||We have an interest on
the effects of lead on children, particularly as it relates to the auditory system, and
whether lead causes hearing loss or deafness. Our research studies are conducted at the
organismic level and at the cellular level. At the organismic level, we utilized auditory
assessment methods such as Video Otoscopy, Real Ear (acoustic characteristics of the ear
canal), Middle Ear Impedance, Otoacoustic Emissions, Auditory Brain Stem Evoked Responses,
and Late Auditory Evoked Potentials. For our cellular studies, we utilized combined
techniques of Cell Culture, Patch Clamp Electrophysiology, Immunocytochemistry,
Photomicrography, and Molecular Biology.
||The normal development
of the young central nervous system (CNS) is vulnerable to a number of environmental
factors, including lead (Pb2+). Harmful levels of lead have concerned educators
and researchers for a number of years due to its debilitating effect on learning and
memory. Pb2+ exists in the air, drinking water, soil, wall fixtures, dust,
lead-based paints, venetian blinds and several industrial products. It is a potent
environmental toxicant that has been associated with adverse CNS and behavioral disorders
of both laboratory animals and humans. Surveys conducted by the Public Health Service
concluded that environmental Pb2+ poisoning is among the top four diseases of
young children. Pb2+ is so potent that the Center for Disease Control has had
to lower its risk for neurotoxicity several times, from blood-lead levels of 60 mg/dl to
the current accepted level of 10 mg/dl.
majority of research that has examined the effects of Pb2+ exposure has
identified children exhibiting deficits of the CNS. Children exposed to high levels of Pb2+
prenatally and others who were exposed to Pb2+ postnatally exhibited poorer
scores on measures of cognitive function and central auditory processing abilities. Pb2+
-induced impairments are of concern because they are believed to lead to learning and
memory disorders. Some researchers report that Pb2+ intoxication is most
intense during the first two years of life, suggesting a critical period for impairment.
The period coincides with the critical period for normal language and speech development.
Some investigators previously believed that Pb2+
exposure posed more of a threat to the young developing CNS than to the developed CNS
system. However, it has been reported that the cochlear nerve and central auditory
structures were preferentially sensitive to the effects of Pb2+ exposure in
both developing and mature systems. In fact, elevated hearing thresholds in both young
children and adults and increased latencies of auditory brainstem responses in adults have
been reported as a result of exposure to environmental Pb. Cases of
occupationally exposed workers with acute and chronic episodes of Pb2+
intoxication have been investigated. The highest levels of blood-Pb2+ levels
ranged from 40 mg/dl to 175 mg/dl, with a mean of 83 mg/dl. Abdominal pain, headache and
fatigue were among the many reported symptoms among the population.
Limited information is available concerning the effects of Pb2+
on sensory function and the mechanism(s) responsible for lead toxicity. However,
sufficient data are available which support the occurrence of elevated hearing threshold
levels, as well as an increase in the threshold of activation for the initiation of an
action potential in the presence of varying levels of Pb2+. In addition,
histological studies of auditory structures have found segmental demyelinization and
axonal degeneration of the cochlea nerve with no apparent effect on the vestibular and
spiral ganglia. Unlike other voltage-gated ionic channels (e.g., Ca2+) and
ligand-gated ionic channels, the question still remains, do hair cells or spiral ganglion
cells (SGCs) of the inner ear exhibit normal pharmacological and kinetic channel activity
in the presence of Pb2+ within the mammalian auditory system?
In an attempt to identify the mechanism(s) responsible for Pb2+
neurotoxicity, pharmacological studies have investigated the effects of Pb2+ on
synaptic transmitter release, kinetic properties of ionic currents and sensitivity to
neuronal development. A group of investigators in 1984 studied neurotransmitter release at
the neuromuscular junction of rats and found that Pb2+ (100 mM) effectively
blocked the nerve-evoked end-plate potential (EPP). Both effects were reversible when
washed with normal external solutions. Another investigator in 1990 investigated the
effects of Pb2+ on two receptor operated ion channels [Serotonin or 5-HT and
neuronal nicotinic acetylcholine (ACh) receptors] and two voltage-gated ion channels (Na+
and Ca2+) of mouse neuroblastoma cells. The ACh induced inward current was
blocked by nanomolar concentrations of Pb2+. Comparatively, the transient
inward current mediated by 5-HT receptors required a larger quantity of Pb2+
(1.0 mM) before a steady reduction of current amplitude was observed. High concentrations
of barium (Ba2+) produced a fast transient as well as a noninactivating inward
current. Both types of currents were reduced in the presence of 10 mM of Pb2+.
However, the Na+ current remained unaffected up to 100 mM of Pb2+.
Abnormalities in the movement, distribution, as well as
inhibition in the functional capacity of Ca2+ channels in the CNS due to Pb2+
neurotoxicity may play an important role in neuronal development. One investigator found
that chronic exposure of rats to low levels of Pb2+ reduced the number of
inositol triphosphate (IP3) second messenger receptors and thus reduced the
capacity of IP3 to mobilize Ca2+ from intracellular sources. This
action may alter normal cell development and thus lead to CNS dysfunction.
The NMDA glutamatergic receptor is known to be involved in the
processes of learning and plasticity as well as playing a key role in the early stages of
neuronal development. Thus, it was demonstrated that Pb2+ blocked NMDA induced
currents of cultured hippocampal neurons in an age-dependent manner. In other words, 10 mM
Pb2+ decreased the NMDA response by 57% during the first week; however, the
same concentration of Pb2+ during the fourth week of exposure only reduced the
NMDA response by 15%.
Two other investigators examined the response of divalent
cations (Ca2+, Pb2+, Cd2+) on both tetrodotoxin-sensitive
(TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels of rat dorsal root ganglion
(DRG) cells. The peak TTX-S current was reduced by 20% in the presence of externally
applied Pb2+ compared to 22% by the addition of 5 m M Ca2+. The
activation voltage was unaffected by Ca2+ but shifted in the depolarized
direction in the presence of Pb2+ (50 mM). Conduction-voltage curves showed a
minimal decrease in the maximal conductance of the TTX-S currents in the presence of Pb2+.
Peak TTX-R currents were more sensitive to the actions of Pb2+ and Cd2+
and less sensitive to Ca2+ than TTX-S currents. The TTX-R current was reduced
by 70.4% at a membrane level of +10mV by 50 mM Pb2+. Conductance curves were
measured at membrane potentials where conductance attained 50% of its maximal values.
Conductance curves were shifted 25.3 mV by Pb2+. Maximal conductance decreased
55.2% to Pb2+. Effects seen for both TTX-S and TTX-R were reversible after
washing the cell for 1 - 2 minutes with normal external solution.
||Pb2+ is one
of several heavy metals that is toxic to the body and found to cause lead poisoning. It
exerts its toxic effect by combining with one or more reactive groups (ligands) essential
for normal physiological functions. Heavy metals such as Pb2+ react in the body
with ligands containing oxygen and nitrogen. This creates a metal complex formed by a
coordinate bond. Heavy metal antagonists known as chelating agents are designed to reverse
the binding of Pb2+ to body ligands by blocking the binding of Pb2+
to the ligands. One investigator defines a chelate as a complex formed between a metal and
compound that contains two or more potential ligands. This reaction produces a
heterocyclic ring. Chelating agents are designed to compete with the groups of ligands for
the metal, thereby, preventing or reversing the toxic effects and enhancing the excretion
of the metals.
Pb2+ poisoning can be
either acute or chronic. Acute Pb2+ poisoning occurs infrequently and typically
results from ingestion of acid-soluble Pb2+ compounds or inhalation of Pb2+
vapors. Chronic Pb2+ poisoning, also known as plumbism, can have adverse
affects involving one or any combination of the following systems: gastrointestinal
system, neuromuscular system, CNS, hematological and renal systems. The absorption of Pb2+
into the body enters by two major routes, the respiratory and the gastrointestinal tract.
Absorption of inhaled Pb2+ depends upon the form of Pb2+ (vapor vs.
particles) ingested as well as the concentration of ingested Pb2+. Ninety nine
percent of Pb2+ absorbed into the blood stream binds to hemoglobin in
erythrocytes. Inorganic Pb2+ is initially distributed in soft tissue organs
such as the liver and kidneys. It is later found redistributed and deposited in bone,
teeth (seen as lead lines) and hair. Only small amounts of inorganic Pb2+
accumulate in the white matter of the brain, with most of the deposited Pb2+
found in gray matter and the basal ganglia.
N.B.: Several research papers and key references were consulted
in order to write this review. We have chosen not to list the references here for the sake
of brevity. A version of this review is available with references and bibliography. To
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