnormalities of the ears and face, and thalidomide causes limb defects;
but CNS effects are seen with each of these agents, and often at lower doses
than those required to affect other parts of the body.
To understand why the CNS is so subject to developmental injury, it is
necessary to have some basic idea of how the CNS develops and how its development
compares to that in other organs. The nervous system arises from the ectodermal
layer of the germ disc, the flat surface that faces the amnion. A groove
appears along the midline of the disc and the folds on either side touch
and join, creating a tube that is wide open at the head and tail ends of
the embryo. The process of tube formation begins in what will be the cervical
region and proceeds toward the head and then the tail. The closure of the
tube is usually described as occurring between the 21st and 26th day after
conception. Failures of the process are common. About 1 in 1000 births in
the United States exhibits a neural tube defect. Some of these, like anencephaly,
are rapidly fatal. Others, like spina bifida occulta, are compatible with
life, but lead to varying degrees of abnormal innervation of the lower extremities.
Fortunately, a major cause of neural tube defects has been discovered recently,
and it is hoped that folic acid supplementation of the diet will prevent
many of these defects in the future (7).
More common still are failures of the development of the internal structure
of the CNS. Many of the agents we know to be toxic to the developing CNS
act by interfering with specific developmental processes. Some important
processes are represented in Figure 1.
Figure 1. Developmental
processes.
Neuron Proliferation
Even before the neural tube closes, neurons are being formed. The generation
of these critical cells continues throughout gestation and well into the
first year of life. Unlike cells in many organs, where only a few cell types
are repeated thousands of times, the CNS is made of dozens of different
types of neurons. Typically, a set of neurons destined to be similar in
morphology and function is generated in a short period, sometimes as little
as a few weeks or even a few days of gestation. Large motor neurons, like
those that stimulate muscles, are produced first, followed by sensory neurons.
Nuclear groups in the brain stem and diencephalon tend to form early, while
complex layered structures like the cerebral cortex, hippocampus, and cerebellum
add cells over a long period (8). In many structures of the CNS,
cell production creates numbers of neurons in excess of the number actually
needed, and the proliferation period is followed by a wave of cell death
that establishes the proper final number of neurons (see below).
The first panel of Figure 1 depicts the neural tube with cells on its
inner surface dividing. Some divisions add more cells to the generative
population, while others produce cells that leave the mitotic cycle and
become definitive neurons. An insult to cell proliferation affects only
the particular types forming in its presence. Thus, agents with this action
have very different effects on brain development when they are delivered
at different stages. They can reduce the number of a few cell types and
leave many other groups, formed before or after the injury, apparently normal
(9). Environmental agents with the property of killing neurons as
they are born include ionizing radiation (10) and methyl mercury
(11,12).
Obviously, cell proliferation occurs in all parts of the body. Yet, even
agents that interfere with all cell production seem to injure the CNS more
than other organs. This may be because the production of unique units is
a constant feature of CNS development, while other organ systems tend to
acquire all their basic cell types early, with subsequent growth consisting
of increasing the numbers of these cells, rather than adding new cell types.
In addition, we know that the neuron is a cell type that proliferates only
during development. Whereas many tissues retain the capacity to add cells
throughout life, any loss of neurons is permanent.
Cell Migration
The second panel shows that neurons may travel from their place of origin
to their final positions in the nervous system. In structures like the cerebral
cortex, where cells are born on the inner surface of the neural tube and
then move to the outer surface, the distances traveled can be substantial.
Cell migration does not proceed at a constant rate throughout development.
Like cell proliferation, it occurs in waves associated with different cell
types. Most migration occurs early in gestation, when distances within the
brain are small. The long migrations of small cells of the cerebral cortex,
hippocampus, and cerebellum continue for several months after birth.
Occasional neurons in the wrong location occur in normal brains, but
patches of misplaced neurons are characteristic only of brains with serious
developmental injuries. Because toxic agents that lead to migration failure
are often known to interfere with proliferation as well, it has been difficult
to determine whether there are agents that affect migration exclusively,
or whether migration failures result when cells are lost, changing the environment
of the cells that form later. Ionizing radiation (13) and methyl
mercury (14,15) provide examples of the dual effect on cell survival
and migration. In any case, neurons that are out of position cannot make
the proper connections with the neurons that should be their neighbors,
so they cannot develop normal function.
Synaptogenesis
To achieve mature function as transmitters of signals, neurons must form
connections. This requires the development of specialized structures on
the surfaces of the sending and receiving neurons. The point of contact
is a synapse. A typical large neuron is covered with thousands of these.
Research indicates that receptors appear on large groups of like cells simultaneously,
and release of appropriate transmitters from cells projecting into the region
follows soon after. Classic causes of deficient synaptogenesis are malnutrition
(16) and hypothyroidism (17). Lead also interferes with the
process of synaptogenesis (18).
While neurons retain the ability to make new synapses throughout life,
the developmental period is critical for the formation of the basic circuitry
of the nervous system. In addition, many lines of evidence suggest that
some of the early communication of neurotransmitters to their receptors
has a developmental purpose, signaling information for further development,
rather than signaling to control body functions, as in the adult (19).
Because of this, messengers that have transient effects in the adult may
have permanent effects in the developing organism. The result is that agents
that block signals or increase them can interfere with CNS development.
Our society uses countless numbers of products designed to affect neural
transmission. These include drugs for human consumption and drugs directed
at pests. As a class, substances that act as transmitters or hormones, or
which can mimic the actions of these messengers, are suspect for altering
synaptogenesis. Such agents are likely to disturb CNS development. An example
is the herbicide TOK (2,4-dichlorophenyl-p-nitrophenyl ether), which
lowers thyroxin levels. Mice exposed to TOK prenatally have abnormalities
in many systems, including the CNS (20).
Cell Death
Substantial progress has been made in understanding how cells die in
the normal course of CNS development. What determines which cells die has
been more difficult to ascertain. It is likely that one factor is the number
or kind of connections a neuron has made before the cell death period. The
period of cell death typically coincides with the period when connections
are actively forming. Whatever the determining factor, it is clear that
naturally occurring cell death is not a passive process. Rather, the cells
are removed in an aggressive and efficient manner. Presumably, such action
serves to leave the CNS with an optimal number of well-connected neurons.
Indications of failure of the necessary cell loss have been reported in
some brain regions of individuals with autism (21). On the other
hand, the active removal of cells could go beyond what is needed.
Transmitters and Receptors
The story of the differentiation of neurons as message carriers goes
beyond the process of making connections. For example, the level of activity
of a neuron seems to influence the development of receptors in the cells
to which it projects (22). Further, the nature of the transmitting
chemicals a cell produces appears to be controlled by the stimulation the
cell receives at particular stages of development (23).
When the immature brain is compared to that of the adult, there are striking
differences in the location and number of receptors (24). Release
of excitatory amino acids is a response to ischemia at all ages, and contributes
substantially to subsequent cell loss by overstimulating neurons with appropriate
receptors. McDonald and Johnston have proposed that the remarkable effects
of hypoxia-ischemia on the developing brain may be due in part to the rich
supply of excitatory amino acid receptors in the immature tissue (25).
Trimming of Connections
Just as cells form in numbers greater than required by the mature nervous
system, connections form in great excess during development. The winnowing
of these connections to the needed number is a longer process than cell
death. Thus, we see very high numbers of connections in the cerebral cortices
of weanling-age rats and cats (16,26) and in 2-year-old children
(27). As with cell death, we assume that the synapses that disappear
are less useful in some way than those that are retained. However, we know
little about the process by which some connections are eliminated and others
are preserved. This process is represented in the last panel of Figure 1.
Recent data on the interaction of low doses of lead with several processes
involved in transmission at the synapse have suggested the hypothesis that
this metal may interfere with the process of synapse trimming by reducing
the difference in level of activity between active and inactive synapses
(28).
Myelination
The coating of axons by sheets of glial tissue provides insulation and
makes transmission along the axon more rapid. We know from many demyelinating
diseases in the adult how important myelin is for CNS function. A number
of agents are thought to interfere with the deposition of myelin in the
developing brain, and since new waves of myelin formation continue into
adulthood, such agents could be hazardous over an extremely long period
(29).
Development of the Blood-Brain Barrier
In addition to the sensitive processes just described, the developing
brain is distinguished by the absence of a blood-brain barrier. The development
of this barrier is a gradual process beginning in utero and complete
around 6 months after birth in the human (30). Thus, some toxic agents
that never enter the mature brain enter the developing brain freely. Examples
include cadmium (31) and monosodium glutamate (32).
In summary, the brain is vulnerable to agents that interfere with any
of the processes involved in its development. Because of the complexity
of a tissue with thousands of interconnecting circuits, the establishment
of the mature systems of neural tissue involves more developmental processes
than those of other tissues. Because of this, there are more opportunities
for injury. Probably the most important feature of the CNS with regard to
developmental accidents, however, is the sheer length of time over which
development of the CNS proceeds.
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