Manganese is an essential metal necessary for the development, growth, and normal functioning of our bodies. However, when in excess, this metal has many negative effects. It can cause manganism, a serious condition similar to Parkinson’s disease. Furthermore, it is much easier to overload with this metal, than to be manganese deficient. Read on to find out more about manganese, including 11 benefits, 22 negatives, recommended levels, food and contamination sources, associated genes, and ways to combat manganese toxicity.

Contents

Introduction

Manganese (Mn) is essential to all forms of life [R].

It is required for the normal development, growth, and function of our bodies [R, R].

Mn is the 12th most abundant element in the earth’s crust [R, R]. We readily ingest it through food and water.

Mn serves as a an essential part (cofactor) for multiple important enzymes (such as glutamine synthetase, mitochondrial superoxide dismutase, arginase, serine/threonine protein phosphatase I, and pyruvate decarboxylase) [R, R].

These play a role in:

  • Energy (ATP) production (in mitochondria) [R].
  • Fat, protein and sugar metabolism [R, R].
  • Brain development and brain function [R].
  • Bone and connective tissue production [R, R].
  • Immune response [R].
  • Sex hormone production and reproduction [R, R].
  • Digestion [R].
  • Antioxidant defense [R].

Mn is a required part of a healthy diet. However, exposure to excess levels causes toxicity [R].

That is why it is necessary to keep Mn levels in balance.

However, this may not always be easy to accomplish. In fact, Mn levels that may be toxic to some biological processes are beneficial for other processes. And these are further influenced by age and disease state [R].

Manganese Benefits

1) Manganese Protects Against Oxidative Stress

Mn protects against oxidative stress and cell damage, as a part of important antioxidant enzymes [R].

A Mn-containing enzyme, Mn superoxide dismutase (MnSOD), is the principal antioxidant enzyme. It neutralizes the toxic effects of reactive oxygen species (ROS) in mitochondria [R, R].

MnSOD protect cells from various cancer-causing agents, such as toxic chemicals and radioactive materials, oxidative stress and inflammation [R].

Mn deficiency reduces MnSOD activity, which leads to cell damage and dysfunction [R].

Another important enzyme that contains Mn is catalase. This is an essential enzyme that converts hydrogen peroxide into oxygen and water, thereby reducing oxidative stress [R].

A study conducted with 47 young women showed that oxidative stress was lower in women taking Mn supplements [R].

2) Manganese is Important for Brain Function

Several enzymes with important roles in the brain, function only in the presence of Mn [R].

Girls that had higher prenatal exposure to Mn performed better in cognitive function tests (study in 1,265 children) [R].

Low concentrations of Mn are associated with lower IQ scores in children (404 subjects) [R].

However, early-life high Mn exposure can adversely affect children’s behavior (1,265 children) [R], showing again that balanced Mn levels are important.

Mn-deficient diet produces seizures in rats. This additionally shows that Mn is important for normal nerve/brain function [R].

3) Manganese is Important for the Bones

Mn is a component of various enzymes involved in cartilage and bone production [R].

This metal plays an essential role in incorporating calcium into the growing bones [R].

Mn deficiency, although rare, can cause developmental defects including malformation of bones [R].

Mn supplementation effectively reduces the loss of bone mass in female rat models of postmenopausal osteoporosis [R].

4) Manganese May be Beneficial Against Diabetes and Metabolic Syndrome

Studies have reported that diabetic patients had lower levels of Mn in the blood and lymphocytes (white blood cells) [R].

Similarly, patients with hardening of the arteries (atherosclerosis) had lower Mn in the heart and blood vessels[R].

A study conducted with 550 Chinese adults showed that those with higher Mn had a significantly lower risk of metabolic syndrome [R].

In another Chinese population (2111 adults), men with a higher Mn intake were less obese and had lower triglycerides. However, Mn was also associated with low HDL-cholesterol in both men and women [R].

In rats, dietary Mn deficiency can impair insulin production [R].

Similarly, maternal Mn restriction increases the susceptibility of animal offspring to high-fat-diet-induced obesity, high cholesterol and inflammation [R].

On the other hand, Mn supplementation improves glucose tolerance and insulin production in mice on a high-fat diet [R].

Finally, Mn supplementation can also increase adiponectin in diabetic rats [R]. Adiponectin has many beneficial effects and reduces the susceptibility to metabolic syndrome and diabetes.

5) Manganese is Important for Fertility

Mn is important for sperm motility [R].

Mn deficiency can reduce fertility [R].

Defective ovulation and testicular degeneration have been observed in Mn deficient animals [R].

6) Manganese May Help Fight Depression

Depressed patients (with recurrent depressive disorder) had low levels of the MnSOD, a Mn-dependent enzyme (236 subjects) [R].

Low levels of Mn may contribute to the development of depression [R].

Japanese women with higher Mn intake had a lower prevalence of depressive symptoms during pregnancy (1745 pregnant women) [R].

7) Manganese May Protect from Epilepsy

Patients with epilepsy have low blood Mn [R].

In rats, long-term dietary Mn deficiency causes seizures [R].

Some studies suggest that the presence of neurological symptoms in epileptics may correlate with low brain Mn [R].

8) Manganese May Protect from Autism

A U.S. study found that children with autism had marginally lower levels of tooth Mn (representing postnatal exposure) [R].

Autism is associated with an increase of glutamate in the brain [R]. Glutamine synthetase, an enzyme that converts glutamate into glutamine, contains Mn [R]. Therefore, Mn deficiency may result in higher glutamate brain content.

Further, mitochondrial dysfunction is a key feature of autism. MnSOD (Mn superoxide dismutase) protects mitochondria from oxidative damage and dysfunction [R].

Finally, people with autism have low Lactobacillus bacteria levels. These bacteria are depend on Mn for antioxidant protection. Lactobacillus probiotics can treat anxiety, which is a feature of autism [R].

9) Manganese May Protect from Alzheimer’s

A meta-analysis (17 studies, 2090 subjects) showed that patients with Alzheimer’s had significantly reduced blood Mn levels. Therefore Mn deficiency may be a risk factor for Alzheimer’s, but causal proof is still missing [R].

Mitochondrial dysfunction is a key feature of Alzheimer’s [R].

An increase of glutamate in the brain is also associated with Alzheimer’s disease [R].

Both of these can be associated with Mn deficiency [R].

10) Manganese is Good for the Skin

Administration of a Mn peptide complex improved the appearance of several signs of skin photodamage, such as hyperpigmentation, in 15 female subjects [R].

11) Manganese May Help with Premenstrual Syndrome (PMS)

Patients with PMS have lower blood Mn levels (46 PMS subjects, 50 controls) [R].

In a small-scale study, lower dietary Mn increased mood and pain symptoms during PMS (10 women) [R].

However, a larger study found no relationship between Mn and PMS (1,057 PMS cases, 1,968 as controls)[R].

12) Manganese May Protect Against Cancer

Mn is an essential component of Mn superoxide dismutase (MnSOD), an enzyme associated with cancer prevention [R, R, R].

The level of MnSOD was reduced prior to the formation of cancer in mice [R].

This enzyme may help fight many types of cancer, but not all of them.

Many human cancers have low levels of MnSOD. However, some cancers actually have high levels of this enzyme [R].

A meta-analysis (11 studies, 1302 subjects) indicates that patients with breast cancer have lower Mn levels [R].

Manganese Deficiency

Mn deficiency is extremely rare, as sufficient amounts of Mn are obtained from most diets [R, R].

In fact, this condition is so rare that there are only a few vaguely described cases in the medical literature [R, R].

Most of what we know about Mn deficiency is derived from animal studies.

Mn deficiency causes:

  • Bone deformities [R].
  • Feebleness [R].
  • Increased susceptibility to seizures [R, R, R].
  • Birth defects [R].
  • Defective insulin production [R].
  • Diminished reproduction [R].
  • Lower IQ [R].
  • Skin lesions [R].

In rats, long-term dietary Mn deficiency results in decreased bone calcium [R] and seizures [R].

Similarly, in humans, low blood Mn has been found in patients with osteoporosis and epilepsy [R].

Furthermore, mothers with low maternal blood Mn levels have infants with lower mental and psychomotor development scores (2011–2012 NHANES study) [R].

Manganese The Bad

It is much easier to have excess Mn than to be Mn deficient.

Excessive exposure to Mn has many negative effects, especially on the brain, fertility, and development [R].

1) Excess Manganese Increases Oxidative Stress

Mn, when in balance, helps our bodies fight oxidative stress. But too much Mn actually makes it worse.

Mn, when in excess, accumulates in mitochondria and increases the production of reactive oxygen species (ROS) [R, R].

Furthermore, Mn depletes glutathione (GSH) levels. This was shown in both in rats and primates [R, R]. Glutathione is an important antioxidant.

2) Excess Manganese Increases Inflammation

Mn in excess increases the release of several inflammatory molecules, including TNF-α, IL-6,  IL-1β, prostaglandins, and nitric oxide. These can cause brain inflammation and neuron loss [R, R].

In addition, Mn can activate the nuclear factor NF-κB, a master controller of inflammation [R].

In animal studies, Mn-containing compounds increase lung inflammation and cause lung damage [R].

3) Too Much Manganese Lowers IQ in Children

Mn in excess can cause neuro-developmental problems in children [R].

Twelve studies observed an association between elevated early-life Mn exposure and lower IQ [R].

Children who ingested high Mn in the drinking water for three years or more, performed more poorly in school (measured by mastery of language, mathematics, and overall grade average) [R].

In 362 Canadian children aged 6–13 years, higher Mn ingestion in water was significantly associated with lower IQ scores [R].

Similarly, studies among school children in Bangladesh suggest that increased levels of Mn in the drinking water are associated with lower achievement scores in mathematics (201 subjects) [R].

Young school-age children in Mexico exposed to airborne Mn performed worse on intellectual function tests (172 subjects) [R].

Finally, in Brazil,  elevated Mn (measured in hair) was associated with poorer cognitive performance (83 subjects) [R].

It is important to note that both high and low Mn are associated with lower IQ scores [R], therefore Mn levels should be kept in balance.

Two studies found an inverted U-shaped association between blood Mn measured at delivery or at 12 months of age and mental development scores at ages 6 to 12 months. These findings confirm the potential of Mn to act both as an essential element and a toxic metal [R].

4) Manganese Can Contribute to Anxiety

Patients suffering from generalized anxiety have elevated Mn levels (101 subjects)[R].

Mn administration can lead to anxiety-like or compulsive-like behaviors  [R].

15 studies describe adverse mood effects after overexposure to Mn [R].

Older men with higher Mn levels show increased anxiety, nervousness, irritability, and aggression [R].

5) Manganese May Contribute to ADHD

Studies in children and adolescents show that higher exposure to Mn is associated with inattention and hyperactive behavior [R, R].

A study in the United Arab Emirates reports increased odds of ADHD with increased blood Mn levels (92 subjects) [R].

In South Korean children, blood Mn levels were associated with poorer scores on one of the ADHD tests (1089 children) [R].

Similarly, a study of 7- to 12-year olds in Brazil, found that children with higher Mn had impaired attention (70 children) [R].

Air Mn concentration was a risk factor for impaired attention in people living in a mining district in Mexico (288 adults) [R].

Finally, developmental Mn exposure caused lasting impairments in attention and arousal of rats [R].

6) Too Much Manganese Causes Brain Damage

Mn in excess can be toxic to the brain.

Its toxicity has been predominantly observed in occupational settings, following the accidental ingestion of large quantities of this metal, or more often after inhalation of high levels, where this metal can enter the brain directly through the olfactory pathways (the nose) [R, R].

Long-term exposure to high levels of air-Mn can cause mild deficits of cognitive function in adult populations [R].

Welders chronically exposed to Mn had measurable brain volume reductions (globus pallidus, cerebellum). These volume reductions correlated with cognitive and motor deficits (66 subjects) [R].

In 95 workers, exposure to Mn-containing welding fume was associated with poorer working memory [R].

Also, in workers exposed to high Mn, blood BDNF levels decreased significantly (112 subjects) [R]. BDNF is important for brain function.

In Italy, school-age children living near a ferroalloy plant had impaired motor coordination, hand dexterity, and odor identification after exposure to excess levels of Mn in soils (311 subjects) [R].

Mn exposure was associated with an impaired motor function in 195 children living near a Mn plant in Mexico [R].

Chronic exposure to Mn impaired memory in monkeys [R] and rats [R].

Mn also depletes dopamine (striatum), thereby resulting in motor deficits in primates and rats [R].

7) Excess Manganese Causes Manganism (Manganese Toxicity)

Overexposure to Mn causes manganism, a motor syndrome similar to Parkinson’s disease [R].

Occupational exposure of 6 months to 2 years can lead to manganism. The motor and neuropsychiatric symptoms may remain even 14 years after the end of exposure [R].

The early phase of Mn intoxication involves a psychiatric component, characterized by irritability, apathy, aggressiveness, hallucinations and psychosis, It is sometimes called Mn mania [R, R].

Deficits in short-term memory and computational ability are also characteristic [R].

In the early stages of Mn intoxication, the symptoms may be reversible [R].

The symptoms progress to postural instability, uncontrollable tremors (dystonia), slow and clumsy movements (bradykinesia), face muscle spasms, speech disturbance, rigidity, and gait abnormalities [R, R, R].

Mn brain damage, once the signs and symptoms appear, is usually irreversible. It actually continues to progress, despite the removal from the exposure scene [R].

Many symptoms of manganism resemble those found in Parkinson’s disease. However, manganism targets different brain regions (globus pallidus and striatum as opposed to substantia nigra) [R].

A distinguishing feature of manganism is the lack of efficacy that levodopa has in treating patients with Parkinson’s [R].

Manganism ranks among the 10 leading occupational disorders in China, affecting 0.5%–2% in silico- and ferroMn production plant workers [R].

8) Manganese Contributes to Parkinson’s

Several brain regions (globus pallidus, substantia nigra, striatum) are involved in both Mn brain toxicity and Parkinson’s. Thus, it is possible that the elderly may have a propensity for Parkinson’s, that could be “pushed over the edge” by increased doses of Mn [R].

Also, chronic exposure to a high content of Mn may accelerate Parkinson’s disease progression by decreasing dopamine (striatum) and promoting alpha-synuclein protein misfolding and aggregation (a feature of Parkinson’s) [R].

According to several studies, prolonged and chronic occupational exposure to Mn is a risk factor Parkinson’s disease [R], although other studies disagree [R].

Brain Mn accumulation is associated with damage to dopamine systems. Mn injection depletes dopamine levels in rat blood and brain, and in the brain (globus pallidus, putamen) of monkeys [R, R].

9) Manganese May Contribute to Alzheimer’s

A link between advanced–stage manganism and dementia is occasionally reported [R, R].

Mn overload may play a role in Alzheimer’s disease. A patient with elevated Mn levels showed dementia and typical features of Alzheimer’s such as brain plaques and neurofibrillary tangles [R].

High Mn may be involved in the progress of Alzheimer’s, by increasing blood amyloid-beta levels in humans [R].

Chronic Mn treatment in monkeys increased amyloid-like protein 1, a marker of Alzheimer’s disease in the brain (frontal cortex)[R].

Both high and low Mn seem to contribute to Alzheimer’s.

10) Manganese May Contribute to ASL

Mn smelters and miners have a propensity to develop both manganism and amyotrophic laterals sclerosis (ALS) [R, R].

ASL patients have a high content of Mn in the spinal cord (7 subjects) [R].

In addition, ALS is common in patients with liver cirrhosis, a condition with Mn overload due to impaired bile excretion of Mn [R].

11) Manganese in Excess Can Reduce Fertility

An observational study showed that Mn-exposed male workers had significantly fewer children than workers not exposed to Mn, suggesting that this metal may decrease fertility [R].

In rats, Mn delayed male reproductive development, measured by reduced testes weight, sperm count, and blood testosterone and follicle-stimulating hormone concentrations [R].

12) Manganese Can Disturb Sleep

Chronic Mn intoxication decreases REM sleep in humans (15 subjects) and animals. This is similar to the sleep disturbances observed in Parkinson’s disease [R, R].

In rats, chronic Mn intoxication also leads impaired rest-activity rhythms [R] and disturbs the circadian rhythm [R].

13) Too Much Manganese is Toxic to Mitochondria

In the cell, Mn preferentially accumulates in the mitochondria [R].

Elevated Mn interferes with mitochondrial function, leading to excessive production of radical oxygen species (ROS) [R].

14) Microbes Use Manganese for Infection

Invading microbes can use Mn to resist the effects of host-induced defenses (oxidative stress) [R].

Mn uptake is essential for the virulence of many bacteria [R].

15) Manganese May Exacerbate Prion Disease

Mn overload may trigger misfolding and aggregation of prion proteins [R, R].

Animals and humans with prion disease show increased Mn levels in blood, brain, and liver [R].

To date, there is no definitive proof that Mn overload can trigger prion disease. The observed high Mn levels in affected subjects could simply be a result of prion disease. Nonetheless, a causal relationship can not be excluded at this point [R].

16) Manganese May Impair Heart and Blood Vessel Function

Excess Mn inhibits heart muscle contraction, expands blood vessels, and induces hypotension (low blood pressure) [R].

Mn can affect heart function by blocking calcium channels. However, this happens only at very high concentrations of Mn [R].

Smelters had significantly faster heart rates than control subjects [R].

Workers with the highest level of exposure to Mn exhibited the lowest systolic blood pressure [R].

Overexposure to the contrasting compound used in MRI, Mn-DPDP, causes flushed face and the head and ears feeling hot. Postural hypotension (a decrease in blood pressure upon standing) has also been observed [R].

17) Manganese Can Blunt the Sense of Smell

People exposed to airborne Mn can end up with decreased olfactory function (impaired sense of smell)(30 subjects) [R].

18) Manganese Can Cause Asthma

Mn belongs to a group of agents called “transitional metals” that are known to induce occupational asthma [R].

Nevertheless, so far there is only a single well-documented case of Mn-induced asthma [R].

19) Excess Manganese Increases Infant Mortality

Environmental exposure to Mn may increase the risk of preeclampsia (a disorder in pregnancy) [R].

Increased Mn levels in water have been linked to increased infant mortality [R].

Across North Carolina counties, the increase in groundwater Mn was associated with the increase in county-level infant deaths [R].

In Bangladesh, infants exposed to higher water Mn had an elevated mortality risk during the first year of life (26,002 births) [R].

20) Excess Manganese Increases Cancer and Liver Disease Mortality

In a Chinese population (14 towns and 28 villages), the concentration of Mn in drinking water correlated with cancer incidence and mortality [R].

Airborne concentrations of on-road Mn were positively correlated with North Carolina county-level chronic liver disease mortality [R].

21) Manganese Increases Prolactin

Mn-exposed welders have increased prolactin levels (251 and 179 welders) [R, R].

Children living in the proximity of a Mn-rich zone in Mexico also had increased prolactin (77 children) [R].

Mn increases blood prolactin levels in rats [R].

Mn suppresses dopamine, and dopamine suppression, in turn, increases prolactin [R].

High prolactin levels can cause reproductive problems in both men and women.

22) Manganese May Accelerate Female Puberty

Mn is capable of stimulating the hypothalamic-pituitary axis and advancing female puberty [R].

Prepubertal exposure to Mn induces precocious puberty in rats, associated with early elevations in puberty-related hormones, including estradiol [R, R].

Exposure to a supplemental dose of Mn causes accelerated pubertal breast gland growth in rats [R].

Who’s at Risk for Elevated Manganese?

1) Infants and Children

Younger children have increased gut Mn absorption [R].

Newborns in particular exhibit high Mn absorption rates, up to 40% of ingested Mn by some estimates, compared to roughly 3% absorption in adults [R].

Children also have increased accumulation of Mn in the brain, due to the increased permeability of neuronal barriers to Mn [R].

In addition, children have reduced bile excretion capacity [R].

Therefore, children may easily exceed the recommended dietary intake of Mn through a combination of airborne and dietary sources [R].

The 2011–2012 National Health and Nutrition Examination Survey (NHANES), found higher Mn levels in the younger population, with the highest levels in 1-year-old infants [R].

2) Formula-Fed Infants

Cow milk–based and soy-based infant formulas have higher Mn concentration than human milk.

That is why formula-fed infants have higher Mn levels than in their breast milk-fed counterparts [R].

However, the body usually adapts by reducing gut absorption and increasing bile excretion. These mechanisms are effective, even in preterm infants [R].

3) Patients On Parenteral Nutrition

Parenteral nutrition solutions (IV solutions) are routinely used in critically ill infants and preterm infants who cannot tolerate sufficient gut nutrition. These solutions can contribute to excessive Mn exposure because intravenous administration circumvents normal gut control mechanisms [R].

In newborns on total parenteral nutrition, Mn burden can be increased by 100-fold, compared to infants receiving human milk [R].

Furthermore, liver dysfunction and cholestasis, common complications of prolonged parenteral nutrition in infants, may further magnify the risks of excessive Mn exposure [R].

Mn toxicity has also been reported in adult patients receiving long-term parenteral nutrition [R].

Mn accumulates in the brain of patients on parenteral nutrition, and this can be detected before clinical symptoms are present. If parenteral nutrition is removed, Mn decreases and gets cleared from the brain [R].

4) Patients with Liver Disease

Another population at risk includes patients suffering from liver failure. This is because Mn is excreted from the body predominantly through the bile, and bile production is impaired in liver diseases [R].

Any existing liver damage may delay or decrease Mn elimination and increase the mount of this metal in the blood [R].

Patients with cirrhosis have increased blood and brain manganese. Further, increased brain Mn (measured by MRI) has been found in patients with liver dysfunction and liver failure [R].

5) Iron-Deficient People

Iron has a strong influence on Mn balance. Both metals share transporters (transferrin and DMT1) [R]. Iron deficiency increases the production of these transporters and the accumulation of Mn [R].

Individuals with iron deficiency are at risk for increased Mn body burden [R]. This is especially important for vegetarians, as they already have higher Mn levels [R].

Humans and rats with chronic iron deficiency accumulate Mn in the brain (basal ganglia) [R].

In rodents, iron deficiency is associated with increased Mn gut absorption and [R].

Prolonged breast-feeding, which is a risk factor for iron deficiency in infants, is associated with increased blood Mn levels [R]. Babies who are breast-fed for prolonged periods should be given plain, iron-fortified cereals or other good sources of dietary iron [R].

6) Women

According to the 2011–2012 NHANES study of U.S. residents, women have significantly higher blood Mn levels than men [R].

In the Chinese general population, women’s blood Mn levels are about 29% higher than men’s [R].

Korean and Italian women have 25% higher and Canadian women have about 23% higher levels than men [R].

Additionally, the 2011–2012 NHANES showed that pregnant women accumulate higher levels of Mn than other persons [R].

7) People with Neurological Diseases

Those with pre-existing neurological diseases may be at higher risk of developing Mn toxicity, because of the potential for combined effects [R].

8) Patients with Kidney Failure

Patients subjected to microdialysis due to chronic kidney failure may develop manganism in the absence of external exposure [R].

9) People with Occupational Exposure to Manganese

Ingested Mn is under tight control. Only 3-5% of ingested Mn is absorbed through the gut [R].

Inhaled Mn, however, can bypass bile excretion and enter the brain directly across the blood–brain barrier [R].

Occupational exposure to Mn is a health hazard for miners, welders, ferroalloy workers, battery manufacturers and car mechanics [R, R].

Excessive Mn exposure also occurs in the manufacture of glass and ceramics [R].

Finally, Mn toxicity can occur in rural workers exposed to Mn-containing pesticides such as maneb [R].

Manganese Metabolism

Of the ingested Mn, only 1–5% is absorbed into the blood. This level is tightly regulated based on the concentration of Mn in the diet. Less Mn is absorbed into the blood when more Mn has been ingested [R].

Excess Mn is transported to the liver. There its is incorporated into the bile and then passed through the intestine for fecal excretion. Mn can also be detected in small amounts in urine, sweat and breast milk [R].

Bile excretion of Mn accounts for 80% of Mn elimination [R].

The highest concentrations of Mn is found in the bone, liver, kidney, pancreas, and adrenal and pituitary glands [R].

Bone contains about 40% of the total body Mn [R].

Mn can readily cross both the blood-brain and placental barriers [R].

Manganese Levels

Normal ranges of Mn for adults are 4–15 μg/L in blood, 1–8 μg/L in urine and 0.4–0.85 μg/L in serum (the liquid component of blood)[R].

The normal concentration of Mn is 1 mg/kg in the bone, 1.04 mg/kg in the pancreas, and 0.98 mg/kg in the kidney (cortex) [R].

The normal concentration of Mn in the brain is estimated to lie between 5.32 and 14.03 ng/mg protein [R].

Manganese in Food

The primary route of typical Mn intake is through diet [R].

The adult dietary intake of Mn has been estimated to range from 0.9 to 10 mg per day [R, R].

Safe and adequate dietary intake is 2.3 mg/day for men, and 1.8 mg/day for women [R]. Depending on the study, the values range from 2–5 mg Mn [R].

The recommended dietary intake for children is from 0.003 mg/day for 0-6-month-old infants to 1.6-1.9 mg/day for  9-13 year children [R].

Legumes, rice, nuts and whole grains contain the highest levels Mn [R, R], in excess of 30 mg/kg [R].

This metal is also found in seafood, seeds, chocolate, tea, leafy green vegetables, spices, soybean, and some fruits such as pineapple, blueberries, and acai [R, R, R].

A cup of tea contains as much as 0.4 to 1.3 mg Mn [R].

People eating vegetarian diets and Western-type diets may have Mn intakes as high as 10.9 mg/day, which is the upper limit from all sources [R].

Manganese Supplements

To supplement or not to supplement? That is the question.

Most people already have more than an adequate intake of Mn, and should be careful when supplementing this metal.

There are various Mn supplements available on the market. Multivitamins also often contain Mn.

Mn-containing supplements usually contain 5–20 mg of Mn [R]. That said, 11 mg/day is often cited as the upper limit no-observed-adverse-effect-level for Mn.

Around the web, Mn is discussed as a histamine-lowering and dopamine-increasing agent, although there is little research to support this. In fact, manganese may actually decrease dopamine in the long run [R, R].

Manganese supplements can cause a short-term boost in energy, but people often report side effects such as emotional instability, mood issues, racing pulse, nausea, and fatigue.

You should especially be careful if your liver is not functioning properly, because that makes you prone to Mn accumulation and toxicity.

As a plant-rich diet provides more than enough magnesium for most of us, you may want to skip on Mn and opt for other supplements that can provide the same benefits but without the toxic effects.

Manganese in Water, Air, and Other Sources

Overexposure to Mn can occur through diverse sources: drinking water, infant milk formula, industrial pollution, and mining wastes [R].

Water concentrations of Mn typically range from 1–100 μg/L, with most values below 10 μg/L [R].

Approximately 5.2 % of the 2167 wells surveyed across the USA exceeded the health benchmark of 300 µg/L Mn [R].

In the industry, the majority of Mn is used to make alloys and steel [R].

Mn is also used in the manufacturing of dry cell batteries, fuel additives (MMT), fungicides (e.g., maneb and mancozeb), paint, adhesives, ceramics, cosmetics, leather, glass and textiles [R, R].

In occupationally exposed humans, inhalation of Mn is an important additional intoxication route [R].

Inhaled Mn can bypass the liver to enter the bloodstream. From there, it can enter the brain bypassing the blood-brain barrier [R].

Exposure to Mn can also occur as a result of combustion of MMT (methylcyclopentadienyl Mn tricarbonyl), a petrol antiknock additive [R].

Mn poisoning has been reported in drug-addicted subjects using ephedrone [R], and ‘Bazooka’ [R].

Additionally, Mn is used as a contrast agent for MRI [R].

However, Mn in MRI is not toxic owing to acute, less frequent exposure, fast elimination, and low body burden in clinical diagnosis [R].

Mn Levels Test

Studies do not recommend using Mn levels in blood, urine, or saliva to test for Mn exposure [R, R].

This is because blood (and urine or saliva) Mn level is a poor indicator of Mn brain accumulation and exposure [R].

The half-life of Mn in the blood is less than 2 h [R], while in the brain it is 53 days [R].

MRI is noninvasive, but it is only good for recent exposures. In human studies of smelters or intravenous ephedrone users, the signal in the brain almost completely disappeared 5– 6 months after cessation of exposure [R].

For subjects with long-term, low-dose Mn exposure, particularly those who were previously, but not currently exposed to Mn, neither blood Mn nor MRI can provide a valid measure of historical exposure [R].

Studies of Mn toxicity often use hair Mn content [R, R].

A relatively long half-life (about 8–9 years in human) of Mn in the bones, renders bone Mn an ideal indicator to assess the body burden of Mn [R].

More convenient methods of measuring Mn exposure will likely arise in the near future.

Decreasing Mn

1) High-Iron Diet

The best way to keep your Mn levels in check is to make sure you take adequate amounts of iron.

High iron diets suppress Mn absorption [R].

2) Iron supplements

Iron supplementation helps reduce blood Mn levels and lowers Mn body burden [R].

Supplements and Natural Substances that Combat Manganese Toxicity

Substances that combat Mn toxicity include antioxidants (for instance, vitamin E), plant extracts, iron chelating agents, precursors of glutathione (GSH), and synthetic compounds [R].

1) Taurine

Taurine improves the impairment of learning and memory caused by excessive Mn in rats [R].

You can find taurine in energy drinks.

2) Vitamin E

Vitamin E and Trolox (a water-soluble analog of vitamin E) protect the brain of rodents from the toxic effects of Mn [R].

Exposure of lactating rats to Mn caused brain oxidative stress and motor impairments, which were prevented by Trolox [R].

3) Magnesium

Magnesium can reduce manganese toxicity in rats [R].

Elevated Mn intake reduces the amount of magnesium in rats [R].

On the other hand, magnesium deficiency increases the amount of Mn in rat blood, heart, muscles, and kidneys [R], and pig hearts [R].

High Mn and low magnesium are found in some diseases, such as the inherited neurodegenerative Machado Joseph Disease [R].

4) N-Acetylcysteine and Glutathione

Glutathione (GSH) and N-Acetylcysteine (NAC), a precursor of GSH, can also decrease the toxicity of Mn (shown in cells). Both act as indirect antioxidants [R].

5) Melatonin

Melatonin significantly alleviates Mn-induced motor dysfunction and neuronal loss in mice [R].

This hormone also suppresses the increase of IL-1β and TNF-α caused by Mn in brain cells [R].

6) Quercetin

Quercetin prevents Mn-induced motor deficits and brain damage in rats [R].

It also increases antioxidant enzyme activities and glutathione levels, while suppressing inflammation (and caspase-3 activity) in Mn-treated rats [R].

Finally, quercetin reverses Mn-induced decreases in reproductive hormones (luteinizing hormone, follicle-stimulating hormone, and testosterone) and increases sperm quality and quantity in rats [R].

7) Acai

Although acai (Euterpe oleracea) on its own is a source of Mn, its extract protected rat brain cells from Mn-induced oxidative stress. These protective effects may be associated with the antioxidant and anti-inflammatory effects of its anthocyanin components [R].

8) Lemon Balm

Lemon balm (Melissa officinalis) extract reduces Mn-induced brain oxidative damage (striatum, hippocampus) in mice [R].

9) Milk thistle

Silymarin obtained from milk thistle (Silybum marianum) protects brain cells and prevents Mn-induced oxidative stress in brain, liver, and kidney of rats [R].

10) Lycopene

Lycopene decreases the neurotoxicity of Mn in rats [R].

11) Chelating agents

Treatment with a calcium disodium salt of the chelator EDTA (CaNa2EDTA) reduced Mn-induced dopamine oxidation, enhanced urinary excretion of Mn in humans and reduced Mn levels in the brain and liver of Mn-exposed rats [R].

12) Anti-inflammatory Compounds

Anti-inflammatory agents decrease Mn neurotoxicity. Mesalazine (5- aminosalicylic acid) and para-aminosalicylic acid increased mitochondrial and cell viability following Mn exposure [R].

Ibuprofen protected from neuron atrophy (striatum) and spine loss in rats treated for 2 weeks with the drug prior to Mn exposure [R].

Technical

Mn Transport

  • The majority of Mn brain-blood barrier transport occurs via DMT1 [R].
  • Additional brain Mn transporters include the Mn-citrate transporters (MCT) and the Mn-bicarbonate symporters (ZIP-8 and ZIP-14) [R].
  • SLC30A10, a solute carrier, has been suggested to regulate Mn export from the cells [R].
  • Mn accumulates mainly in the liver and the brain, particularly in the basal ganglia and globus pallidus [R].
  • Mn is most concentrated in the globus pallidus, caudate, and putamen and is less concentrated in cortical areas of the brain [R].

Toxicity Mechanisms

  • Excess Mn interferes with mitochondrial function. Mn can interfere with energy (ATP) production and decreases ATP [R].
  • Too much Mn causes oxidative stress. Mn exposure increases metallothionine,  NFκB, and AP-1, and decreases in glutathione (GSH) [R]. In Mn-exposed nonhuman primates, Mn increases cell death and inflammation [R].
  • Excess Mn reduces dopamine. Mn can promote the autooxidation of dopamine, which leads to the creation of reactive (toxic) dopamine quinones [R]. In nonhuman primates, high exposures to Mn > 300 mg/kg reduced striatal concentrations of dopamine [R]. Mn also decreases D2-like dopamine receptor levels [R].
  • Excess Mn increases glutamate in the brain. Increased glutamate levels in the brain have been documented in rodents exposed to Mn [R]. In nonhuman primates, Mn  decreased protein levels of GLAST and GLT, the two main astrocytic glutamate transporters, and GS, the enzyme that converts glutamate into glutamine, in multiple brain regions [R].
  • Too much Mn can damage glial cells. Accumulating evidence indicates that Mn may indirectly affect neuronal function by damaging glial cells (cells that support neurons) [R]. Mn increases proinflammatory TNF-α, iNOS, P-p38, P-ERK, and P-JNK in glial cells [R].

Mn and Related Genes

DMT1 (SLC11A2)

Divalent metal transporter 1 (DMT1) is important for the absorption and transport of Mn.

ZIP8 (SLC39A8)

SLC39A8 acts as a Mn and zinc transporter [R].

SLC39A8 variants have been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy [R].

A SLC39A8 variant causes Leigh-like mitochondrial disease, with profound developmental delay, movement disorder (dystonia), seizures and failure to thrive [R].

ZIP14 (SLC39A14)

Zinc transporter. Also, transports Mn.

SLC30A10

SLC30A10 is a Mn transporter [R].

Loss-of-function mutations in SLC30A10 cause a heritable Mn metabolism disorder resulting in Mn overload and parkinsonian-like movement deficits [R, R].

In patients with SLC30A10 mutations, Mn accumulates in the brain (basal ganglia, white matter), even in the absence of exposure to high Mn levels [R].

SLC30A10 deficient mice develop hypothyroidism [R].

CYP2D6

Mn miners with the CYP2D6∗2 variant had relatively low Mn concentrations, indicating that CYP2D6 could be involved in the fast metabolism of blood Mn [R].

Transferrin

Transferrin is the primary transporter for trivalent Mn [R].

Ferroportin (SLC40A1)

Ferroportin acts as a Mn exporter [R].

MnSOD (SOD2)

A Mn-containing enzyme, Mn superoxide dismutase (MnSOD), is the principal antioxidant enzyme which neutralizes the toxic effects of reactive oxygen species (ROS) in mitochondria [R, R].

FDA Compliance

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3 COMMENTS

  • Karen

    ^^^What she said!! LOL I just read the article and was going to comment that far too much emphasis was put on manganese excess, when I see that Alethea already brilliantly summarized the current state of most people’s manganese status! The only thing I’ll add to her comment is that if anyone wants more information on the impact Glyphosate has on manganese, check out the research Dr. Stephanie Seneff from MIT has done on the topic!

  • Alethea Black

    Oh and one more: Manganese powers arginase, a manganese-dependent enzyme, which helps to lower arginine levels in the body. High arginine increases viral activity (e.g. Epstein-Barr), and viruses damage thiamine chemistry. Low thiamine activity leads to reduced Krebs/energy cycle (NOTHING can happen without TPP – thiamine pyrophosphate, the active form of thiamine), as well as lactic acidosis and hypokalemic hypersensitivity — all factors, I believe in ME/CFS (chronic fatigue). This could be one of the ways B1 (thiamine) and manganese support each other in the body.

  • Alethea Black

    Great article, but far too much emphasis on the negative (toxicity) aspect over the benefits of manganese, especially considering that manganese metabolism is severely damaged by Glyphosate (Round-Up), which we all consume nowadays, even if we mostly try to eat organic. Glyphosate makes people manganese-deficient. In addition, many with chronic illness suffer (unknowingly or knowingly) from B1 deficiency, and B1 metabolism requires manganese. In fact, a lot of my chronic fatigue problems were related to a backlog of by-products of oxidative metabolism in the mitochondria, which put back-pressure on Krebs/energy cycle. What helped fix it? Manganese, which powers MnSOD. (Eric also writes very knowledgeably about MnSOD and chronic fatigue over at HOW I RECOVERED). On top of that, many with hereditary hemochromatosis genes (HFE) will unknowingly store iron — at a cost to manganese. Lastly, copper toxicity/dysregulation — also an epidemic among the chronically ill — and its attendant iron overload — the #1 favorite topic of Morley Robbins — will deplete manganese. In fact, B1 (remember B1 and manganese share a special synergy) will chelate iron. Did I say lastly already? I was premature. LASTLY, Lyme and other infections can leave people very seriously manganese depleted. The greater danger these days, by far — unless you are a miner or a welder — is manganese DEFICIENCY, not toxicity. Everyone should be getting an RBC manganese test with routine blood work (RBC is the only meaningful metric; serum is meaningless). And let’s not confuse manganese “excess” with manganese simply showing up in higher amounts in one place because it’s not getting where it needs to go somewhere else. That’s not toxicity, it’s disrupted transport or damaged manganese chemistry — from genetics, iron overload, Glyphosate, etc. And it’s not just us! Our gut microbes need Mn, too. Pineapple (organic, needless to say) is a terrific source, but to be honest, I was so deficient that no amount of pineapple would have done the trick. I suspect manganese and B1 deficiency are far more common than we realize.

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