Full text of DOI:10.1080/10915810050178761

Effects of Subchronic Exposure to Manganese Chloride
on Tissue Distribution of Three Essential Elements in Rats
Pascale Missy,1 Marie-Claire Lanhers,1 Lisiane Cunat,1 Michel Joyeux,2
and Daniel Burnel1
1
´ ´
´
`
´
´
Laboratoire de Chimie Generale Appliquee a la Medecine, Departement Environnement
´
´
´
´
´
et Sante Publique, Faculte de Medecine, Universite Henri Poincare, Nancy I,
Vandoeuvre-le`s-Nancy, France
2S.E.R.E.S., De´partement Environnement et Sante´ Publique, Faculte´ de Me´decine,
Universite´ Henri Poincare´, Nancy I, Vandoeuvre-le`s-Nancy, France
case of overexposure, the main entry route being the gastroin-
(
)
(
)
testinal tract and the respiratory tract WHO 1981 . The sources
A subchronic treatment of manganese chloride MnCl2 was ad-
(
)
(
ministeredtoratsby intraperitoneal IP route 6 mg Mn/kg of body
weight/day or oral PO route 75 mg Mn/kg of body weight/day
for 4 weeks. After a 2-week interval, different tissues plus the blood
were sampled. An increase of manganese Mn concentrations was
observed in most of the tissues, particularly in the nervous system
(
of overexposure to Mn are essentially work related extraction
and crushing of Mn ores, iron and steel industry and metallur-
gical processes, fabrication of dry batteries, use of pesticides in
agriculture . However, thegeneral public isalso atrisk ofoverex-
posure, notably through contaminated drinking water Kondakis
)
(
)
(
)
(
)
)
(
(
)
brain and spinal cord and in femur, with the exception of liver,
adrenal glands, and esophagus by IP treatment and liver, jejunum,
ileum, and adipose tissue by PO treatment. Tissue accumulation
of Mn was greater by IP treatment. During each of the two treat-
ments, urinary and fecal excretion of Mn increased. The presence
of Mn observed in whole blood, bone marrow, and spleen after IP
treatment could be explained by the existence of competition be-
)
(
et al. 1989 and the combustion of MMT methylcyclopenta-
)
dienyl manganese tricarbonyl , an antiknock agent sometimes
used as an additive in lead-free gasoline Zayed, Vyscocil, and
Kennedy 1999 . The effects of overexposure are mainly ob-
served as neurological disturbances due to neuron degenera-
(
)
(
)
tween iron Fe and Mn that may appear, notably, as a disturbance
(
) (
tion of the basal ganglia globus pallidus principally Verity
(
in the functioning of the respiratory chain in the cells incomplete
)
1999 .
The toxic effects of Mn have been widely studied, using
animal models, notably concerning the accumulation of Mn
in tissues search for target organs and interactions with var-
)
[ ] ]
ious other elements e.g., iron Fe , zinc Zn , copper Cu
O2 reduction and formation of free radicals and oxygenated com-
)
pounds , leading to cellular degeneration. In these experimental
conditions, no obvious competition could be observed with zinc
(
)
(
)
(
)
Zn and copper Cu . Despite a large accumulation of Mn in the
bones, no disturbance of the phosphorus-calcium metabolism was
(
[
]
[
observed.
after subchronic or chronic administration. Nonetheless, there
is wide disparity between the different experimental protocols
Keywords Essential Elements Interactions, Excretion, Manganese,
Oxygenated Radicals, Route of Exposure, Tissue Distri-
bution, Toxicity
(
used concerning the doses of Mn, the administration routes in-
)
]
[ ]
[
]
[
traperitoneal IP , oral PO , intravenous IV , the length of
(
)
treatment 4 to 12 weeks , as well as the number of target or-
(
)
[ ]
gans studies limited to brain or extended over several organs
(
)
Despite the fact that manganese Mn is considered an es-
(
[
]
and the elements studied magnesium Mg , phosphorus P ,
sential element, due to its participation in numerous enzymatic
reaction either as a cofactor or as an integral part of the enzy-
matic protein Frederick 1994 , it can also prove to be toxic in
)
[ ]
[
]
[
]
calcium Ca , sodium Na , potassium K . Thus, it is impos-
sible at the present time to present an overall evaluation of the
data. The objective of our work was thus to conduct a compar-
ative study, as complete as possible, based on one experimental
(
) (
)
(
)
protocol, that is, subchronic daily exposure 4 weeks to Mn
Received 26 March 2000; accepted 9 June 2000.
(
)
chloride MnCl2 , a chemical form that makes it possible to
Address correspondence toPr Daniel Burnel, Laboratoire de Chimie
Ge´ne´rale Applique´e a` la Me´decine, De´partement Environnement
et Sante´ Publique, Faculte´ de Me´decine, Universite´ Henri Poincare´,
Nancy I, 9, Avenue de la Foreˆt de Haye, BP 184, 54505 Vandoeuvre-
le`s-Nancy Cedex, France. E-mail: p.missy@caramail.com
(
obtain satisfactory retention in the tissues Cahill et al. 1980;
)
Gianutsos et al. 1985; Roels et al. 1997 . The distribution of
Mn and three other essential elements Fe, Zn, and Cu were
studied in 20 tissues. We also determined their concentrations
(
)
–
International Journal of Toxicology, 19:313 321, 2000
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c
°
Copyright 2000 Taylor & Francis
313
1091-5818/00 $12.00 + .00

P. MISSY ET AL.
314
(
in the blood, plasma, and urine, as well as the concentration of
The urine and feces were collected on precise dates before,
)
Mn in feces. In addition, changes in the animals’ body weight during, and after the 4 weeks of exposure to Mn . To this end, the
were monitored. With the same basic protocol, two administra- animals were kept in individual metabolism cages for 24 hours
tion routes were used: the IP route, commonly used in toxicity immediately after administration of the solutions; they were sub-
studies, and the PO route, common in cases of accidental over- jected to a solid diet in order to avoid contamination of the
(
exposure. The daily IP dose administered 6 mg Mn/kg body urine and feces. The different samples were treated with nitric
)
(
weight was determined on the basis of the literature Seth and acid.
Husain 1974; Singh, Chandra, and Tandon 1975; Singh et al.
After the different treatments, a 2-week rest period was ob-
1974; Tandon 1973; Tandon and Mathur 1976; Tandon and served. During this waiting time, Mn that was not bound to
)
(
Singh 1975; Tandon et al. 1975 ; the daily PO dose 75 mg the tissue could be eliminated. The rats were then sacriŽ ced,
)
(
Mn/kg body weight was determined in such a way as to ob- after being anesthetized with sodium pentobarbital 60 mg/kg
)
tain a quantity of absorbed Mn close to that obtained by the IP body weight . Blood samples were taken with heparin tubes
(
route, taking into account the data in the literature related to by puncture of the abdominal vein with an infusion set Mi-
)
absorption rates, the in uence of Mn present in food, and the cro ex, Vigon, Ecouen, France . Part of the sample was im-
fasting required in our study during phases of urine and feces mediately centrifuged at 3000g for 3 minutes in order to re-
(
sampling Abrams et al. 1976a; 1976b; Davis, Zech, and Greger cover the plasma. The plasma and blood samples were then
±
+
1993; Greenberg, Copp, and Cuthbertson 1943; Lee and Johnson stored at 4 C. Just before assay, the blood was diluted 1:2
(
1988; Roels et al. 1997; Weigand, Kirchgessner, and Helbig with ultrapure water. Different tissues brain, spinal cord, fe-
)
1986 .
mur, bone marrow, heart, lungs, liver, spleen, pancreas, kid-
neys, adrenal glands, testicles, esophagus, stomach, duodenum,
jejunum, ileum, colon, skeletal muscle, fur and skin, adipose
)
tissue were rapidly collected, weighed, frozen, and kept at
¡
MATERIALS AND METHODS
Chemical Products
18±C. Before assaying, they were thawed and treated with
nitric acid.
(
)
Manganese dichloride tetrahydrate, MnCl2 4H O was sup-
¢
2
(
)
plied by Fluka St Quentin Fallavier, France , sodium chloride
(
)
(
NaCl was supplied by Aldrich St Quentin Fallavier, Determination of Metals
)
(
)
France , and Suprapur nitric acid solution HNO3, 65% was
Concentrations of Mn, Fe, Zn, and Cu were determined in
(
)
supplied by Merck Nogent-sur-Marne, France . Ultrapure wa-
(
the biological media by atomic emission spectrometry Spectra-
(
)
ter Milli-Q, Millipore was used for the preparation of all the
solutions.
)
metrics Spectra Span V .
Data Analysis
Animals
Results in Ž gures, tables, and text are expressed as the mean
§ standard deviation. Student’s t test was used for comparison
of the means of unpaired data. For multiple comparison, analy-
(
Outbred male albino rats of the Wistar strain Iffa Credo,
)
l’Arbresle, France , weighing 345 § 20 g were housed individ-
(
)
(
)
sis of variance ANOVA complemented with Fisher’s PLSD
ually in standard plastic cages in an air-conditioned room. The
room was maintained at a temperature of 22± to 23±C with a
test was performed. The null hypothesis was rejected at the 5%
(
)
(
)
signiŽ cance level p < .05 .
12-12 hours light-dark cycle lights off at 7 PM . Water and stan-
(
)
dard diet food pellets, M20 Extralabo, Provins, France were
available ad libitum.
RESULTS
Weight Changes During Exposure to Mn
IP Treatment
Experimental Protocol
(
The rats were divided randomly into four equal groups n
=
Exposure to Mn caused a signiŽ cant slowing of weight gain
)
8 . The animals in the group treated by IP route received injec-
(
)
determined against the reference value from the third day of
tions of MnCl2 dissolved in 0.9% NaCl at a dose of 6 mg Mn/kg
treatment till sacriŽ ce; the shortfall being not made up during
(
)
body weight/day for 4 weeks 5 days per week . Those in the
group treated by the PO route were intubated with MnCl2 dis-
solved inultrapurewater at a dose 75mg Mn/kgbody weight/day
(
)
the 2-week rest period Figure 1 .
PO Treatment
(
)
for 4 weeks 5 days per week . Each treatment group had a cor-
responding control group that received the solvent in the same
Weight gain was signiŽ cantly slowed from the 10th day of
experimental conditions. The animals were weighed every day treatment to the 6th day of rest period, the shortfall being made
( )
up from the 7th day of the rest period onward Figure 2 .
and the administered doses were adjusted accordingly.
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EXPOSURE TO MN AND MINERAL METABOLISM
315
FIGURE 1
Weight variations in rats intraperitoneally exposed to MnCl2. RV: reference value before treatment; RP: rest period; D: day of
treatment; S: sacriŽ ce; C: control group; T: treated group. SigniŽ cantly different from control group: ## p < .0001.
FIGURE 2
Weight variations in rats orally exposed to MnCl2. RV: reference value before treatment; RP: rest period; D: day of treatment;
S: sacriŽ ce; C: control group; T: treated group. SigniŽ cantly different from control group: ¤p < .05.
Downloaded from ijt.sagepub.com at UNIV OF NORTH DAKOTA on May 31, 2015

P. MISSY ET AL.
316
FIGURE 3
( )
( )
Urinary a and fecal b excretions of Mn before, during, and after IP exposure to MnCl2. RV: reference value before treatment;
RP: rest period; D: day of treatment; C: control group; T: treated group. SigniŽ cantly different from control group: ¤p < .05;
¤¤p < .01.
signiŽ cant modiŽ cation was observed. After PO treatment, no
change of Mn levels in whole blood and in plasma was observed
Excretion of Mn and Other Essential Elements Studied
IP Treatment
Excretion of Mn in the urine increased signiŽ cantly during
the entire treatment period; it returned to normal during the rest
(
)
results not reported .
(
)
period Figure 3a . On the contrary, the urinary excretion of Fe,
Tissue Concentrations of Mn, Fe, Zn, and Cu
IP Treatment
After 4 weeks of IP treatment, the concentration of Mn in-
creased signiŽ cantly in all of the tissues, except the liver, adrenal
(
)
Zn, and Cu was not signiŽ cantly modiŽ ed results not shown .
Excretion of Mn in the feces increased signiŽ cantly from the
14th day of treatment onward and returned to normal during the
(
)
rest period Figure 3b .
(
)
glands, and the esophagus Table 1 . The most statistically
(
)
marked modiŽ cations p < .0001 were obtained in the femur
PO Treatment
(
)
(
)
(
)
(
)
£27.6 , spleen £3.5 , spinal cord £2.3 , brain £2.1 , skele-
Excretion of Mn in the urine increased during the entire treat-
ment period; it returned to normal during the rest period Figure
(
)
(
)
(
)
(
)
talmuscle £1.7 , kidneys £1.6 , lungs £1.5 andheart £1.4 .
(
Many modiŽ cations were observed in the tissue distribu-
)
4a . In the case of Fe, Zn, and Cu, no marked disturbance was
(
tion of the other elements studied Table 2; only signiŽ cant
changes reported . Thus, the concentration of Fe increased sig-
niŽ cantly in the pancreas 162% , colon 40% , duodenum
(
)
observed results not shown . Excretion of Mn in the feces in-
)
creased signiŽ cantly from the 6th day of treatment and returned
to normal during the rest period Figure 4b .
(
)
(
)
+
+
(
)
(
)
(
)
15% , whereas it decreased in the
+
+
17% , and stomach
(
)
(
)
( )
10% . A sig-
spleen
36% , kidneys
14% , and heart
¡
¡
¡
Blood and Plasma Concentrations at the Time of SacriŽce
niŽ cant increase in the concentration of Zn was obtained in the
(
)
+
After IP treatment, level of Mn in whole blood increased stomach
(
10% . The concentration of Cu increased signiŽ -
(
)
+
signiŽ cantly by a factor of 18.5 controls
)
10.3 § 2.4 l g/l; cantly in the colon 8% , whereas it decreased in the kidneys
=
(
) ( )
24% and heart 8% .
treated 191 § 39 l g/l; p < .0001 , whereas in plasma, no
=
¡
¡
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EXPOSURE TO MN AND MINERAL METABOLISM
317
FIGURE 4
( )
( )
Urinary a and fecal b excretions of Mn before, during, and after PO exposure to MnCl2. RV: reference value before treatment;
RP: rest period; D: day of treatment; C: control group; T: treated group. SigniŽ cantly different from control group: ¤p < .05;
¤¤p < .01.
( )
6 mg of Mn/kg body weight/day IP and 75 mg of Mn/kg body
PO Treatment
(
)
weight/day PO ; these 2 concentrations enabling the absorption
After 4 weeks of PO treatment, the concentration of Mn had
signiŽ cantly increased in all of the tissues with the exception of
of similar quantities of Mn.
(
)
The comparison of the two routes of exposure IP and PO
(
)
the liver, jejunum, ileum, and adipose tissue Table 3 . The most
shows greater accumulation with the IP route. This result seems
logical in as much as the gastrointestinal barrier is bypassed, the
metallic solution is directly in contact with the different organs
located in the abdominal cavity. In addition, with IP admin-
istration, a larger quantity passes into the blood. After transit
through the liver, which appears not to accumulate Mn in a last-
ing manner, the element is distributed to the other organs such
(
)
statistically marked modiŽ cations p < .0001 were observed in
(
)
(
)
(
)
the femur £4.0 , stomach £2.4 , spinal cord £1.5 , skeletal
(
)
(
)
muscle £1.5 , and spleen £1.3 . We observed a large increase
(
)
(
)
in the lungs £48.3 , less marked statistically p < .01 due to
wide intragroup variability.
Few modiŽ cations were observed in the tissue distribution
of the other elements studied Table 4; only signiŽ cant changes
reported . Thus, a signiŽ cant decrease in the concentration of Fe
was obtained in the adrenal glands 19% and brain 11% .
The concentration of Zn increased signiŽ cantly in the adrenal
glands 10% . Lastly, the concentration of Cuincreased signif-
(
(
as the femur principal target organ regardless of the adminis-
)
)
tration route , brain, spinal cord, skeletal muscle, and heart. The
(
)
(
)
¡
¡
changes in urinary and fecal excretion of Mn, observed during
(
)
both treatments IP and PO , conŽ rm the observation of greater
tissue Ž xation following IP treatment. Thus, urinary excretion,
an indication of the metallic fraction absorbed but not retained
by the body, is increased in a relatively comparable manner in
both treatments; on the contrary, fecal excretion, indicating es-
sentially the not absorbed fraction, is greater in the case of oral
(
)
+
(
)
(
)
+
+
icantly inthe adipose tissue 26% , liver 18% , and pancreas
(
)
+
11% .
DISCUSSION
This research was undertaken with the objective of conduct- treatment.
(
)
ing a comparative study of two types of treatment IP and PO
Comparisons of our results with those of previous studies
remain difŽ cult, due to the wide heterogeneity among the ex-
perimental protocols used. In the case of oral treatment, it is
based on the same toxicological experimental protocol, that is,
subchronic intoxication with MnCl2 for 4 weeks at a dose of
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P. MISSY ET AL.
318
TABLE 1
(
Tissue Mn concentrations after IP exposure to MnCl2 l g/g wet weight; except femur,
)
lg/g dry weight
Groups
Factors
Tissues
Femur
Spleen
Spinal cord
Brain
Skeletal muscle
Kidneys
Lungs
Control
Treated
SigniŽ cances
treated/control
1.20 § 0.10
0.31 § 0.02
0.32 § 0.02
0.43 § 0.04
0.08 § 0.01
1.51 § 0.15
0.23 § 0.02
0.43 § 0.03
33 § 8
£27.6
£3.5
£2.3
£2.1
£1.7
£1.6
£1.5
£1.4
1.10 § 0.18
0.74 § 0.16
0.90 § 0.10
0.14 § 0.01
2.36 § 0.20
0.35 § 0.06
0.60 § 0.04
p < .0001
Heart
Stomach
Pancreas
Fur, skin
0.82 § 0.19
1.13 § 0.16
0.08 § 0.02
0.34 § 0.17
0.46 § 0.03
1.53 § 0.33
1.70 § 0.34
1.78 § 0.41
0.12 § 0.02
1.63 § 1.15
1.46 § 0.86
2.63 § 0.73
£2.1
£1.6
£1.5
£4.8
£3.2
£1.7
p < .001
p < .01
Ileum
Testicles
Colon
Jejunum
0.28 § 0.13
0.57 § 0.10
0.22 § 0.09
0.09 § 0.03
2.11 § 2.19
3.36 § 2.89
1.15 § 0.74
0.20 § 0.13
£7.5
£5.9
£5.2
£2.2
Duodenum
Bone marrow
Adipose tissue
p < .05
Adrenal glands
Liver
Esophagus
3.12 § 1.00
1.88 § 0.21
0.17 § 0.06
3.58 § 1.01
2.02 § 0.27
0.29 § 0.14
—
—
—
NS
Note: NS, not signiŽ cantly different from control group.
interesting to mention that a Mn accumulation in the brain was
TABLE 2
Changes in Fe, Zn, and Cu concentrations due to IP exposure
(
also observed with a lower dose of Mn 24.3 mg Mn/kg body
) (
)
weight/week for 4 weeks Roels et al. 1997 . In other experi-
(
)
to MnCl2 l g/g wet weight; except femur, lg/g dry weight
(
mental conditions 150 mg Mn/kg body weight every 2 days for
)
60 days , a reversible accumulation in the liver was observed
Groups
%
(
within the 30 days that followed the end of treatment Nikolova
)
1993 . Such phenomenon could explain the absence of effect on
Elements
Fe
Tissues
Control
Treated
variations
liver in our study. Finally, it should be noted that the important
increases of Mn concentration in the lungs and to a lesser ex-
tend in the skin and fur are most likely related to force-feeding
possible regurgitation and must be considered carefully.
In the case of IP treatment, we can mention great differ-
ences between our results and those found in literature, such
as a great accumulation of Mn in pancreas considered by the
authors as a speciŽ c target organ for Mn toxicity Sheuhammer
and Cherian 1983 and a more or less delayed accumulation in
55 § 17a
+
162
Pancreas
Colon
21 § 4
9.2 § 1.2 12.9 § 1.7b
40
17
15
36
14
10
+
+
+
¡
¡
¡
Duodenum 19.6 § 1.6 23.0 § 3.1d
(
)
Stomach
Spleen
Kidneys
Heart
16.8 § 1.6 19.3 § 2.2d
933 § 207 601 § 114c
74 § 6
67 § 4
64 § 4c
60 § 5c
(
Zn
Cu
Stomach
19.4 § 1.5 21.3 § 1.9d
10
)
+
(
liver Jiang et al. 1992; Murthy, Srivastava, and Chandra 1981;
1.3 § 0.1d
5.6 § 0.7d
4.6 § 0.3c
8
+
Colon
Kidneys
Heart
1.2 § 0.1
7.4 § 1.8
5.0 § 0.3
)
Scheuhammer and Cherian 1982; Tandon and Mathur 1976 .
Concerning the presence of Mn in the brain, our results conŽ rm
those previously obtained with lower doses administered 3 and
24
¡
8
¡
(
Note: SigniŽ cantly different from control group: a p < .0001; b p <
)
4.16 mg of Mn/kg body weight/day and different lengths of
) (
.001; c p < .01; d p < .05.
(
treatment 30, 60, and 84 days Jiang et al. 1992; Scheuhammer
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EXPOSURE TO MN AND MINERAL METABOLISM
319
TABLE 3
(
Tissue Mn concentrations after PO exposure to MnCl2 lg/g wet weight; except femur,
)
l g/g dry weight
Groups
Factors
Tissues
Femur
Control
Treated
SigniŽ cances
treated/control
1.2 § 0.2
0.88 § 0.34
0.32 § 0.02
0.08 § 0.01
0.30 § 0.02
4.8 § 1.9
2.1 § 0.3
£4.0
£2.4
£1.5
£1.5
£1.3
Stomach
Spinal cord
Skeletal muscle
Spleen
0.49 § 0.05
0.12 § 0.01
0.38 § 0.03
p < .0001
Lungs
0.24 § 0.02
0.08 § 0.01
0.16 § 0.04
0.40 § 0.03
2.8 § 0.4
11.6 § 9.1
0.24 § 0.12
0.48 § 0.22
0.79 § 0.27
3.7 § 0.5
£48.3
£3.0
£3.0
£2.0
£1.3
£1.2
£1.1
£1.3
Fur, skin
Esophagus
Brain
Adrenal glands
Kidneys
Heart
p < .01
1.5 § 0.2
1.8 § 0.1
0.46 § 0.04
0.52 § 0.09
0.53 § 0.04
0.69 § 0.09
Duodenum
Pancreas
Colon
Testicles
1.2 § 0.1
1.5 § 0.2
£1.2
£1.2
£1.1
1.3 § 0.2
1.6 § 0.2
p < .05
0.43 § 0.04
0.49 § 0.02
Adipose tissue
Liver
Jejunum
Ileum
0.08 § 0.02
0.14 § 0.07
—
—
—
—
1.9 § 0.2
2.0 § 0.2
NS
0.25 § 0.13
0.34 § 0.18
0.32 § 0.10
0.44 § 0.31
Note: NS, not signiŽ cantly different from control group.
)
and Cherian 1982; Scheuhammer and Cherian 1981 . Finally, the hepatic lobes, particularly the left lobe situated just under
(
the non-negligible accumulation of Mn observed in the intesti- the peritoneum swollen edges, lobes retracted, adhesive and
)
naltractmustbe considered carefully; the digestive systembeing hardened .
in direct contact with the element administered by the IP route.
The presence of Mninwholeblood butnotinplasma, which is
This could also explain the adherent aspect of the intestines only signiŽ cant after IP treatment and after 2 weeks of rest, leads
observed during autopsy, but also the macroscopic damage to us to believe that this element may associated with certain blood
elements, such as hemoglobin, instead of Fe, thus supporting
(
results of previous studies Borg and Cotzias 1958; Scheuham-
TABLE 4
)
mer and Cherian 1983 . The progressive disappearance of Mn in
Changes in Fe, Zn, and Cu concentrations due to PO exposure
the blood would thus be closely related to the length of life and
the renewal of the erythrocytes. This hypothesis correlates well
with the observation of a decrease in Fe and an accumulation of
Mn in spleen, the organ in which old erythrocytes are destroyed,
and an accumulation of Mn in the bone marrow, often called
“red marrow” due to its richness in blood cells, which plays an
important role in hematopoiesis. As opposed to the spleen, no
notable change in the concentration of Fe could be observed
in whole blood or bone marrow, probably due to the high Fe
content of these tissues, as demonstrated by the Fe/Mn ratios
(
)
to MnCl2 lg/g wet weight; except femur, l g/g dry weight
Groups
%
Elements
Tissues
Control
Treated
variations
Adrenal glands 128 § 18
104 § 5c
19
11
¡
¡
Fe
Brain
17.3 § 1.4 15.4 § 1.9d
+
+
Zn
Adrenal glands 12.9 § 0.6 14.2 § 1.1d
10
26
Adipose tissue 0.19 § 0.02 0.24 § 0.06d
calculated using concentrations expressed in mmol l¡1 for the
¢
3.8 § 0.4 4.5 § 0.7d
0.9 § 0.1 1.0 § 0.1d
18
11
+
+
Cu
Liver
Pancreas
blood and in mmol g¡1 for bone marrow controls Fe/Mn blood
(
¢
43,000; treated Fe/Mn blood 2,115; controls Fe/Mn bone
=
=
Note: SigniŽ cantly different from control group: c p < .01; d p < .05.
=
=
)
marrow 472; treated Fe/Mn bone marrow 92 .
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P. MISSY ET AL.
320
+
+
Assuming Mn2 takes the place of Fe2 in hemoglobin,
the Mn-substituted hemoglobin is incapable of ensuring the O2
transport. However, no disturbance in O2 transport in blood will
be observed, considering Fe/Mn blood ratios. In tissues, where
Fe/Mn ratios are generally much lower, consequences may be
(
Lastly, we must indicate that the treatments carried out IP
)
(
and PO did not disturb phosphorus-calcium metabolism no
major disturbance in the tissue distribution of P and Ca; results
not shown . Even if our work conŽ rmed the large accumulation
of Mn in the bones mentioned in literature, the Ca/Mn ratios
in the femur remain very high controls 127,000; treated
)
+
+
more deleterious; indeed Mn2 could take place of Fe2 in cy-
tochromes of cellular respiratory chain that have a structure
close to hemoglobin. This can lead to incomplete reduction of
O2 with the formation of free radicals and possibly oxygenated
compounds such as O2¡ and H2O2, responsible for cellular
degeneration, particularly in the brain, thus explaining the neu-
rotoxicity of Mn. Effectively, in the different cytochromes of the
(
=
=
)
32,000 and the substitution of Ca by Mn thus remains very
partial.
In conclusion, we observed that the greatest disturbances ob-
served were obtained in the case of subchronic treatment by IP
route, the route commonly used in testing on laboratory animals,
but not very representative of real conditions in which intoxica-
tion occurs. On the other hand, treatment by oral route causes
+
+
cellularrespiratory chain, thestandard potentialoftheFe3 /Fe2
couple 0.77 V in the absence of complexation varies according
to the environment of Fe, from 0.07 V cytochrome b to 0.55 V
(
fewer effects, despite the high dose of Mn administered equiva-
lent to 5 g Mn/day for humans , rarely encountered in everyday
(
)
)
(
)
life. Thus, the risks of intoxication by oral route appear to be
very limited. Nonetheless, cases related to pulmonary intoxica-
(
)
)
cytochrome a3 , that is to say a decrease of 0.22 V in the case of
(
a3 0.77 0.55 ; the potential of the O /H O couple being 0.82
¡
2
2
(
tion concerning Mn workers highly exposed to dust essentially
(
)
V at pH 7, the last cytochrome a3 of the cellular respiratory
+
+
chain can thus reduce O2 to H2O. In the case of Mn3 /Mn2
)
MnO2 cannot be neglected. Damage to the tissues observed in
our study could certainly be found in this third type of intoxi-
(
couple standard potential of 1.50 V in the absence of complex-
+
+
ation , forming complexes in a way similar to the Fe /Fe2
3
(
)
cation, with risks of sequelae cellular degeneration , as it has
already been demonstrated for the nervous system.
)
couple, we should be able to observe a comparable decrease in
(
)
its redox potential i.e., 1.50 0.22 1.28 V ; in these condi-
¡
=
tions, the reduction of O2 to H2O is no longer possible, the last
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