![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
*
Department of Animal and Range Science, North Dakota State University (NDSU), Fargo, ND 58105
United States Department of Agriculture,1 Agricultural Research Service, Biosciences Research Laboratory, Fargo, ND 58105, and
**
United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center (GFHNRC), Grand Forks, ND 58202
2To whom correspondence should be addressed.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
KEY WORDS: • manganese • magnesium • toxicity • heart • swine
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Acute Mn toxicity in
humans is characterized by a crippling neurological disorder resembling
Parkinson’s disease in humans (Chandra et al. 1974
,
Cotzias 1958
). Although Mn toxicity also has been
reported in animals (Grummer et al. 1950
,
Khan et al. 1997
), Leibholz et al. (1962)
fed growing swine 72.8 mmol Mn/kg diet without mortality
or severe morbidity. Grummer et al. (1950)
fed growing
swine up to 9.1 mmol Mn/kg diet and observed "retarded appetite and
growth especially during the latter part of the trial," but no
deaths. However, Grummer et al. (1950)
did speculate
that Mn may cause some symptoms of toxicity at concentrations between
0.91 and 1.82 mmol Mn/kg diet.
Magnesium (Mg) is present in soft tissues and bone, and functions as a
component or activator of enzymes involved in cellular respiration
(Wacker and Parisi 1968a
, Wacker and Parisi 1968b
, Wacker and Parisi 1968c
). Mg deficiency, as a consequence of various factors
such as low dietary intake and inhibition of absorption by fats, has
been linked to an increased risk of ischemic heart disease
(IHD),3
irreversible cardiac failure (Altura et al. 1981
,
Wu et al. 1992
) and reduced coronary blood flow as a
result of coronary vasospasm (Altura and Altura 1990
,
Altura and Altura 1996
, Chipperfield and Chipperfield 1978
, Johnson et al. 1979
,
Karppanen et al. 1978
, Raab 1969
). IHD is
a pathophysiologic state caused by blood vessel constriction or
blockage that results in inadequate blood flow to the myocardium.
Epidemiological research suggests Mg deficiency as a risk factor for
several cardiovascular disorders, such as myocardial infarction and
congestive heart failure in addition to IHD (Altura and Altura 1985
, Eisenberg 1992
, Rasmussen 1993
, Seelig 1989
).
There are several possible points of interaction between Mn and Mg. The
body can replace Mn with Mg with similar efficiency in Mn-activated
proteins (Wapnir 1990
). Similarly, Mn can occupy Mg
allosteric sites in Mg-activated proteins, such as the sarcoplasmic
reticulum calcium ATPase (Chiesi and Inesi 1981
).
Mn-supplemented diets increased Mg excretion through the urine in
rats (Gaillard et al. 1996
), and Mg deficiency increased
the Mn absorption and retention in rats (Sanchez-Morito et al. 1999
). Scheuhammer and Cherian (1983)
reported
that Mn decreases Mg concentrations in both heart and bone by an
undefined mechanism. Sanchez-Morito et al. (1999)
found
that feeding rats a diet deficient in Mg decreased urinary and fecal Mn
excretion. They also observed greater Mn retention in skeletal muscle,
heart and kidney in Mg-deficient rats as compared to control.
In the present communication we report that Mg-deficient pigs had greater mortality when fed moderately high, as compared to low dietary Mn; however, Mn concentrations were well below previously reported toxic levels. A follow-up investigation was performed to more carefully examine the cause of death of pigs fed high Mn.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
All studies were approved by the Animal Care and Use Committee of the Grand Forks Human Nutrition Research Center, and pigs were maintained in accordance with the National Research Council guidelines for the care and use of laboratory animals.
Study 1.
Crossbred barrow pigs (n = 14, initial weight 22 kg;
North Dakota State University Swine Research Unit, Fargo, ND) were
randomly assigned to diets with either high (0.95 ± 0.10 mmol
Mn/kg, n = 8) or low (0.040 ± 0.003 mmol Mn/kg,
n = 6) Mn (Table 1
). Pigs were placed into individual pens with free access to diet and
water. Pigs that died prior to the study completion were examined by a
veterinary diagnostic laboratory for gross pathology.
|
. Diets were: (i) basal diet (4.1 mmol Mg/kg and 36.0 µmol
Mn/kg); (ii) basal diet + high Mn (4.1 mmol Mg/kg and 0.91 mmol
Mn/kg); (iii) basal diet + high Mn + ultratrace element
premix (4.1 mmol Mg/kg and 0.91 mmol Mn/kg); (iv) basal diet + high Mn + ultratrace + adequate Mg (41.1 mmol Mg/kg and 0.91
mmol Mn/kg). Pigs were placed into individual pens with free access to
diet and water. After 5 wk on diets, pigs were killed by electrical
stun and exsanguination. Organs (heart, liver, brain, lung and skeletal
muscle) and fluids (bile and serum) were collected and immediately
frozen. Two pigs (one fed diet 1 and the other diet 3) died prior to
the 5-wk completion; organ samples were collected at the time of death. Laboratory analyses
Mn and Mg concentrations in organs and fluids were determined by
atomic absorption spectrometry (Perkin-Elmer 3030B, Norwalk,
CT). Samples were prepared for analysis by digesting
lyophilized material with concentrated nitric acid and hydrogen
peroxide as previously described (Bock 1979
). Lanthanum
oxide was added to samples for determination of Mg concentration to
prevent phosphorus interference during spectrometry (AOAC 1990
).
Quality control
Duplicate samples of National Institute of Standards and Technology (NIST) standards (Bovine Liver 1577b, NIST) were analyzed with each run to maintain quality control. Runs were acceptable if the NIST analyzed values fell within the stated range. The run-to-run CV averaged 3–6%, and the detection limits for Mn and Mg were 1.8 and 41.0 nmol/g, respectively.
Statistical analyses
Mortality data from study 1 were analyzed by a chi-square test. Data from study 2 were analyzed by one-way ANOVA for effect of diet on tissue Mn and Mg concentrations (SAS; SAS Institute, Cary, NC). Data were considered different if P < 0.05. Contrasts between treatments were determined by Tukeys Studentized Range Test.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
All pigs fed the high-Mn diet died before the end of the study (2
moribund pigs were euthanized), but only 2 fed the low-Mn diet died
(P = 0.003). The pigs that died were observed paddling
with their feet while lying on their sides, convulsing and hemorrhaging
from the nose and mouth prior to death; pathology included severe,
necrotizing myocarditis. An initial veterinary pathologist diagnosis
was death from Mulberry Heart Disease (MHD) as a result of Se
deficiency. Livers from the pigs contained 50.3 ± 1.4 nmol
-tocopherol/g and 21.5 ± 1.2 nmol selenium (Se)/g; normal
ranges are between 42–63.4 and 12.5–31.5 nmol/g for -tocopherol
and Se, respectively. Subsequently pigs were injected with Se (BoSe;
Shering-Plough, Union, NJ). The deaths continued after the pigs
were given supplemental vitamin E and Se injections.
Study 2.
After 5 wk, pigs fed diet 4 were significantly heavier (Table 2
) than those given other treatments (P < 0.05). Mn
concentrations in the liver and skeletal muscle were greater
(P < 0.01) in pigs fed high-, as compared to low-,
dietary Mn (Table 2)
. Increased dietary Mn did not affect heart Mn, but
high Mn depressed heart Mg concentrations in pigs without ultratrace
mineral supplementation (P < 0.01) (Table 2)
. Brain Mg
concentrations were not significantly (P > 0.05)
affected by dietary Mn, but were numerically lower in the pigs
fed high-Mn without ultratrace minerals. Dietary Mn did not affect
the Mg concentrations of any other tissues or fluids measured. Plasma
Mg was increased (P < 0.001) by increased dietary Mg
(Table 2)
.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). Leibholz et al. (1962)
reported that "no toxicity symptoms were observed
in pigs fed 72.8 mmol Mn/kg"; however, there was evidence of growth
depression and stiffness. Leibholz et al. (1962)
summarized that pigs have a high tolerance to Mn and that there exists
a "considerable margin of safety between levels of Mn likely to be
ingested in the diet and detrimental levels." Likewise,
Grummer et al. (1950)
fed growing swine for 16 wk a
corn-soybean-based diet and reported only moderate growth inhibition at
Mn concentrations of up to 2.4 mmol Mn/kg. In the present study, pigs
fed diets with 0.91 mmol Mn/kg and moderately deficient in Mg were
dying after only 3 wk.
Mg is essential for energy metabolism and bone structure. Growing pigs
require ~16.4 mmol Mg/kg per day to maintain maximal growth
(NRC 1988
). The dietary Mg intake at which acute
deficiency results in death is conflicting. Mayo et al. (1959)
reported fatal deficiency (intake at which half the
animals on test died) within 21 d when pigs were fed 2.8 mmol
Mg/kg diet. However, they also reported that other pigs fed 2.6 mmol
Mg/kg diet for 42 d survived, although they developed severe
deficiency symptoms (Mayo et al. 1959
). In the present
study, both the high- and low-Mn diets were formulated to contain
4.1 mmol Mg/kg diet. Because of the above reports, and because only two
of six pigs died in the low-Mn group, as compared to all eight fed
the high-Mn diet, we concluded that dietary Mg deficiency was not
solely responsible for their deaths.
Symptoms of acute hypomagnesemia, or grass tetany in ruminants, include
grinding of teeth, paddling of limbs and convulsions prior to death
(Church 1988
, Merck Veterinary Manual 1990
). Church (1988)
reported that despite the
lack of characteristic postmortem lesions, subendocardial lesions may
be caused by severe tetanic convulsions associated with Mg deficiency.
Signs of Mg deficiency in pigs also include muscular twitching,
reluctance to stand, loss of equilibrium and tetany followed by death
(Mayo et al. 1959
, Miller et al. 1965
).
Similar symptoms were observed in the present study.
A veterinary pathologists diagnosis of MHD was deduced from both the
sudden death and cardiac muscle degeneration observed in necropsy;
however, subsequent treatment of all remaining pigs with supplemental
vitamin E and Se prophylaxis failed to prevent mortality. Moreover, the
liver -tocopherol and Se concentrations were not deficient providing
further evidence that MHD as a result of inadequate -tocopherol and
Se was not the cause of death. The veterinary pathology summary of pigs
fed the high-Mn diets included "myodegeneration, necrosis and
mineralization of heart," "moderate myocardiocyte necrosis" and
"severe, multifocal, myocardial necrosis." In contrast, pigs fed
the low-Mn diet were reported to have "mild, nonsupportive
myocarditis" and "mild myocardial fibrosis." The heart tissue
pathology of MHD includes "severe, necrotizing myocarditis" and
"myocardial lesions," symptoms that are also associated with Mg
deficiency (Wutzen and Rozycka 1975
).
In the second study, brain Mg was numerically lower in the pigs fed high-Mn and low-Mg. We recognize the link between Mn toxicity and neurological disorders. Electroencephalograms were recorded for each pig, and the data will be presented elsewhere, although initial visual analysis revealed no major differences.
The reduction of Mg in the hearts of pigs fed high-Mn implicates Mn as a potential Mg antagonist in that organ. Heart Mg concentrations were increased by supplementation with ultratrace minerals. Ultratrace minerals included in the supplemental mix were chromium (Cr), fluorine (F), silicon (Si), nickel (Ni), lithium (Li), molybdenum (Mo), vanadium (V) and selenium (Se) and copper (Cu). Copper was supplied in both the ultratrace and mineral premix at 0.09 mmol/kg diet. The mechanism through which supplementation of these minerals increased the heart Mg concentration is unknown.
In humans, the link between hypomagnesemia in the heart and the
increased risk of IHD as well as coronary vasospasm, cardiac
dysrhythmia and altered cellular respiration has been
well-documented (Altura and Altura 1985
,
Eisenberg 1992
, Rasmussen 1993
,
Seelig 1989
). If high dietary Mn displaces Mg from the
heart, then people suffering from depressed Mg status could be at
greater risk for Mn toxicity.
In conclusion, these data suggest that Mn exacerbates Mg deficiency and is responsible for a decrease in heart muscle Mg concentrations. This reduction of Mg concentrations in the heart may therefore be a contributing factor in the deaths observed in pigs fed high Mn.
|
FOOTNOTES |
|---|
3 Abbreviations used: IHD, ischemic heart disease; Mg, magnesium; Mn, manganese; MHD, Mulberry Heart Disease; MHD, mulberry heart disease; NIST, National Institute of Standards and Technology; Se, selenium; UT, ultra-trace minerals.
Manuscript received October 20, 1999. Revision accepted March 22, 2000.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Abraham A. S., Rosenmann D., Kramer M., Balkin J., Zion M. M., Farbstein H., Eylath U. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch. Intern. Med. 1987;147:753-755[Abstract]
2. Altura B. M., Altura B. T. Magnesium ions and contraction of vascular smooth muscles: relationship to some vascular diseases. Fed. Proc. 1981;40:2672-2679[Medline]
3. Altura B. M., Altura B. T. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. Magnesium 1985;4:226-244[Medline]
4. Altura B. M., Altura B. T. Magnesium and its role in biology, nutrition and physiology. Siegel H. Siegel A. eds. Metal Ions in Biological Systems 1990;Vol. 26:359-416 Marcel Dekker, Inc. New York, NY.
5. Altura B. M., Altura B. T. Role of magnesium in pathophysiological processes and the clinical utility of magnesium ion selective electrodes. Scand. J. Clin. Lab. Invest. Suppl. 1996;224:211-234[Medline]
6. AOAC Helrich K. eds. Official Methods of Analysis 15th Ed. Volume 1 1990 AOAC Arlington, VA.
7. Bock R. A Handbook of Decomposition Methods in Analytical Chemistry 1979 John Wiley & Sons New York, NY.
8. Ceremuzynski L., Jurgiel R., Kulakowski P., Grebalska J. Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am. Heart. J. 1989;118:1333-1334[Medline]
9. Chandra S. V., Seth P. K., Mankeshwar J. K. Manganese poisoning: Clinical and biochemical observations. Environ. Res. 1974;7:374-380
10. Chiesi M., Inesi G. Mg and Mn modulation of Ca transport and ATPase activity in sarcoplasmic reticulum vesicles. Arch. Biochem. Biophys. 1981;208:586-592[Medline]
11. Chipperfield B., Chipperfield J. R. Relation of myocardial metal concentrations to water hardness and deathrates from ischemic heart disease. Lancet 1978;2:709-712[Medline]
12. Church D. C. The Ruminant Animal: Digestive Physiology and Nutrition 1988 Prentice Hall, Inc., Division of Simon & Schuster Englewood Cliffs, NJ.
13.
Cotzias G. C. Manganese in health and disease. Physiol. Rev. 1958;38:503-532
14. Eisenberg M. J. Magnesium deficiency and sudden death. Editorial. Am. Heart J. 1992;124:544-549[Medline]
15. Gaillard E., Laurant P., Robin S., Berthelot A. Effects of long-term high manganese intake on magnesium metabolism in rats. Magnes-Res 1996;9:119-123
16. Grummer R. H., Bentley O. G., Phillips P. H., Bohstedt G. The role of manganese in growth, reproduction, and lactation of swine. J. Anim. Sci. 1950;9:170
17.
Johnson C. J., Peterson D. R., Smith E. K. Myocardial tissue concentrations of magnesium and potassium in men dying suddenly from ischemic heart disease. Am. J. Clin. Nutr. 1979;32:967-970
18. Karppanen H., Pennanen R., Passinen L. Minerals, coronary heart disease and sudden coronary death. Adv. Cardiol. 1978;25:924
19. Khan K. N., Andress J. M., Smith P. F. Toxicity of subacute intravenous MnCl2 administration in beagle dogs. Toxicol. Pathol. 1997;25:344-350[Medline]
20.
Leibholz J. M., Speer V. C., Hays V. W. Effect of dietary manganese on baby pigs performance and tissue manganese levels. J. Anim. Sci. 1962;21:772
21.
Mayo R. H., Plumlee M. P., Beeson W. M. Magnesium requirement of the pig. J. Anim. Sci. 1959;18:264
22. Merck Veterinary Manual A Handbook of Diagnosis, Therapy, and Disease Prevention and Control for the Veterinarian 6th Ed. 1990 Merck & Co., Inc. Rahway, NJ.
23. Miller E. R., Ullrey D. E., Zutaut C. L., Hoefer J. A., Luecke R. W. Mineral balance studies with the baby pig; Effects of dietary magnesium level upon calcium, phosphorus, and magnesium balance. J. Nutr. 1965;86:209[Medline]
24. National Research Council Nutrient Requirements of Swine 7th Ed 1973 National Academy Press Washington, D.C.
25. National Research Council Nutrient Requirements of Swine 9th Ed. 1988 National Academy Press Washington, D.C.
26. Raab W. Myocardial electrolyte derangement: crucial feature of pluricausal, so-called coronary, heart disease. Ann. NY Acad. Sci. 1969;147:629-686
27. Rasmussen H. S. Justification for magnesium therapy in acute ischemic heart disease. Clinical and experimental studies. Danish Med. Bull. 1993;40:84-99
28. Rasmussen H. S., McNair P., Norregard P., Backer V., Lindeneg O., Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet 1986;1:234-236[Medline]
29.
Sanchez-Morito N., Planells E., Aranda P., Llopis J. Magnesium-manganese interactions caused by magnesium deficiency in rats. J. Am. Coll. Nutr. 1999;18:475-480
30. Scheuhammer A. M., Cherian M. G. The influence of manganese on the distribution of essential trace elements. II. The tissue distribution of manganese, magnesium, zinc, iron, and copper in rats after chronic manganese exposure. J. Toxicol. Environ. Health. 1983;12:361-370[Medline]
31. Seelig M. S. Cardiovascular consequences of magnesium deficiency and loss: pathogenesis, prevalence and manifestations—magnesium and chloride loss in refractory potassium repletion. Am. J. Cardiol. 1989;63:4G-21G[Medline]
32. Wacker W.E.C., Parisi A. F. Magnesium metabolism. New Engl. J. Med. 1968a;278:658-663
33. Wacker W.E.C., Parisi A. F. Magnesium metabolism. New Engl. J. Med. 1968b;278:712-717
34. Wacker W.E.C., Parisi A. F. Magnesium metabolism. New Engl. J. Med. 1968c;278:772-776
35. Wapnir R. A. Protein nutrition and mineral absorption, Chapter 10 1990 CRC Press Boca Raton, FL.
36. Wu F., Zou L., Altura B. T., Barbour R. L., Altura B. M. Ferrylmyoglobin formation induced by acute magnesium deficiency in perfused rat heart causes cardiac failure. Magnesium & Trace Elem 1992;10:364-373
37. Wutzen J., and Rozycka Z. Electron microscopic lesions of the myocardium of rats fed a low-magnesium diet. Polish Med. Sci. Hist. Bull. 1975;4:407-414
This article has been cited by other articles:
|
|
 |
|
  C. J. Klein, F. H. Nielsen, and P. B. Moser-Veillon Trace Element Loss in Urine and Effluent Following Traumatic Injury JPEN J Parenter Enteral Nutr, March 1, 2008; 32(2): 129 - 139. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
