Manganese is a chemical element with the element symbol Mn. It is the 12th most abundant element in the Earth’s crust at about 0.1% – hydrosphere (surface and subsurface water) and lithosphere (Earth’s crust including the outer part of the outer mantle) included – and the third most abundant transition metal after iron and titanium. Of the possible oxidation states Mn-3 to Mn+7, Mn2+, Mn4+ and Mn7+ are the most significant. In biological systems, Mn2+ (manganese II) is the predominant form along with Mn3+. Manganese is a constituent of > 100 minerals including sulfides, oxides, carbonates, silicates, phosphates, and borates. Manganese II salts, with the exception of manganese phosphate and manganese carbonate, are usually readily soluble in water, whereas manganese compounds in higher oxidation states are usually sparingly soluble. In the human organism, manganese plays the role of a specific integral component of certain enzymes, such as the antioxidant superoxide dismutase (MnSOD, conversion of superoxide anions formed endogenously during cellular respiration to hydrogen peroxide, which is reduced to water by other enzymes and thus detoxified) and arginase (degradation of the amino acid arginine to ornithine and urea), which is integrated in the urea cycle (conversion of nitrogen (N)-containing degradation products, especially ammonium (NH4+) to urea, which is excreted via the kidneys → detoxification of ammonia (NH3)), play an essential role. In addition, manganese – either by conformational change of the protein or by binding to the substrate – is an activator or cofactor, respectively, of numerous enzymes, such as glycosyltransferase in the synthesis of glycosaminoglycans (linear built from repeating disaccharide units, acidic polysaccharides) and proteoglycans (strongly glycosylated glycoproteins consisting of a protein and one or more covalently bound glycosaminoglycans), respectively, is an important component of the extracellular matrix (extracellular matrix, intercellular substance, ECM, ECM; tissue lying between cells – in the intercellular space), such as cartilage and bone. The binding of manganese (Mn2+ to Mn7+) to its ligands occurs preferentially via oxygen (element symbol: O). Manganese is a trace element that is essential (necessary for life) on the one hand and has a high toxicity (toxicity) on the other, with divalent manganese (Mn2+) being more toxic than trivalent (Mn3+). Accordingly, care should be taken to ingest manganese in adequate amounts but not in excessive doses. Manganese is present in all plant and animal tissues due to its ubiquitous occurrence (Latin ubique: “distributed everywhere”), with the reproductive organs of plants being the richest in manganese. While high amounts of manganese are sometimes found in foods of plant origin, such as whole grains, rice, legumes (pulses), nuts, green leafy vegetables, fruits, and tea leaves, the manganese content in foods of animal origin, such as meat, fish, and milk, and in highly purified starch and sugar products is usually very low.
Absorption
Orally supplied manganese enters the small intestine for absorption. To date, there is little knowledge about the mechanism. Some authors have demonstrated that manganese shares the same absorption pathway with the trace element iron. Accordingly, manganese in the form of Mn2+ is absorbed into the enterocytes (cells of the small intestinal epithelium) predominantly in the duodenum (duodenum) and jejunum (jejunum) with the help of the divalent metal transporter-1 (DMT-1), which transports divalent transition metals together with protons (H+). This process is energy-dependent and occurs according to saturation kinetics. According to Tallkvist et al (2000), manganese (Mn2+) – analogous to iron (Fe2+) – enters the bloodstream through the basolateral membrane (facing away from the intestine) of enterocytes by means of the transport protein ferroportin-1. Whether a passive absorption mechanism is available for manganese in addition to active absorption requires further investigation. The absorption rate of manganese from food under physiological conditions is between 3-8%. It may be higher in infants and young children, in poor manganese supply status or low manganese intake. When the supply of manganese exceeds the requirement, its bioavailability decreases. The level of manganese absorption is influenced by numerous dietary components:
- Calcium – according to several studies, calcium supplementation at 500 mg/day results in decreased bioavailability of manganese, with calcium phosphate and carbonate having the greatest effect and calcium from milk having the least effect; some other studies showed only minimal effects of calcium supplementation on manganese metabolism
- Magnesium – with magnesium supplementation of about 200 mg/day, manganese absorption is decreased
- Phosphate – dietary phosphates, such as from cured meats, processed cheese, and soft drinks, impair intestinal (affecting the gut) absorption of manganese
- Phytic acid, oxalic acid, tannins – phytates from cereals, legumes, etc., oxalates, for example, from cabbage vegetables, spinach and sweet potatoes, and tannins from tea reduce the bioavailability of manganese
- Iron – mutual inhibition of absorption → iron and manganese compete for the same absorption and transport mechanisms, for example, DMT-1.
- Manganese absorption from a meal decreases as dietary iron content increases because DMT-1 expression is downregulated in enterocytes (cells of the small intestinal epithelium)
- According to Davis and Greger (1992), iron supplementation-60 mg/day for 4 months-is associated with decreased serum manganese levels and reduced manganese-dependent superoxide dismutase (MnSOD) activity in leukocytes (white blood cells), indicating a decreased manganese status
- Individual iron supply is a major factor influencing manganese bioavailability. If iron deficiency is present, manganese absorption may be increased 2-3-fold due to increased expression of DMT-1 in enterocytes. “Full iron stores” – measurable by serum ferritin (iron storage protein) levels – on the other hand, are associated with a decrease in intestinal manganese uptake – due to downregulation (downregulation) of cellular DMT-1 synthesis. In light of the fact that higher iron stores are generally detectable in men compared to women, men generally reabsorb less manganese than women.
- Cobalt – Cobalt and manganese interfere with each other’s intestinal absorption because both transition metals use the DMT-1
In addition, excessive intake of dietary fiber, of the trace elements cadmium and copper, of refined carbohydrates such as industrial sugar and white flour products, as well as increased alcohol consumption, also leads to decreased manganese absorption. Similarly, the use of certain medications, such as magnesium-containing antacids (neutralizing stomach acid), laxatives (laxatives), and antibiotics, is associated with impaired intestinal manganese absorption once they are taken together with Mn-containing foods or supplements. In contrast to the factors listed above, milk increases the bioavailability of manganese.
Transport and distribution in the body
Absorbed manganese is transported in free form or bound to alpha-2-macroglobulins (proteins of the blood plasma) via the portal vein to the liver. There, the majority of manganese enters the enterohepatic circulation (liver–gut circulation), which involves delivery from the liver with bile to the intestine, reintestinal absorption, and portal transport to the liver. A small fraction of manganese is released from the liver into the bloodstream and, after a valence change from Mn2+ to Mn3+, which occurs by oxidation by coeruloplasmin (alpha-2 globulin of blood plasma), is bound to transferrin (beta globulin, which is primarily responsible for iron transport) or a specific transport protein, such as beta-1 globulin, to be taken up by extrahepatic (outside the liver) tissues. Since manganese competes with iron for the same transport proteins, the binding of manganese to transferrin is increased in iron deficiency, whereas it is decreased in iron excess. High levels of iron in the body can ultimately lead to reduced manganese concentrations in tissues and thus to reduced activity of manganese-dependent enzymes. Manganese is also transported in blood plasma as a component of erythrocytes (red blood cells) – bound to porphyrin (organic chemical dye consisting of four pyrrole rings). The manganese content of the human body is about 10-40 mg.The mean tissue concentration of manganese varies between 0.17-0.28 mg/kg body weight and is significantly lower than that of iron and zinc. Approximately 25% of total body manganese is found in bone, primarily in bone marrow. High concentrations of manganese can also be detected in the liver, kidney, pancreas (pancreas), pituitary gland (pituitary gland), and intestinal epithelium (intestinal mucosa). Manganese is also found in hair, muscle, mammary gland, and sweat. In children and young animals, manganese is preferentially concentrated in specific brain regions. Intracellularly (within the cells), manganese is mainly localized in the mitochondria (“energy power plants” of the cells), where the trace element acts as an integral component or activator of certain enzyme systems, such as pyruvate carboxylase (gluconeogenesis (new formation of glucose from organic non-carbohydrate precursors, such as pyruvate)) and prolidase (provision of the amino acid proline for the synthesis of collagen (the most important structural protein of the extracellular matrix, such as cartilage, bones, tendons, skin and vessels)). Furthermore, a manganese pool is available in the lysosomes (cell organelles that store enzymes for the degradation of endogenous (cellular) and exogenous (non-cellular) materials – bacterial, viral, etc.) and in the nucleus, among others. Specific storage proteins, such as ferritin for iron, are not known for manganese. Thus, unlike iron and copper, the trace element is not stored in the liver at high intakes, but accumulates (accumulates) in certain tissues, such as the brain. For this reason, manganese has a toxic (poisonous) effect in high doses. Manganese intoxications due to excessive dietary intake have not been observed. In the case of intake of drinking and mineral water with a high manganese content (maximum permissible manganese concentration in drinking water: 0.05 mg/l), long-term intake of manganese supplements, and occupational chronic exposure – inhalation of Mn-containing dusts or vapors (> 1 mg/m3 air) in manganese mines, manganese mills, metal smelters, metal industry factories, and Mn-processing plants – can, however, result in intoxication with the trace element, especially in children because of the preferential accumulation of manganese in the brain [5, 6, 7, 14, 21, 25, 29, 30, 34, 37, 41, 45, 47]. Manganese from drinking water and supplements is more available than from food, resulting in higher accumulation of the trace element in the body, primarily in the brain. Manganese particles inhaled via the respiratory tract, unlike intestinally absorbed manganese, are transported directly to the brain without first being metabolized (metabolized) in the liver. High concentrations of Mn3+ lead to oxidative conversion of the neurotransmitter dopamine to a trihydroxy compound that damages dopamine-synthesizing neurons in the central nervous system (CNS). The symptoms of manganese intoxication thus result from a dopamine deficiency and affect the CNS in particular. In addition, damage to the liver, pancreas and lungs – cough, bronchitis (inflammation of the bronchi) and pneumonia (inflammation of the lungs) due to inhaled manganese particles – can also occur. Mild manganese intoxication results in nonspecific symptoms, such as profuse sweating, fatigue, and dizziness. At higher levels of manganese, central nervous symptoms are prominent, beginning with apathy (listlessness), asthenia (weakness), anorexia (loss of appetite), insomnia (sleep disturbances), and myalgia (muscle pain) and progressing to sensory disturbances, reflex abnormalities, muscle cramps, and gait unsteadiness with latero-, pro-, and retropulsion (tendency to fall to the side, forward, backward). In the late stages, symptoms similar to Parkinson’s disease (neurological disorder characterized by a deficiency of dopamine), such as rigor (muscle rigidity), tremor (muscle tremor), postural instability (postural instability), bradykinesia (slowed movements) to akinesia (lack of movement), and/or mental disorders such as irritability, aggressiveness, depression, disorientation, memory loss, and hallucinations – “manganic madness.” These symptoms partially respond to therapy with L-dopa (L-3,4-dihydroxyphenylalanine for endogenous dopamine synthesis).In addition to individuals who have inhaled manganese particles or consumed Mn-rich drinking and mineral water or supplements containing Mn over many years due to their occupation, there is also an increased risk of manganese intoxication in the following groups of individuals or diseases:
- Individuals, especially neonates, infants, and young children, on total parenteral nutrition (TPE, form of artificial feeding that bypasses the gastrointestinal tract) – excessive manganese concentration in the infusion solution and/or contamination of the nutrient solution with manganese can cause intoxication; infants on Mn-containing TPE are exposed to manganese concentrations approximately 100 times higher than breastfed infants
- Chronic liver disease – impaired formation of bile in the liver and reduced delivery to the intestine leads to decreased manganese excretion in the stool resulting in increased serum manganese concentrations
- Neonates – preferential concentration of manganese in the brain, partly due to increased expression of transferrin receptors in developing neurons and partly due to limited elimination of manganese with feces (stool) as a result of not yet fully matured liver function to produce bile
- Children – in contrast to adults, infants and children have higher intestinal manganese absorption and lower biliary (affecting the bile) manganese excretion (manganese excretion)
- Elderly (> 50 years) – are more likely to have liver disease associated with decreased manganese excretion and increased serum manganese concentrations compared with young adults
- Iron deficiency – manganese absorption is increased because of increased incorporation of DMT-1 into the brush border membrane of enterocytes (cells of the small intestinal epithelium).
Because of the high risk of intoxication, a specific UL (English : Tolerable Upper Intake Level – maximum amount of a micronutrient that does not cause any side effects in almost all individuals of any age when taken daily) for manganese. According to the FNB (Food and Nutrition Board, Institute of Medicine), the UL for children 1-3, 4-8, and 9-13 years of age is 2 mg, 3 mg, and 6 mg/day, respectively; for adolescents (14-18 years), 9 mg/day; and for adults (≥ 19 years), 11 mg/day. For infants (0-12 months), no UL for manganese has yet been established. Here, manganese intake should be exclusively through breast milk or breast milk substitutes and foods. Because the elderly (>50 years of age) are more susceptible to manganese intoxication than young adults due to, among other things, a higher incidence of liver disease, the UK National Expert Group has set an Acceptable Total Manganese Intake (safe maximum level of manganese that will not cause adverse effects with daily, lifetime intake from all sources) of 8.7 mg/day for this age group.
Excretion
Excretion of manganese is largely via the bile with the feces (stool) (99%) and only slightly via the kidney with the urine (<0.1%). Manganese excretion in humans is biphasic with half-lives of 13-34 days. Manganese homeostasis is regulated primarily by adjusting endogenous (endogenous) excretion, rather than intestinal absorption. The liver is of crucial importance in this process, releasing manganese into the intestine with the bile in variable amounts, depending on the state of supply. In manganese excess, excretion exceeds intestinal reabsorption, whereas in deficiency, more manganese is reabsorbed in the intestine than excreted via the feces. In neonates, this homeostatic regulation is not yet fully developed. In contrast to manganese reabsorption, manganese excretion remains unaffected by the endogenous supply status of other chemically similar trace elements, as shown by studies with radiolabeled manganese.
