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Magnes Res 1990 Sep;3(3):219-26

Historical review of the effects of marginal intake of magnesium in chronic experimental magnesium deficiency


K. S. Kubena1 and J. Durlach2

1Graduate Faculty of Nutrition, Department of Animal Science, Texas A & M University, College Station, Texas, USA; 2President of SDRM, 64 Rue de Longchamp, Neuilly sur Seine, France


Summary: After the discovery of magnesium as an essential nutrient in 1926, research focused upon the identification of effects of an acute deficiency state and determination of the requirement for the mineral for normal growth and reproduction. In this early work, marginal intakes of magnesium were reported to result in alterations of tissue composition. Since the 1970s, research has shown that the ability to adapt to a marginal intake of magnesium, which is commonplace in developed countries, is limited. In fact, a low intake of the mineral for an extended period of time may be associated with abnormalities in reproduction, growth, and development and may be a factor in the pathogenesis of disorders of neuromuscular, cardiovascular, renal, and immune function. Problems related to the use of pharmacological agents or to trace metals, such as aluminium, may be worsened in the presence of a low intake of magnesium. Evidence presented illustrates that, although physical signs of magnesium deficiency may be absent, that is to say in cases of latent clinical forms, a marginal dietary inadequacy of the mineral over a long period of time could result in significant problems.

Key words: Chronic magnesium deficiency, magnesium, magnesium deficit, magnesium deficiency, marginal intake, suboptimal intake.

Introduction

Dietary intake of magnesium in developed countries is often far below recommended amounts1. Furthermore, the recommendations have been set at levels less than those amounts of magnesium required to achieve equilibrium in balance studies with humans2. Consequently, a chronic dietary inadequacy of magnesium is commonplace.

Magnesium deficiency and its effects were first reported about 19303,4. This early work involved feeding diets containing very little magnesium, inducing an acute deficiency state. Repletion of the animals with magnesium allowed elucidation of the physiological roles of the mineral5. However, it was some time before chronic marginal magnesium deficiency, a circumstance which is much closer to that seen in humans, was investigated.

The purpose of this paper is to review briefly studies which included, if not necessarily focused upon, marginal intakes of magnesium in experimental magnesium deficiency. The National Research Council (NRC) has recommended levels of energy and nutrients to be included in diets of laboratory animals6. For example, diets for the laboratory rat should include 16.5 mmol magnesium/kg diet6. However, the level of magnesium used as 'normal' varies considerably between authors. For example, a commonly-used commercial rat chow has been reported to contain 86.4 mmol magnesium/kg diet7. In addition, the particular level of magnesium in the diet which would allow the diet to be considered marginally deficient varies depending upon a number of factors, including stress8, other dietary components8,9, and species10. For the purpose of this discussion, a marginal intake of magnesium is defined as one which is tolerated by the subject for a prolonged period of time without the development of major abnormalities which, in the case of the studies reviewed here, involves a magnesium concentration approximating 4 mmol/kg.

Early studies were often conducted for a brief period of time. With severe restriction of magnesium, deficiency signs occur rapidly, while with more moderate restriction, more time is required before symptoms of deficiency become evident. In (illegible), Osborne and Mendel attempted to induce a deficiency state in rats with a diet containing more than 4.1 mmol magnesium/kg diet11. They observed no 'untoward effects' of this regime and stated that magnesium deficiency had not developed in these rats.

In early work with minerals, environmental contamination, coprophagy, and other circumstances often increased magnesium availability such that the actual level of magnesium consumed by the animals was much higher than that which was contained in the diet. These potential problems are routinely controlled in research with minerals today, but their importance was not recognized in early work. In addition, the ability to analyse substances for small amounts of magnesium was not as reliable as desired until the advent of atomic absorption spectrophotometry.

Magnesium requirements

A conclusion of a study reported in 194812 was that 8.2 mmol/kg was an adequate level of magnesium to permit optimal growth in the rat. Although the data supported the conclusion, the study lasted only 12 days.

Hegsted et al.13 conducted one of the first studies in which problems associated with a marginal intake of magnesium were described. In this study, rats fed 10.3 mmol magnesium/kg diet grew as well as those fed higher levels of the mineral and better than those fed 4.9 mmol/kg. However, when rats fed the 10.3 mmol diet were maintained at a cold temperature (13° C), they grew less than those fed higher levels of magnesium. Even more striking was the fact that no animal which was fed a high calcium diet with 10.3 mmol magnesium/kg and which was kept at this temperature survived, while many which were fed higher levels of magnesium survived. These workers concluded that stress, in this case cold stress, increased the requirement for magnesium, as did a high calcium diet.

The objective of studies performed with levels of magnesium which varied from severe restriction to a generous intake generally was to determine the requirement of the mineral for growth, reproduction, and maintenance of the animal. Through these studies, some effects of moderate magnesium restriction were identified in spite of the fact that this had not been an original intent of the work.

McAleese & Forbes14 used regression analysis to determine that maximal growth in rats could be achieved with 4.1 mmol magnesium/kg while greater amounts were needed for maximal bone and blood magnesium, 8.2 and 14.4 mmol/kg, respectively. This research was the basis for the NRC recommendation for magnesium for (illegible) reported earlier13, additional magnesium was needed if the diet was high in calcium. McAleese & Forbes suggested that, since the use of weight gain as the only criterion for magnesium adequacy was insufficient in their study, and index such as kidney calcification might be used as an indication of borderline deficiency. The relationship of marginal magnesium deficiency to renal function and disease thus was identified.

Magnesium metabolism is closely related to that of many other nutrients, especially calcium. A study in which this was illustrated was conducted by Forbes15. Typical signs of magnesium deficiency were noted in rats fed 5.8 mmol magnesium/kg only when it contained a high calcium level as well. In this work, the moderately low magnesium diet was associated with the development of brittle bones, a finding which was confirmed by Miller et al.16 in a study with pigs. Bone strength in the pigs which were fed 5.1 mmol magnesium/kg was less than in those animals fed normal amounts of the mineral. A possible role for marginal magnesium deficiency in bone disease was suggested by these findings.

Early studies which had assessed magnesium adequacy by weight gain had been replaced by those which also included assessment of mineral content and function of tissues, e.g. renal calculosis and bone strength. The interaction of a marginal magnesium intake with other nutrients, especially minerals, was being recognized.

A 1966 study by Forbes17 resulted in the observation that a diet containing half of the recommended level of magnesium was associated with significant alterations of electrolytes in tissues of rats. Serum magnesium and phosphate and bone magnesium and potassium were lower, while renal calcium was increased, in the animals fed the low magnesium diet.

Effects of magnesium deficiency, which had been reported to be exacerbated by high protein intakes in severe magnesium restriction18, were also intensified by high protein with a more moderate level of restriction, 4.1 mmol/kg19. Protein intake was directly correlated with growth rate, with faster growth apparently increasing the requirement for magnesium.

Hunt20 fed young, mature, and old rats 1/2, 1/4, or 1/8 of the control level (0.8-1.2 mmol/100 g body weight) of magnesium. Weight was about the same in all groups by the end of the study. Bone magnesium was less as magnesium intake decreased, although this effect was attenuated in the older rats. This researcher suggested that new bone mirrored magnesium intake while composition of bone in older animals was less labile. Magnesium in skeletal muscle was not affected by any of the deficient diets; however, cardiac magnesium was reduced with the low magnesium diets.

Magnesium and cardiovascular disease

The study by Hunt20 demonstrated the potential impact of marginal magnesium deficiency on cardiovascular function. An earlier study by Hellerstein et al.21 illustrated the influence of moderate magnesium restriction on serum lipids. Rats fed 9.9 mmol magnesium/kg with added cholesterol and cholic acid had higher serum cholesterol levels than did those which were fed four or eight times that amount of magnesium.

In 1975, Heroux et al.22 reported results of an experiment which lasted 517 days in which rats were fed 4.9 or 20.6 mmol magnesium/kg. Magnesium balance, magnesium content of plasma, tibia, and fat free dry carcass, and bone strength were reduced in the low magnesium group. Another 517 day study, again by Heroux et al.23, involved exposure of rats to cold stress. This stress resulted in the development of calcified cardiac lesions in the low magnesium (4.1 mmol/kg) group as compared to uncalcified lesions in the control-fed rats. The authors concluded that results from their work confirmed the hypothesis that chronic suboptimal intake of magnesium may not cause overt signs of deficiency but may reduce stress resistance with time and, in fact, may predispose humans to myocardial infarction. Evidence was presented that the ability of animals to adapt to a low magnesium intake over a long period of time was limited. Previously, Britton & Stokstad24 observed aortic calcification in magnesium-deficient rats (4.1 mmol/kg diet). Elastin was the site of calcification, and elastin metabolism was altered in the deficient animals.

In the 1980s, several studies have addressed the relationship between marginal dietary magnesium intake and cardiovascular disease. The report by Altura et al.25 of microvascular changes and elevated arterial pressure associated with moderate magnesium deficiency (4.9 mmol/kg with or without 3.9 mmol Mg/litre water) in rats received a great deal of attention. They reported reduced lumen size, less blood flow in capillaries, and more vasoconstriction in rats with a marginal intake of magnesium.

However, other reports contain contradictory results. Magnesium deficiency has been reported to exert a normotensive or hypotensive rather than hypertensive effect in vivo26,27. In addition, individuals with primary magnesium deficit generally have normal serum levels of magnesium while hypertensives are usually normomagnesaemic. Nishiyama et al.28 stated that blood pressure was not altered in rats which were magnesium-deficient for 7 months. It has been suggested that, rather than magnesium being a major antihypertensive nutrient, magnesium deficiency may enhance the effect of a hypertensive factor because of the effects of the mineral on renal, (illegible). This point is illustrated by results of the study by Berthelot & Esposito which indicated that a low magnesium diet (3.3 mmol/kg) accelerated the development of hypertension in the spontaneously hypertensive rat (SHR)29. Another example of this point is a report by Overlack et al.30 who did not observe an effect of magnesium deficiency (4.1 mmol/kg) on blood pressure in rats but reported that this moderate deficiency of magnesium attenuated the action of a calcium antagonist in lowering blood pressure. Likewise, a recent report by Stein & Classen31 indicated that action of a beta-adrenergic blocking agent was impaired in the presence of a moderate magnesium deficiency (4.1 mmol/kg).

Fischer & Giroux32 found that activity of cardiac Na+-K+ ATPase was less in rats fed 8.2 mmol magnesium/kg than in controls, although the concentration of molecules of the enzyme was unchanged. This would partially explain changes in electrolyte levels within cells, including the heart, found in magnesium deficiency (higher levels of sodium and calcium and lower levels of magnesium and potassium)33. Previously, Fischer & Giroux34 had suggested that the elevated calcium to magnesium ratio which they observed in cardiac tissue of magnesium-deficient rats (3.3 mmol/kg diet) could result in an increased contractile response in the coronary arteries and venous smooth muscles. Subsequently, coronary artery spasm could develop leading to ischaemia and arrhythmia. These researchers also stated that the increased cardiac sodium of the magnesium-deficient rats might change the membrane potential, making the heart more susceptible to arrhythmias34. Ito et al.34a observed in swine that a suboptimal magnesium intake (around half the recommended requirement) in combination with a moderate excess of Vitamin D (usual for the average American population), intensifies ultrastructural changes in the coronary arteries.

Experiments with diets severely deficient in magnesium have shown that lipid metabolism is abnormal and platelet function is altered, with a predisposition to thrombosis. Moderate magnesium deficiency has the potential to be linked to an increased risk of cardiovascular disease. An elevation in serum total cholesterol which was seen in rats fed a low magnesium diet (3.3 mmol/kg) by Brilla & Lombardi35 was also reported by Luthringer et al.36 in rats fed a diet which contained the same amount of magnesium. The latter group noted hypertriglyceridaemia and a drop in high-density lipoprotein cholesterol (although hypertension did not occur in their hypomagnesaemic animals). Also of interest in Luthringer's report was the fact that vascular reactivity to noradrenaline was higher in magnesium-deficient animals. Cunnane et al.37 reported changes in fatty acid composition of diet (4.4 mmol/kg).

Prostanoid synthesis is altered in magnesium deficiency. Rats fed a diet containing 3 mmol magnesium/kg were reported by Nigam et al.38 to have higher levels of 6-keto-PGFla, TXB2, and PGE2 than control animals. These authors suggested that magnesium deficiency may reduce inhibition or may stimulate production of prostaglandins. Soma et al.39 found increases in these prostanoids, as well as PGI2, from the mesenteric artery bed in rats fed a diet with magnesium concentration of 4.5 mmol/kg. They attributed the increases to a stimulatory effect of magnesium deficiency.

One of the risk factors for cardiovascular disease is diabetes mellitus. A study which addressed glucose metabolism with magnesium deficiency (4.1 and 8.2 mmol/kg) was conducted by Legrand et al.40. Results indicated that magnesium inadequacy was associated with abnormal glucose tolerance and reduced pancreatic insulin as compared to rats fed 30.9 mmol magnesium/kg diets. This supported results of an earlier study by McNeill et al.41 in which a 3.3 mmol magnesium diet was associated with a lower insulin to glucagon ratio.

Magnesium and renal function

Although its aetiology is unclear, renal calcium accumulation has been reported to occur with magnesium deficiency, the degree proportional to the degree of deficiency42. Recently, renal calculosis was observed in animals fed levels as high as 24.7 mmol magnesium/kg43. One hypothesis for this phenomenon in mild, as well as acute, deficiency is that renal conservation of magnesium causes a reduction in the magnesium-to-calcium ratio within the tubular lumen allowing calcium to precipitate42.

Magnesium and stress

Neuromuscular hyperexcitability has been shown to occur in moderate as well as severe magnesium deficiency44. Through EEF and EMG tracings, Pocnaru et al.44 observed a diffuse neuromuscular hyperexcitability in rats fed a low magnesium diet (2.1 mmol/kg).

Hypersensitivity to stress is commonly seen in magnesium deficiency. In the work of Heroux et al.23, rats mildly deficient in magnesium had a shorter lifespan than did the controls when exposed to cold stress. After travelling from the Houston-based supplier during particularly cold weather in December, several weanling rats fed a magnesium-deficient diet (3.1 mmol/kg) for five days suffered audiogenic seizures and died45. Magnesium deficit may be a conditioning factor for the development and potentiation of stress46,47.

Since the mid-1970s, studies examining the role of marginal magnesium intake on reproduction have been reported 45, 48-61. Results from a study by Broccia et al.60 indicated that the requirement for magnesium during gestation of rats was between 10.3 and 20.6 mmol/kg diet.

Buck and colleagues noted problems with lactation of dams fed diets containing either 8.248 or 5.1 mmol magnesium/kg52. Growth of rat pups was correlated with milk yield and magnesium content of milk, both of which were decreased with the low magnesium diet52.

Rayssiguier et al.49 reported that a moderate deficiency of magnesium (4.5 mmol/kg) interfered with normal parturition and uterine involution. These effects may have been related to magnesium lack impairing function of oxytocin in the former and collagen metabolism in the latter. A further investigation of collagen metabolism involved the combination of a marginal intake of magnesium (4.5 mmol/kg) and ingestion of ethanol62. In this study, Rayssiguier et al. saw higher collagen concentrations in livers of magnesium-deficient alcohol-fed rats than in controls due to increased collagen production in magnesium deficiency.

In a study conducted by Gunther et al.50, rats were fed diets containing gradations of magnesium from 4.5 to 14.8, as well as 82.3 mmol/kg. A threshold for maternal serum magnesium, which was a reflection of dietary intake, seemed to exist, below which resorptions, growth retardation, and malformations occurred. Diets providing 4.5, 6.6, and 10.7 mmol magnesium/kg were inadequate to maintain serum magnesium above this threshold. Vormann et al.51 showed that a magnesium gradient across the placenta existed which was maintained regardless of serum magnesium level of the mother.

A series of studies was conducted by Kubena and colleagues45,53,54,57-59,61 in which weanling rats were fed diets varying in magnesium from 5.1 to 9.3 mmol/kg during postweaning growth, breeding, gestation, and, in most of the studies, lactation. These investigations showed that, over time, tissue content of magnesium decreased so that effects of a moderate magnesium deficiency were more severe than would have been observed in shorter studies. For example, in a report of severe maternal magnesium restriction, Hurley et al.63 noted a reduction in zinc status of pups. This effect was also seen with long-term moderate magnesium restriction (5.1 mmol/kg)54.

The relationship between dietary magnesium and calcium continues to be unclear as shown by the fact that a high calcium low magnesium (8.2 mmol/kg) diet fed to rats from weaning through lactation was associated with larger and more viable pups than those in the low magnesium, normal calcium group59. (illegible) effect of high calcium with a low magnesium diet comes from a recent study by Wright et al.64 in which chicks were fed 40% of the recommended level of magnesium. Intestinal calcium absorption in these birds was reduced. The second hydroxylation of vitamin D that takes place in the kidney is a magnesium-requiring step. The combination of renal calculosis and magnesium lack could reduce availability of activated vitamin D which would result in less calcium-binding protein. The end result would be impaired absorption of calcium. However, when intestinal calcium binding protein (CaBP) in duodenum, ileum, and jejunum was measured by RIA, no significant differences were detected between control rats and those fed a diet containing only 2.1 mmol magnesium/kg diet65.

In a recent study61, a magnesium-deficient (8.2 mmol/kg) diet fed to rats from weaning through gestation was associated with impaired humoral immunity in pups, an effect which was not reversible with magnesium repletion of dams during lactation. The role of magnesium in the function of complement and phagocytic activity was further elucidated in a study of rats fed a diet containing 4.1 mmol magnesium/kg66.

Magnesium and other systems

Kleber & Fehlinger67 reported impaired development of odontogenesis and posteruptive adaptability to dental microbial plaque in progeny of rat dams magnesium-deficient during gestation and lactation (7.0 mmol/kg). Previously, a slowing of the rate of clinical emergence of incisors in pups from dams fed low magnesium diets (6.2 mmol/kg) from weaning through lactation had been reported58. The impetus for the recent animal study by Kleber & Fehlinger67 was observations which they had made in patients suffering from the tetanic syndrome.

Arpad et al.67a observed after an 8 month period of chronic magnesium deficiency in rats, not only the known consequences on kidney, bone, cartilage, and teeth but also effects on the sexual organs including atrophy of testes, ovaries and uterus.

Magnesium and new areas of research

During the past few years, investigations of marginal magnesium deficiency have focused on areas such as nutrient-drug interaction. Caddell68 observed that magnesium deficiency (7.8 mmol/kg) exacerbated calcification of kidney associated with furosemide administration. Cerklewski69 reported that rats fed marginal magnesium-deficient diets (6.2 mmol/kg) had higher tissue accumulation of lead than did controls. He suggested that this may have resulted because calcium, iron, and zinc all affect toxicity of lead and (illegible) later study, this researcher observed an inverse relationship between magnesium and absorption of fluoride in rats fed 8.2 mmol magnesium/kg70. Nielsen et al.71 reported interactions between magnesium deficiency and the trace metals, boron and aluminum. Magnesium-deficient rats (4.9 mmol magnesium/kg) experienced more severe symptoms in the presence of dietary aluminium, while boron deprivation was worsened by magnesium deficiency.

With the growing interest in nutrition in sports and exercise, two studies in which rats were fed moderately magnesium-deficient diets (4.1 or 8.2 mmol/kg72, 8.2 mmol/kg73) have been published recently. In both of these investigations, magnesium deficiency was associated with reduced endurance.

Conclusion

Information on the influence of a marginal magnesium-deficient diet is accumulating. It is clear from these studies that magnesium deficiency may be present in spite of the absence of overt signs of deficiency and may be instrumental in changes within tissues which impair function and/or promote disease.

The philosophy that absence of overt deficiency symptoms in countries with low intakes of the nutrient is an indication that the recommended levels are too high and should be reduced does not agree with evidence presented here8.

References

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16. Miller, E.R., Ullrey, D.E., Zutaut, C.L., Baltzer, B.V., Schmidt, D.A., Hoefer, J.A. & Luecke, R.W. (1965): Magnesium requirement of the baby pig. J. Nutr. 85, 13-20.

17. Forbes, R.M. (1966): Effects of magnesium, potassium and sodium nutriture on mineral composition of selected tissues of the albino rat. J. Nutr. 88, 403-410.

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21. Hellerstein, E.E., Nakamura, M., Hegsted, D.M. & Vitale, J.J. (1960): Studies on the interrelationships between dietary magnesium, quality and quantity of fat, hypercholesterolemia and lipidosis. J. Nutr. 71, 339-346.

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29. Berthelot, A. & Esposito, J. (1983): Effects of dietary magnesium on the development of hypertension in the spontaneously hypertensive rat. J. Am. Coll. Nutr. 4, 343-353.

30. Overlack, A., Zenzen, J.G., Ressel, C., Muller, H.M. & Stumpe, K.O. (1987): Influence of magnesium on blood pressure and the effect of nifedipine in rats. Hypertension 9, 139-143.

31. Stein, C. & Classen, H.G. (1988): Influence of magnesium aspartate hydrochloride and acebutolol on blood pressure, pulse frequency and electrolyte distribution in spontaneous hypertensive rats (abstract). Magnesium Res. 1, 100.

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34. Fischer, P.W.F. & Giroux, A. (1984): Effect of magnesium deficiency on mineral excretion and concentration in rat serum, heart and kidney. Nutr. Res. 4, 51-57.

34a. Ito, M., Cho, B.S.H. & Kummerow, F.A. (1990): Effect of a dietary magnesium deficiency and excess vitamin D3 on swine coronary arteries. J. Am. Coll. Nutr. 9, 155-163.

35. Brilla, L.R. & Lombardi, V.P. (1987): Variable response of serum magnesium and total cholesterol to different magnesium intakes and exercise levels in rats. Magnesium 6, 205-211.

36. Luthringer, C., Rayssiguier, Y., Gueux, E. & Berthelot, A. (1988): Effect of moderate magnesium deficiency on serum lipids, blood pressure and cardiovascular reactivity in normotensive rats. Br. J. Nutr. 59, 243-250.

37. Cunnane, S.C., Soma, M., McAdoo, K.R. & Horrobin, D.F. (1985): Magnesium deficiency in the rat increases tissue levels of docosahexaenoic acid. J. Nutr. 115, 1498-1503.

38. Nigam, S., Averdunk, R. & Gunther, T. (1986): Alteration of prostanoid metabolism in rats with magnesium deficiency. Prostaglandins Leukotrienes Med. 23, 1-10.

39. Soma, M., Cunnane, S.C., Horrobin, D.F., Manku, M.S., Honda, M. & Hatano, M. (1988): Effects of low magnesium diet on the vascular prostaglandin and fatty acid metabolism in rats. Prostaglandins 36, 431-441.

40. Legrand, C., Okitolonda, W., Pottier, A.M., Lederer, J. & Henquin, J.C. (1987): Glucose homeostasis in magnesium-deficient rats. Metabolism 36, 160-164.

41. McNeill, D.A., Herbein, J.H. & Ritchey, S.J. (1982): Hepatic gluconeogenic enzymes, plasma insulin and glucagon response to magnesium deficiency and fasting. J. Nutr. 112, 736-743.

42. Fischer, P.W.F., Giroux, A., L'Abbe, M.R. & Nera, E.A. (1981): The effects of moderate magnesium deficiency in the rat. Nutr. Rep. Int. 24, 993-1000.

43. (illegible) deficiency and renal alterations in rats (abstract). Magnesium Res. 1, 115.

44. Poenaru, S., Durlach, J., Rouhani, S., Rayssiguier, Y., Gueux, E., Iovino, M. & Reba, A. (1983): Etude électrophysiologique de la carence magnésique du rat. Magnesium 2, 299-312.

45. Kubena, K.S., Landmann, W.A. & Carpenter, Z.L. (1983): Suboptimal intake of magnesium in rats: Effects during growth and gestation. Nutr. Res. 3, 385-394.

46. Durlach, J. (1988): Magnesium in clinical practice, pp. 140-146. London: John Libbey & Company Ltd.

47. Classen, H.G. (1989): Stress and magnesium with special regard to the gastrointestinal tract. In Magnesium in health and disease, eds Y. Itokawa & J. Durlach, pp. 271-278. London: John Libbey and Co. Ltd.

48. Buck, D.R., Mahoney, A.W., Hendricks, D.G. & Johnson, R.M. (1977): Dietary magnesium effects on magnesium status of rats during lactation (abstract) Fed. Proc. 36, 1130.

49. Rayssiguier, Y., Badinand, F. & Kopp, J. (1979); Effects of magnesium deficiency on parturition and uterine involution in the rat. J. Nutr. 109, 2117-2125.

50. Gunther, T., Ising, H., Mohr-Nawroth, F., Chahoud, I. & Merker, H.J. (1981): Embryotoxic effects of magnesium deficiency and stress on rats and mice. Teratology 24, 225-233.

51. Vormann, J., Forster, R., & Gunther, T. (1983): Foetal and maternal magnesium metabolism: effect of magnesium deficiency and isoproterenol. J. Clin. Chem. Clin. Biochem. 21, 765-773.

52. Buck, D.R. & Bales, J. (1983): Maternal dietary magnesium effects on lactation success and on milk yield and composition in the rat. J. Nutr. 113, 2421-2431.

53. Kubena, K.S., Carpenter, Z.L. & Landmann, W.A. (1983): Parturition and pregnancy outcome in rats as influenced by marginal intake of magnesium. Nutr. Res. 3, 477-485.

54. Kubena, K.S., Landmann, W.A., Young, C.R. & Carpenter, Z.L. (1985): Influence of magnesium deficiency and soy protein on magnesium and zinc status in rats. Nutr. Res. 5, 317-328.

55. Keen, C.L., Gershwin, M.E. & Hurley, L.S. (1985): Influence of magnesium upon development survival, and immune function in mice. Magnesium 4, 201-220.

56. Vormann, J. & Gunther, T. (1986): Development of fetal mineral and trace element metabolism in rats with normal as well as magnesium- and zinc-deficient diets. Biol. Trace Elem. Res. 9, 37-53.

57. Kubena, K.S., McLaughlin, C.B. & Carson, D.D. (1987): Magnesium restriction and soy protein during gestation and lactation in rats. Nutr. Repo. Int. 36, 357-364.

58. Kubena, K.S., Edgar, S.E. & Veltmann, J.R. (1988): Growth and development in rats and deficiency of magnesium and pyridoxine. J. Am. Coll. Nutr. 7, 317-324.

59. (illegible) low dietary magnesium and high calcium on pregnancy outcome and tissue mineralization in rats. Magnesium Res. 1, 147-153.

60. Broccia, G.E., Roverski, P.M. & Vismar, C. (1988): The minimum content of magnesium in the diet for a normal pregnancy in the rat. Nutr. Res. 8, 509-516.

61. Kubena, K.S., Cohill, D.T. & McMurray, D.N. (1989): Effect of varying levels of magnesium during gestation and lactation on humoral immune response and tissue minerals in rats. Ann. Nutr. Metab. 33, 7-14.

62. Rayssiguier, Y., Chevalier, F., Bonnet, M., Kopp, J. & Durlach, J. (1985): Influence of magnesium deficiency on liver collagen after carbon tetrachloride or ethanol administration to rats. J. Nutr. 115, 1656-1662.

63. Hurley, L.S., Cosens, G. & Theriault, L.L. (1976): Magnesium, calcium, and zinc levels of maternal and fetal tissues in magnesium deficient rats. J. Nutr. 106, 1261-1264.

64. Wright, S., Delaney, N. & Martin, W.G. (1988): Changes in intestinal calcium transport and binding in magnesium-deficient chicks. Magnesium 7, 16-22.

65. Rayssiguier, Y., Thomasset, M., Garel, J.-M. & Barlet, J.-P. (1982): Plasma parathyroid hormone levels and intestinal calcium binding protein in magnesium deficient rats. Hormone Metab. Res. 14, 379-382.

66. Kawanobe, Y. & Sakamoto, M. (1989): Complement systems and phagocytic activities in magnesium deficient rats (abstract). Magnesium Res. 2, 81.

67. Kleber, B.-M. & Fehlinger, R. (1989): Dental and periodontal disturbances due to magnesium deficit. Magnesium Res. 2, 235-237.

67a. Arpad, B., Karoly, B. & Laszlo, H. (1989): Biological, biochemical and morphological observations on animals with chronic magnesium deficiency (abstract). Magnesium Res. 2, 228.

68. Caddell, J.L. (1985): Protection by magnesium of renal calcinosis in furosemide-treated weanling rats with moderate magnesium deficiency. Biol. Neonate 48, 49-58.

69. Cerklewski, F.L. (1983): Influence of maternal magnesium deficiency on tissue lead content of rats. J. Nutr. 113, 1443-1447.

70. Cerklewski, F.L. (1987): Influence of dietary magnesium on fluoride bioavailability in the rat. J. Nutr. 117, 496-500.

71. Nielsen, F.H., Shuler, T.R., Zimmerman, T.J. & Uthos, E.O. (1988): Dietary magnesium, manganese and boron affect the response of rats to high dietary aluminum. Magnesium 7, 133-147.

72. Keen, C.L., Lowney, P., Gershwin, M.E., Hurley, L.S. & Stern, J.S. (1987): Dietary magnesium intake influences exercise capacity and hematologic parameters in rats. Metabolism 36, 788-793.

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