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THE ADVERSE EFFECTS OF MANGANESE DEFICIENCY ON REPRODUCTION
AND HEALTH
(BOOKLET) The impairment in mucopolysaccharides synthesis associated with manganese deficiency has now been related to the activation of glycosyltranferases by this element, which are vital constituents both in polysaccharide and in glycoprotein formation (2,27-28). The critical sites of manganese function have been found to be related to the synthesis of chondroitin sulfate, the major polysaccharide of the cartilage, and the mucopolysaccharide most severely affected in manganese deficiency (2,27-29). Chondroitin sulfate consists of a polypeptide backbone, to which is attached a carbohydrate side chain, composed of xylose and two molecules of galactose. To this is attached the main carbohydrate portion of the molecule, a repeating unit of glucuronate and N-acetyl-galactosamine. Research has now established that manganese is the most efficient divalent cation in the activation of the glycosyltransferase enzymes, essential in the chondroitin sulfate formation (2,27-29). In animal experiments, manganese deficiency has been found to result in abnormalities in cell function and ultrastucture, particularly involving the mitochondria. For example, when oxidative phosphorylation was studied in isolated liver in manganese deficient mice and rats, in both species, ratios of ATP formed to oxygen consumed were normal, but oxygen uptake was greatly reduced. Electron microscopy of these mitochondria revealed ultrastructure abnormalities, including elongation and reorientation of cristae (2,30). Subsequently, it was confirmed by the same authors, that dietary deficiency of manganese will lead to alterations in the integrity of all tissue cells examined, which included the liver, the kidney, the pancreas and the heart. In addition, the endoplasmic reticulum was found to be swollen and mitochondria were found to be irregular, with elongated stacked cristae in liver, heart, and kidney cells. Furthermore, there was found to be an overabundance of lipid in liver parenchymal and kidney tubule cells. The lowered oxidation in mitochondria from manganese deficient animals was believed by the authors to be possibly related to all morphological changes observed (2,31). Research has also established, that injected manganese is cleared rapidly from the bloodstream in three phases (2,32). The first, and the fastest of these, is identical with the clearance rate of other small ions, suggesting the normal transcapillary movement. The second can be identified with the entrance of manganese into the mitochondria of the tissue, and the third has been found to indicate the rate of nuclear accumulation of the metal. These findings support the early preferential accumulation of manganese m the mitochondrial-rich organs of the body (2,33). Manganese has also been found to play a part in the formation of thyroxine, the active principle of the secretion of the thyroid gland (34). Manganese being a mitochondrial element, it is also the key component of the superoxide dismutase found in mitochondria of the cells, that protects the fragile mitochondrial membrane from the attack of free radicals. Without manganese the mitochondrial SOD would simply be inactive and accumulation of free radicals would lead to severe membrane damage (4,10,27,35). Other forms of superoxide dismutases, found in the cytosal, require copper and zinc and iron for their activity (10,27,35). Manganese is important in the building and breakdown cycles of protein and nucleic acids, and for the RNA chain initiation (10,27,36). The process of RNA synthesis consists of three major steps; initiation, elongation and termination. For the RNA chain reaction, manganese has been found to be a superior effector to any other metal, including magnesium. Research has also confirmed the findings, establishing that manganese was found to be a far better effector in binding calf thymus RNA polymerase to DNA than magnesium (27,37). In a study on newborn guinea pigs severely affected by manganese deficiency, they were found to exhibit aplasia, or marked hypoplasia, of all cellular components of the pancreas. Compared to controls, the number of islet cells were found to be greatly reduced. The same with beta cells, which were also found to be far less granulated than in control animals. In addition, young adult manganese-deficient guinea pigs were observed to have subnormal numbers of pancreatic islets, with less intensely granulated beta cells and more alpha cells, than manganese-supplemented controls (2,27,38). When glucose was administered orally, or intravenously, the manganese-deficient animals revealed a decreased capacity to utilize glucose, and displayed a diabetic-like curve in response to the glucose loading. Manganese supplementation completely reversed the reduced glucose utilization in these animals (27,38). Similar findings have been found in human subjects (39-40). The role of manganese in glucose tolerance is not yet been well defined, but it is believed to be due to its vital role in the involvement with enzymatic reactions, particularly with glycosyltransferases, discussed previously (2,27-28). Furthermore, it has been suggested, that the impairment of glucose utilization in manganese deficiency, may be related to some connective tissue defects that occur with defective carbohydrate metabolism, as decreased concentration of stainable mucopolysaccharides have been found on skins of young rats born to diabetic mothers (27,41). An association between manganese and choline metabolism has been recognised already for some years (2,27). For example, when rats were placed on a choline deficient diet, they exhibited lower hepatic manganese levels than those of controls (2,27,42). Furthermore, it has been observed that choline deficiency, produces similar changes in liver ultrastructure, including perosis in chicks, to those found in manganese deficiency states(2). As the result, it is suggested that these two nutrients may be linked with some common pathway to ensure normal structure of the mitochondrial and cellular membranes, either directly through effect, on the membrane synthesis, or indirectly through some alteration of the mitochondrial oxidations (2,31). Since prothombin is a glycoprotein, its synthesis should also be influenced by manganese through its activating effects on glycosyltranferases. Evidence is now accumulating to that effect. Moderate manganese deficiency in chicks has been shown to reduce the clotting response of vitamin K, compared to that of chicks receiving an ample dietary supply of manganese (2,43). Moreover, a human patient suffering from both manganese and vitamin K deficiency was unable to elevate his depressed clotting protein given only vitamin K, until manganese was also restored to his diet (43). Manganese has been found to stimulate adenylate cyclase activity in the brain and other tissues of the body (27,44). This s of importance because cyclic-AMP plays a regulatory role in the action of several brain neurotransmitters, by acting as a second messenger within cells in transmitting the messenger hormone (27,34). One study with rats, found that manganese was a potent stimulator of adenyte cyclase activity in different parts of the rat brain, whereas lead, mercury, zinc and copper were found to be powerful inhibitors of the enzyme. It was also established that the site of interaction of manganese with adenylate cyclase was found to be the catalytic subunit of the cyclase rather than the receptive or regulatory subunit (27,45). Adenylate cyclase activities that require specifically manganese for their action have been found in animal studies both in the striae cortex (34) and in the neurospora cassa (27,46). In man, high manganese concentrations are usually found in the basal ganglia, where the ion is believed to stimulate acetylcholine storage activity (34). In humans, manganese deficiency has also been linked with reduced levels of the neurotransmitter, dopamine (10). Manganese chloride was first tested, and found effective, in treating schizophrenia as early as the 1920s (47-48). Somewhat later three micronutrients, in particular copper, zinc and manganese, started to generate much research in a variety of mental disorders, particularly in schizophrenia (27). Heilmeyer et al. presented one of the earliest studies implicating an excess of copper in 32 of 37 schizophrenics (49). This was followed by Dr Pfeiffer and his colleagues, who carried on observing an excess of body copper and low manganese status in a variety of mental and physical disorders, such as in schizophrenias, depression, alcoholism, epilepsy, also in some infectious diseases and cancers (27). In order to eliminate the excess body burden of copper, both manganese and zinc supplementation were used, as the two nutrients together were found to be far more effective for the copper elimination than either of them alone (27,34,50- 53). An additional study found considerably lower hair manganese levels in schizophrenic patients compared to controls (54). Hurley and his colleagues were the first to demonstrate a significantly reduced seizure threshold in manganese deficient animals given manganese supplementation (55). Further studies found considerably lower blood manganese levels m epileptic patients when compared to controls (56- 57). Thereafter several uncontrolled trials have found manganese supplementation being helpful in controlling seizures, of both minor and major types, possibly due to its central role, with choline, in the control of membrane stability (53). The side effects of prolonged medication with neuroleptic drugs are known to lead to tardive dyskinesia. This condition is sometimes reversible after cessation of medication. However, in many subjects, this condition seems to become irreversible. Research has now shown, that neuroleptics are able to chelate body manganese (58), binding it electrochemically, thus making it unavailable as an enzyme activator (59). Research by Kunin (60) found, when treating 15 patients suffering from tardive dyskinesia with manganese supplementation, that seven were cured outright, three were much improved, four were improved, and only one was unimproved. As a result, it has been suggested, that manganese can be of value in the treatment of tardive dyskinesias, as well as possibly in preventing this iatrogenic disorder from occurring (27). In addition to the conditions mentioned above, manganese deficiency has been associated with back ache, due to its essential role in the cartilage formation (27,61). Also, manganese deficiency has been associated with cancer formation, due to its central role as Superoxide dismutase in the protection of the cell nucleus, and the mitochondria, from free radical formation (10). Manganese deficiency has also been linked with heart disease, as manganese has been found to be equally effective as a calcium antagonist as modern drugs (10). In addition, a study reported hair manganese levels of both male and female patients diagnosed as multiple sclerotic (MS), to be half that found in control subjects (62). The earliest studies on animals were able to demonstrate that a manganese deficient diet can lead to defective ovulation, testicular degeneration, and to infant mortality (63-66). In the female, three stages of manganese deficiency are now recognised. In the least severe stage the animals may give birth to young with a variety of malformations. In the second, more severe stage, the young are born dead, or die shortly after birth. In the third, or in the acute stage of manganese deficiency, estrous cycles are absent or irregular, the animals will not mate, and sterility results. A delayed opening of the vaginal orifice may also occur (67). The severely manganese deficient male animals exhibit sterility and absence of libido, associated with seminal tubular degeneration, lack of spermazoa, and accumulation of degenerating cells in the epididymis (67-68). The precise locus mode of action of manganese in preventing the reproductive defects, in both male and female animals, have not yet been established. However, a suggestion has been put forward, that the lack of manganese may inhibit the synthesis of cholesterol and its precursors, thus limiting the synthesis of sex hormones, and possibly other steroids, with the consequent infertility (69). As discussed previously, it is now known, using animal experiments, that maternal manganese deficiency during embryonic development produces a variety of irreversible congenital malformations in the offspring, including multiple skeletal and joint malformations, as well as a variety of structural defects of the skull and the otoliths, resulting in ataxia, loss of equilibrium, tremors etc. (2,10-29). Similar findings have now been established in the human offspring. Saner and co-workers (70) investigated hair manganese status of mothers and their infants at delivery using flameless atomic absorption technique. The study was carried out on 31 full-term, 18 pre-term, and 12 newborn infants with congenital malformations and their mothers. The types of congenital malformations in this study included; anencephaly, meningomyelocele, double cleft lip and cleft palate, spina bifida occulta, hydrocephalus, hermaphroditism, and digital aplasia of both hands and feet. The control group consisted of 11 nulliparous women of comparable ages. None of the mothers showed any clinical evidence of nutritional deficiencies. The final results found significantly lower hair manganese concentrations both in the mothers, and in the infants with congenital malformations, when compared to the control subjects. In addition, it was found, that hair manganese levels in both full-term and pre- term infants with congenital malformations were almost identical, suggesting that manganese transfer seems to occur to the foetus at an early stage, well before the third trimester of the pregnancy. The study concludes that early gestational manganese deficiency can indeed be a potential factor in intrauterine malformations. Additionally, that the interrelationship between manganese transfer from the mother to the foetus seems to be regulated by a homeostatic mechanism which is directly dependent on the manganese status of the mother. Furthermore, that low prenatal maternal hair manganese status may provide a reliable indicator of potential malformations in the offspring (70). Additional research has also shown, that through certain enzymes, manganese seems to affect the glandular secretions underlying maternal instinct (34,71-72). This has been observed repeatedly in animal studies, which have found that manganese deficient mothers do not nurse their pups readily (72). The stress on the female manganese stores appears to be the greatest during the gestational period, when the foetal brain and other organs are developing (73). If during this most critical time of cellular development, an essential element such as manganese is deficient, this can not only lead to a variety of physical malformations, but also to deficiencies in mental functioning. The brain, after all, requires the same nutrients for cellular development as other foetal organs. In animal studies, maternal manganese deficiency has been found invariably to lead to a variety of behavioural disorders in the offspring, mainly related to the incomplete development of the otoliths (72,73). However, other studies have linked maternal manganese deficiency to other subtle central nervous system developmental disorders, including to inadequate clasping and righting performance (72). In conclusion, even though the often bizarre behavioural patterns found in manganese deficient offspring can be related to the inner ear changes, there still remains enough circumstantial evidence of a link between maternal manganese deficiency and foetal brain development to indicate that maternal manganese deficiency may also lead to other subtle behavioural and central nervous system dysfunctions in the offspring (73). Manganese is absorbed slowly and poorly throughout the length of the small intestine by a two-step mechanism involving initial uptake from the lumen, then transferred across the mucosal cells into the liver and other organs (2,10,74). Manganese absorption is dependent largely on the concentration of manganese already found in the body, i.e. the amount of manganese absorbed will not increase appreciably with dietary increases above that needed for normal body functioning (2). Within the intestinal mucosa, manganese has been found to compete with iron for common binding sites for absorption, manganese having far less affinity to the carrier proteins than iron (10,27,74.75). Manganese absorption is also negatively related to the presence of other trace minerals, such as copper, zinc, cobalt, phosphorus and calcium, as well as soyprotein (10,27), whereas lecithin, choline and ethanol seems to enhance intestinal and liver uptake of manganese (10). Most of the manganese ions which are absorbed into the portal circulation are almost completely removed by the liver and excreted into the bile. If bile flow is for some reason or other blocked and the hepatic pathway is overloaded, excretion takes place via the pancreatic juice, the duodenum, the jejunum and, to a smaller extent, via the terminal ileum (10,27). This highly efficient manganese excretory mechanism ensures that manganese toxicity, through the use of oral supplementation, is highly improbable (10,27). In fact, manganese toxicity in man, arising from excessive oral intake, has never been recorded (2). However, chronic manganese poisoning has been reported to occur from industrial sources, particularly among miners, following prolonged working with manganese ores, where the excess manganese oxide dust has entered into the body via lungs from the highly contaminated working environment. Chronic manganese poisoning is characterized by a severe psychiatric disorder (locura manganica) resembling schizophrenia, followed by a permanently crippling neurological disorder, clinically similar to Parkinson's disease (2,34). The minimum dietary requirement of manganese varies within species and the genetic strain of the animal (2). Even though manganese is considered an essential trace element, no official daily recommendation of manganese for humans has been set (4). However, about 4-5mg of manganese daily is generally accepted to be an average daily requirement, as a healthy human body uses approximately 4mg manganese each day in bone/cartilage replacement, lipid and carbohydrate metabolism, as well as in other manganese-dependent enzymatic processes (34,76-77). An average Western diet has been calculated to provide between 1-8mg manganese daily. Among tea-drinking nations the amount has been thought to be about 4.6mg, as tea leaves are known to contain a fair amount of the mineral (77). Other rich food sources are considered to be nuts, whole grains, spices and legumes; white meat, fish and dairy products contain only insignificant amounts (27,53,78). Only about 3-5% of dietary manganese is absorbed, so daily intakes must be sufficient to allow for the losses (4,77). It is generally believed that manganese deficiency cannot arise in humans, because the element is widely distributed in foodstuffs. However, it has now been found, that most Western diets, even those best planned, tend to be deficient in this important trace mineral, as many of our most frequently eaten foods, such as meat, fish and dairy products contain only insignificant traces of manganese. As far as the foods are concerned that are considered to be high in manganese, such as whole grains, legumes and nuts, they will only contain the amount of manganese that is available from the soil they have been grown on. Unfortunately current farming methods, particularly the excessive use of agrochemicals, are known to cause severe manganese deficiencies, both in the soil and in the crop it yields. In fact, a recent global investigation of micronutrient status of soils and plants has found a particularly low level of manganese, as well as zinc and iron, in the samples studied (79,80). Furthermore, liming the soil greatly increases the foliage, with the corresponding depletion of manganese (27,34). Furthermore, insecticides, which are used widely in the modem agriculture, are known to inactivate choline containing enzymes, which in turn prevents the uptake of manganese by the plants (71). The present trend of an increased consumption of excessive sugar, as well as of processed and refined foods, further reduces the manganese status. For example, the germ of the grain, which can be high in manganese, is discarded during the milling process (4,27,34). Therefore, the combination of the use of agrochemicals with food processing can hardly provide adequate dietary intake of manganese, particularly when one considers that only 3-5% of the mineral is absorbed. The main manifestations of foetal manganese deficiencies; namely gross skeletal and cartilage abnormalities, defective development of the skull and the otoliths, ataxia, defects of lipid and carbohydrate metabolism, and depressed or disturbed reproduction function, have been found in all animal species studied. In addition, manganese deficiency has been associated with impaired mitochondrial oxidation and glucose tolerance, inadequate protein and nucleic acid synthesis, hydrocephalus, spina bifida, hermaphroditism, digital aplasia of both hands and feet, defective blood clotting, back problems, convulsions, as well as with other neurological disturbances. Despite the seriousness of manganese deficiency, it is most surprising to find that there are still no official recommendations for this important trace mineral. Particularly when taking into account the most serious, and irreversible, manifestations of foetal manganese deficiencies found in animal studies, the general lack of concern for a possible human manganese deficiency during the gestational period is difficult to comprehend. After all, even though human foetuses are slightly higher up in the phyletic tree than animal foetuses, that can not make them utterly invulnerable to gestational manganese deficiencies. Already studies on humans have shown that mothers with infants with congenital malformations have far lower hair manganese concentration than controls, indicating that maternal manganese deficiency can be a cause of malformed human offspring (70). Furthermore, gestational manganese deficiency can also lead to the development of other disorders, such as changes in the inner ear function, ataxia, diabetes etc. As mentioned before, contrary to current belief, nutritional manganese deficiency in humans can easily arise due to its poor absorption rate, combined with modem food production, which strips manganese from the foodstuffs from the soil to the table. As mentioned previously, manganese absorption is also greatly hindered by the presence of other trace minerals, particularly iron, as these two metals compete for the same binding sites, manganese having far inferior affinity to the carrier protein than iron. This observation is particularly noteworthy, as during pregnancy most women are routinely prescribed iron supplementation, which further reduces the body manganese status. For the reasons above, one could suggest that gestational manganese deficiency could really be more a norm than a rarity, particularly as animal studies have shown that the stress of the female manganese stores are the greatest during the gestational period (72). Even though manganese has been known for a long time to be officially an essential trace element, it is still greatly underrated. One of the reasons may be the assumption that, as the trace mineral is fairly widely distributed in most foodstuffs, manganese deficiencies will not arise, therefore there is nothing whatsoever to worry about. Unfortunately this assumption is not correct. Even if dietary manganese deficiency was not detrimental to healthy non-pregnant adults, an adequate amount of this trace mineral would be absolutely vital during gestation, for normal foetal growth and development. This being the case, all would-be mothers should be informed about the importance of adequate dietary manganese before, and during pregnancy. The medical profession is already stressing the importance of folic acid in the prevention of spina bifida. Similar action should be taken with manganese. In order to assess body manganese status, blood tests are unfortunately misleading, as normal human blood shows widely varying concentrations of the trace element, with higher concentrations in the red cells than in the serum (2,82-86). However, hair mineral analysis, when using correct measures and sample preparations, is an extremely valuable diagnostic tool for obtaining body manganese status (70,87-89). Hair mineral analysis is also an outstanding way of finding out whether the would-be mother may also be suffering from heavy metal contamination, such as lead and/or cadmium, both known to lead to low birth-weight infants (89-90). Low birth-weight in turn has been associated, in later years, with a great variety of both neurological and physical defects (89-96). If hair mineral analysis records low manganese status, manganese supplementation should be prescribed. Fortunately manganese is well tolerated, due to its highly efficient excretory mechanism, its absorption not increasing above that which the body needs. However, it should be noted, that most trace metals exert an inhibitory effect on the absorption of others. Therefore, it would be prudent to prescribe a balanced vitamin/mineral combination, which includes sufficient manganese, in order to avoid creating deficiencies in others. Particularly, an adequate dietary zinc status is known to be absolutely vital both for reproduction and for healthy foetal development (90,96). In conclusion, manganese, with other trace elements and vitamins, is absolutely essential in the development of a healthy baby. Therefore, all would-be mothers must be made immediately aware of this most important fact, as now they have been made aware of the importance of folic acid in the prevention of spina bifida. As seen from the above, lack of other nutritional substances, such as manganese, also leads to a variety of foetal malformations. The sooner this point is put forward the better, as the latest U.K. statistics reveal that, out of every 100 live births, six babies are now born either with 'minor' or 1major' physical malformations. Furthermore, one in four babies are now born with some degree of learning disability and/or mental deficiency (97). These statistics are absolutely appalling! After all, our children are our future, so we must to try our utmost to secure our future. As things are, because of our present ignorance of the basic reproductive biochemistry, we seem to be re-populating our world with the physically sick and the mentally infirm. We must take heed, before it is too late!
This study was supported by a grant from Foresight, The Association for the Promotion of Preconceptual Care. A special recognition is given to Mrs Belinda Barnes, who has fought tirelessly to draw attention to dangers of manganese deficiency on reproduction and health. This article was accepted for publication in the Journal of Orthomolecular Medicine, Volume II, Number 3, September, 1996. (16 Florence Avenue, Toronto, Canada M2N 1E9)
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