Manganese - Toxicology of Metals - page 644

support the hypothesis that oxidative damage is a
mechanism of action in manganese-induced neurotox-
icity in rat.
The role of mitochondrial energy metabolism in
manganese toxicity was indicated by two studies
(Aschner and Aschner, 1991; Gavin et al ., 1990). A study
by Brouillet et al . (1993) suggested that the mitochon-
drial dysfunctional effects of manganese result in vari-
ous oxidative stress to cellular defense mechanisms
and secondary free radical damage to mitochondrial
DNA. At the previously mentioned Conference on
Manganese, the mitochondria were singled out as
critical organelles in the cell, and the role they might
play in manganese-induced cellular damage was tar-
geted as an important subject for further investigation
(Aschner, 2002). Oxidative stress generated through
mitochondrial perturbation may be a key event in the
demise of the affected central nervous system cells.
Studies with primary astrocyte cultures have revealed
that they are a critical component in the defenses
against manganese-induced neurotoxicity (Dobson
et al ., 2004). Enhanced oxidative stress may take place
particularly in catecholaminergic (i.e., dopamine) cells
(Erikson et al ., 2004).
Transcriptional patterns of genes related to oxida-
tive stress of infl ammation were examined in the brains
of rats exposed to inhaled manganese during either
gestation or early adulthood (HaMai et al ., 2006). The
expression of genes encoding for proteins critical to an
infl ammatory response and/or possessing prooxidant
properties, including TGFß and nNOS, were slightly
depressed by prenatal exposure, whereas inhalation
exposure to manganese during adulthood markedly
down-regulated their transcription. When exposure
to manganese occurred during gestation, the extent
of altered gene expression induced by subsequent
exposure to manganese in adulthood was reduced.
The obtained results suggest that prior exposure to
manganese may have attenuated the effects of inha-
lation exposure to manganese in adulthood, in which
the expression of infl ammation-related genes were
suppressed.
Some experimental evidence suggests that the
mechanisms of manganese toxicity may depend on
the oxidation state of manganese. However, both the
trivalent (MnIII) and divalent (MnII) forms have been
demonstrated to be neurotoxic (Aschner and Aschner,
1991), but it is important to note that the oxidation of
catechols is more effi cient with Mn(III) than with Mn(II)
or Mn(IV) (Achibald and Tyree, 1987). Formation of
Mn(III) may occur by oxidation of Mn(II) by superox-
ide (Hussain et al ., 1997). Both Mn(III) and Mn(II) can
cross the blood-brain barrier, although it is suggested
that Mn(III) is predominantly transported bound to the

protein transferrin, whereas Mn(II) may enter the brain
independently of such a transport mechanism (Murphy
et al ., 1991). A large portion of manganese is bound to
manganese metalloproteins, especially glutamine syn-
thetase in astrocytes. A portion of manganese prob-
ably exists in the synaptic vesicles in glutamatergic
neurons, and manganese is dynamically coupled to
the electrophysiological activity of the neurons. Man-
ganese released into the synaptic cleft may infl uence
synaptic transmission. So, as pointed out by Takeda
(2002), understanding the movement and action of
manganese in synapses may be important to clarify the
function and toxicity of manganese in the brain.

6.3.1.2 Health Impairment
Syndrome (disease) of neurological effects of man-
ganese is referred to as “manganism.” As early as 1837,
John Couper reported fi ve cases of poisoning, with a
picture similar to paralysis agitans (Parkinson's dis-
ease), among men employed in grinding manganese
dioxide in the manufacture of chlorine for bleaching
powder. Couper's description of the disease remained
forgotten for almost a century. In 1901, Von Jaksch in
Prague and Embden in Hamburg rediscovered the
disease and for three and four cases, respectively, they
provided an accurate clinical description of mangan-
ism. After that time, a large number of cases of chronic
manganese poisoning have been reported. Up to 1935,
152 cases of manganism had been described in the
literature (Voss, 1939). According to the EPA (1993),
7550 cases of manganism had been recorded since the
fi rst report in 1837. A notable increase during the past
50 years may be presumably explained by use of differ-
ent diagnostic criteria for manganism. Although earlier
clinically fully developed cases only had been consid-
ered as manganism, later cases with initial symptoms
and signs might be registered as well.
Neurological effects, as the hallmark of excessive
exposure to manganese in humans, are associated
primarily with inhalation in occupational settings.
Exposure to manganese dioxide in mines or in ore
processing plants had been the most common cause of
the disease. There have been reports of manganism in
Huelva miners in Spain (Dantin Galego, 1935), Sinai
miners (Nazif, 1936), German miners (Büttner and
Lenz, 1937), Morrocan miners (Rodier and Rodier,
1949), Chilean miners (Ansola et al ., 1944), Cuban min-
ers (Garcia Avila and Peñalver, 1953), Romanian miners
(Wassermann et al ., 1954), miners in Mexico (Roldan,
1955), miners in the former U.S.S.R. (Khazan, et al .
1956), Japanese miners (Suzuki et al ., 1960), and Indian
miners (Chandra et al ., 1974). Manganism occurring in
ferromanganese plants have been described by Dogan
and Beritic (1953), Jonderko et al . (1971), Rosenstock