Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IV. Manganese
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lipid composition or an increased rate of lipid peroxidation
in cell membranes, as the activity of MnSOD is lower in
Mn-deficient animals than in controls ( Keen et al. , 2000 ).
Another step at which Mn can be critical for lipid
metabolism is as a cofactor in steroid biosynthesis ( O’Dell
and Sunde, 1997 ). Enhancement by Mn of cholesterol synthesis
from acetate in liver preparations has been demonstrated,
and hypocholesterolemia has been reported in a
human case of Mn deficiency. The metabolic site in cholesterol
synthesis wherein Mn is thought to be required is
farnesyl pyrophosphate synthase, which catalyzes geranyl
and isopentyl pyrophosphate condensation to form farnesyl
pyrophosphate. Defects in subsequent steroid synthesis can
also underlie some of the observed reproductive dysfunctions
in Mn-deficient animals. Mn deficient females have
absent or irregular estrous cycles, whereas Mn-deficient
males have sterility associated with degenerating cells
in the epididymis ( O’Dell and Sunde, 1997 ). In addition,
lipoprotein metabolism is affected in Mn deficiency.
Mn-deficient rats have low plasma cholesterol and low
HDL. In addition, Mn-deficient rats have a shift to a
smaller plasma HDL particle, lower HDL apo E levels,
and higher apo C levels. High levels of dietary Mn have
also been reported to affect lipid metabolism when animals
are fed high-fat diets. Repletion with Mn increases
the activity of several key glycolytic enzymes including
hexokinase, glyceraldehydes-3-phosphate dehydrogenase,
enolase, lactate dehydrogenase, and glycerol-3-phosphate
dehydrogenase. Increases are also found for enzymes of
the pentose phosphate pathway and of lipogenesis. Thus,
the supplementation of Mn to the high-fat diet can increase
the potential for glucose oxidation and for lipogenesis
thereby enhancing carbohydrate conversion to fat. The
mechanism(s) by which excess Mn induces the enzyme
changes is not known, but it is suggested that an effect on
insulin metabolism could be involved ( Keen et al. , 2000 ).
Mn can activate guanylate cyclase and phosphodiesterase,
so another possibility is that Mn might change levels of
cyclic nucleotides, which then act as second messengers.
2 . Manganese Toxicity
Although Mn excess can produce toxic effects, it is often
considered to be among the less toxic of the essential
trace elements to birds and mammals (Subcommittee on
Mineral Toxicity in Animals, 1980). For example, chicks,
calves, pigs, and sheep have been reported to tolerate diets
up to 3000, 1000, 500, and 200 micrograms Mn/g (54.6,
18.2, 9.1, and 3.6 micromol/g), respectively ( Failla, 1999 ;
Subcommittee on Mineral Toxicity in Animals, 1980).
In domestic animals, the major reported biochemical
lesion associated with dietary Mn toxicosis is an induction
of iron deficiency, which is thought to be the result of
an inhibitory effect of Mn on iron absorption. In humans,
incidents of Mn toxicity mainly occur as a result of chronic
inhalation of massive amounts of airborne Mn ( 5 mg/m;
91micromol) with particle sizes less than 5-micrometer
diameter, a situation that can occur in Mn mining. In individuals
working in environments contaminated with Mn,
overt signs of toxicity normally occur after months or several
years of chronic exposure. The initial expression of
Mn toxicity is often characterized by severe psychiatric
disorders that include signs of memory impairment, disorientation,
hallucination, speech disturbances, and compulsive
behavior. If the person is removed from the high Mn
environment, some improvement of the psychiatric signs
can occur. With progression of toxicity, there can be extrapyramidal
signs that are remarkably similar to Parkinson’s
disease ( Crossgrove and Zheng, 2004 ). Removal of a person
or animal from the high Mn area at this time may not
lead to an improvement in clinical condition, even though
tissue Mn levels can return to normal. Secondary conditions
that exacerbate Mn toxicity, such as liver failure, can
be the underlying cause. The mechanisms underlying the
cellular toxicity of Mn have not been clearly identified,
although evidence has been provided that Mn-initiated tissue
lipid peroxidation can be a primary biochemical lesion.
A second lesion that can underlie some of the pathologies
is a disturbance in carbohydrate metabolism ( Crossgrove
and Zheng, 2004 ; Keen et al. , 2000 ). With acute Mn toxicity,
there is a rapid uptake of Mn by the pancreas, a sharp reduction
in circulating insulin, and an increase in plasma glucose.
Thus, similar to Mn deficiency, Mn toxicity can affect
insulin production or release from the pancreas (Aschner
et al. , 2007; Keen et al. , 2000 ).
3 . Other Disorders
Abnormal Mn metabolism occurs in experimental animal
models for diabetes ( Failla, 1999 ). It has been shown that
the high Mn concentrations in the liver of diabetics are
associated with arginase ( Failla, 1999 ; Keen et al. , 2000 ).
Although an increase in arginase activity seems reasonable
in light of the increased gluconeogenic demands of the diabetic,
the functional necessity of this increase has not been
shown. It has been reported that Mn metabolism can also
be abnormal in some forms of epilepsy. The significance of
this observation is underscored by the observation that Mndeficient
animals have a reduced threshold to drug-induced
and electroshock-induced seizures. Finally, whole blood
Mn levels are often low in humans with osteoporosis and
have been proposed to be important to the development
of osteopenic bone disease in aging humans and animals
(Gonzalez-Reyers et al. , 2007; Keen et al. , 2000 ).
F . Evaluation of Manganese Status
Measurement of whole blood Mn concentrations can be
useful in suspected cases of Mn deficiency because low
whole blood Mn levels have been found to reflect low soft