Chemistry Reference
In-Depth Information
the effect of 200
mol/L MeHg on a culture of human
fetal neurons. The normal migration of neurons from
the center of the colony was inhibited followed by a
tdegeneration of neurites with fragmentation of neu-
rites from the cell body. Injuries to the microtubuli
were observed in the electron microscope and at an
early stage also on the plasma membranes. Sager and
Doherty (1982) observed in
in vitro
studies that 40
µ
µ
preparation of sciatic and sartorius nerves. These effects
were observed at a concentration of 10
mol/L MeHg.
Hrdina
et al
. (1976) reported a decrease of cortical ace-
tylcholine and serotonin in the brain stem of MeHg-poi-
soned rats. Concentrations of MeHg in the brain were
not reported (Hrdina
et al
., 1976). Studies of the electri-
cal organ of the
Torpedo oscilata
have shown that MeHg
with high specifi city blocks the acetylcholine receptor
(Eldefrawi and Mansour, 1976; Shamoo
et al
., 1976).
Astrocytes accumulate MeHg that causes swell-
ing of the cell and inhibition of uptake of excitatory
amino acids like glutamate and aspartate. This effect
is seen in astrocyte cultures with MeHg concentration
approximately 10
µ
mol/L of MeHg in the media inhibited the polym-
erization of tubulin by 60%. Tubulin is the basic ele-
ment in the microtubuli of the brain cells. Microtubular
fragmentation has been seen in cultured primary rat
cerebellar granular neurons at a MeHg concentration
as low as 0.5-1
mol/L (Castoldi
et al
., 2000). So far,
no author has determined the intracellular concentra-
tion of MeHg after onset of effect. This shortcoming
prevents a comparison of concentrations between dif-
ferent experiments, because the protein concentration
in the media varies in different investigations.
Effects on mitochondria respiration in the brain tis-
sue have been observed
in vivo
as well as
in vitro
(Verity
et al
., 1975; Von Burg
et al
., 1979). However, these effects
appeared at a MeHg concentration in brain in an order
of magnitude above the concentration at which toxic
effects appear (i.e. 10-100
µ
mol/L (Aschner
et al
., 1993; 2000).
Park
et al
. (1996) demonstrated the importance of exci-
totoxic effects for the neurotoxicity of MeHg on a cul-
ture of rat cerebral neurons, showing that antagonists
of
N
-methyl-D-aspartate (NMDA) receptor inhibit the
toxic effect of MeHg (Park
et al
., 1996).
Extensive studies on animals have been performed
to reveal the toxicology of MeHg. From the preceding,
it is clear that the toxicokinetics of MeHg vary con-
siderably in different species, especially the fraction
of MeHg, which is absorbed and accumulated in the
CNS. This fraction seems to increase phylogenetically
in the animal species with advanced brain develop-
ment. In the rat, 1% of the body burden of MeHg is
retained in the brain, whereas in man 10% is retained.
In other mammals, percentages lie between these two
extremes. There are not only quantitative differences
but also considerable qualitative ones among species.
The CNS is the critical organ in primates, whereas
in rodents, kidneys and peripheral nerves are dam-
aged at lower doses than those that affect the brain
(Magos and Butler, 1972). When the CNS is damaged
by MeHg, the damage occurs in different parts of the
brain for different species. Typically, the MeHg con-
centration in the nerve tissue is between 5 and 10
µ
µ
mol /L MeHg) in the tissue.
Verity and coworkers, Von Burg and coworkers, and
Wakatayashi
et al
. (1976) studied the effects of MeHg,
given parenterally to rats, on the axonal fl ow in the sci-
atic nerve. At a mercury concentration of 20
µ
g/g in
the brain, they found an increased axonal fl ow. Local
injection of MeHg in the vicinity of the sciatic nerve
resulted in total blockage of axonal fl ow locally. Asano
et al
. (1979) studied the enzyme activity in lysosomes of
brains of MeHg-poisoned rats. They found a decreased
activity at highly toxic doses.
MeHg induces generation of reactive oxygen radi-
cals in rat glia cells and neurons (Yee and Choi, 1996). If
the generation of such radicals is inhibited, the toxicity
of MeHg is decreased (Sarafi an
et al
., 1994). MeHg in a
few micromolar concentrations has also been reported
to disrupt Ca
2+
homeostasis causing increased intracel-
lular Ca
2+
concentration (Oyama
et al
., 1994). Adminis-
tration of blockers of voltage-dependent Ca
2+
channels
to rats dosed with MeHg prevents the appearance of
neurological signs (Sakamoto
et al
., 1996).
Studies have also been performed on the effects of
MeHg on neurotransmitter concentrations in the brain,
on specifi c transmitter receptors, and on the synaptic
performance. A concentration of MeHg-chloride of 5-10
µ
µ
g/g when the fi rst morphological damage appears.
In the rat, the fi rst morphological changes appear in
the dorsal root ganglia at a concentration of approxi-
mately 10
g/g. These changes are combined with
degenerative changes in the peripheral nerves. Twice
these mercury concentrations in the brain are neces-
sary to cause changes in the cerebellum, as well as in
the granular cells and the brain stem. At much higher
mercury concentrations, more extensive damage can
be seen in other parts of the brain. These changes are
partly secondary to vascular damage that is mainly
seen in the arterioles (Diamond and Sleight, Fehling
et al
., 1975; 1972; Herman
et al
., 1973; Klein
et al
.,
1972). Such seemingly primary vascular damage has
also been observed at very high doses of MeHg in
primates (Shaw
et al
., 1979).
µ
mol/L added to mouse brain homogenates resulted
in an increased release of transmitter substances such
as dopamine, glutamate, GABA, glycine, and choline
(Bondy
et al
., 1979). Juang (1976) observed that MeHg
increased the presynaptic release of acetylcholine on a
