Manganese Neurotoxicity

Evidence of Manganese Neurotoxicity in Children & Adults and its Regulation by Iron in the Brain

 

AUG 1978 – Institute for Medical Research and Occupational Health, Yugoslav Academy of Sciences and Arts, Zagreb, Yugoslavia

Influence of Age on Metal Metabolism and Toxicity

“The question is raised whether the young, from birth and onward, might be more sensitive to toxic metals in the environment than are adults.”

“It is however, astonishing how little information is available on the pharmacokinetics and effects of metals during the immediate postnatal period. This period, in which rapid changes in organ function and development occur and in which milk is the only nutritional source, has been neglected from the standpoints of both pharmacology and environmental toxicity.”

“The results which we obtained in suckling rats show a high absorption of lead, mercury, cadmium and manganese ranging from 26% to 52% of the oral dose as compared to absorption values of below 1% in older rats on a standard rat diet.”

“We assumed that the milk diet could be an important factor in the increased metal absorption in the sucklings since we also found a very high absorption of lead in older animals fed a milk diet. [Our] results confirm this assumption. Older rats on a milk diet also showed a higher absorption of cadmium, mercury and manganese, although values were never as high as in suckling rats.”

“Highest differences in organ retention were obtained in the brain, where the percentage retention was 8 times higher for lead, 19 times for mercury, and 28 times for manganese in the postnatal period.”

“In the brain, great morphological changes are known to occur in the first month of neonatal life. A higher permeability of the blood brain barrier is also assumed at this age. These conditions could cause a higher metal accumulation in the brain, which might be of special significance since the brain could be the “critical” organ for toxic metals in neonates.”

“Our findings indicate that in the early postnatal period, further accumulation of metals might occur as a result of a higher intestinal absorption and a higher body and organ retention.”

Summary statement: “Differences in the retention and organ distribution of metals in neonates could be anticipated on the basis of their physiological differences from adults. It is astonishing however, that so few data are generally available on this topic.”

 

1990 – University of Rochester Medical Center, Rochester, NY

Manganese and Calcium Efflux Kinetics in Brain Mitochondria

“Manganese shares the uniport mechanism of mitochondrial influx, accumulates in mitochondria and is cleared only very slowly from the brain.”

“With continuing exposure, particularly via inhalation (thus bypassing homeostatic control mechanisms), brain Mn becomes elevated, accumulating preferentially in the basal ganglia. Brain Mn clearance may take up to a year.”

Summary statement: “It is curious that the role of the mitochondrion in Mn toxicity has received so little attention. There thus appear to be sound reasons for looking more closely at both direct and indirect effects of Mn on brain mitochondrial function.”

 

1999 – USDA, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND

Manganese Deficiency and Toxicity: Are High or Low Dietary Amounts of Manganese Cause for Concern?

“Although much remains to be learned of the functions of Mn, at present there are only a few vaguely described cases of Mn deficiency in the medical literature.”

“There may be reasons, however, to be concerned about Mn toxicity under some very specialized conditions. Increasing numbers of young people are adopting a vegetarian lifestyle, which may greatly increase Mn intake. Iron deficiency may increase Mn absorption and further increase the body burden of Mn, especially in vegetarians.”

“Mn is eliminated primarily through the bile, and hepatic dysfunction could depress Mn excretion and further contribute to the body burden.”

Summary statement: “Would such a combination of events predispose substantial numbers of people to chronic Mn toxicity? At present, there is no definite proof of this occurring, but given the state of knowledge at the present time, more studies with longer time frames and more sensitive methods of analysis are needed.”

 

APR 1999 – College of Medicine, Pennsylvania State University, PA

Existing and Emerging Mechanisms for Transport of Iron and Manganese to the Brain

“The metals iron and manganese are essential for normal functioning of the brain. These metals are treated together because they appear to share several transport mechanisms.”

“In addition, several neurological diseases such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease are all associated with iron mismanagement in the brain, particularly in the striatum and basil ganglia. Mn accumulation in brain also appears to target the same brain regions.”

Summary statement: “Therefore, stringent regulation of the concentration of these two metals in the brain is essential. The homeostatic mechanisms for these metals must be understood in order to design neurotoxicity prevention strategies.”

 

JUN 2000 – Wake Forest University Health Sciences, Winston Salem, NC

Manganese: Brain Transport and Emerging Research Needs

“[E]xcessive exposure to Mn is associated with an irreversible central nervous system disorder characterized by prominent psychological and neurological disturbances.”

“Because both Mn and Fe share similarities in their chemistry and biochemistry, it is reasonable to postulate that the mechanisms underlying Mn distribution both in health and disease are dependent on Fe homeostasis.”

“The competition between Fe and Mn for the same carrier transport system is noteworthy and bears significant implications for potential increased accumulation of central nervous system Mn in Fe-deficient populations.”

“These data are consistent with competition between these two metals and support the hypothesis that chronic Fe deficiency may lead to enhanced accumulation of Mn in the central nervous system, potentially leading to aberrant function.”

Summary statements: “The potential for increased central nervous system Mn accumulation…and by inference, the potential health risks associated with elevated brain Mn burden, clearly represent crucial issues of exposure and susceptibility that have yet to be evaluated. Studies on Mn transport across the blood-brain barrier as well as the mechanisms of its neurotoxicity are inconclusive. [New research] is deemed necessary to define pertinent issues of Mn transport and neurotoxicity.”

 

MAY 2001 – College of Medicine, Pennsylvania State University, Hershey, PA

Manganese Toxicity is Associated with Mitochondrial Dysfunction and DNA Fragmentation in Rat Primary Striatal Neurons

“Following exposure to [manganese] for 48 hours, striatal neurons showed dose-dependent losses of mitochondrial membrane potential and complex II activity. The Mn exposure effect on mitochondrial membrane potential was significant at every concentration measured (5, 50, and 500 microM), and the manganese exposure effect on complex ii activity was significant at 50 and 500 microM.”

Summary statement: “These results indicate that manganese may trigger apoptotic-like neuronal death [self-destruction] secondary to mitochondrial dysfunction.”

 

DEC 2001 – Science and Environmental Health Network, Boston, MA

Toxic Threats to Neurologic Development of Children

“More recently, the developmental neurotoxicity of manganese has emerged as a significant public health concern.”

“In several small epidemiologic studies of children, manganese hair levels are associated with ADHD.”

“Compared to adults, children and immature animals absorb more and excrete less manganese. Moreover, in infants, manganese easily gains access to the developing brain because of an immature blood-brain barrier.”

“These observations raise questions about the wisdom of supplementing infant formula with manganese and the widespread use of infant soy formula containing naturally high concentrations of manganese.”

“They also further concerns about the use of gasoline supplemented with an organic manganese compound as an octane enhancer in [unleaded gas in] the United States and Canada.”

“Available data indicate that the brain is vulnerable to long-lasting effects from developmental exposures to manganese.”

Summary statement: “Regulatory agencies have generally failed to require neurodevelopmental testing of chemicals before they are marketed. None of the voluntary testing programs proposed by the chemical industry in the United States includes neurodevelopmental testing.”

 

OCT 2002 – University of California Davis, Davis, CA

Effects of Neonatal Dietary Manganese Exposure on Brain Dopamine Levels and Neurocognitive Functions

“Neonatal exposure to high levels of manganese has been indirectly implicated as a causal agent in attention deficit hyperactivity disorder (ADHD), since manganese toxicity and ADHD both involve dysfunction in brain dopamine systems.”

“This study was undertaken to examine this putative relationship in an animal model by determining if levels of neonatal dietary manganese exposure were related to brain dopamine levels and/or behavioral tests of executive function when the animals reached maturity.”

Summary statement: “These results lend support to the hypothesis that neonatal manganese exposure is related to brain dopamine levels and neurocognitive deficit in the rodent.”

 

JUL 2003 – Dept of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY

Iron Interactions and other Biological Reactions Mediating the Physiological and Toxic Actions of Manganese

“Chronic exposure to the divalent heavy metals, such as iron, lead, manganese and chromium, has been linked to the development of severe, often irreversible neurological disorders and increased vulnerability to developing Parkinson’s disease.”

“Mn disposition in vivo is influenced by dietary iron intake and stores within the body since the two metals compete for the same binding protein in serum (transferrin) and subsequent transport systems (divalent metal transporter, DMT1).”

“The toxicological properties of Mn have been studied extensively in recent years because of the potential health risk created by increasing atmospheric levels owing to the impending use of the gas additive methylcyclopentadienyl manganese tricarbonyl.” (MMT)

 

2006 – University of Kentucky Medical Center, Lexington, KY

Blood-Brain Barrier Flux of Aluminum, Manganese, Iron and Other Metals Suspected to Contribute to Metal-Induced Neurodegeneration

“The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting that environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases.”

“Many metals that have been suggested to contribute to neurodegenerative diseases are also considered to be essential for human health in trace amounts.”

“In addition to the routes of distribution from blood to brain through the blood-brain barrier and choroids plexus, it has been known for some time that proteins (viruses) can distribute from the nasal cavity into the olfactory neuron, the only site where the central nervous system is exposed to the environment and then migrated trans-synaptically beyond the olfactory neuron into other brain regions. It is known from studies in rats and pike fish that manganese, and perhaps nickel, can enter the brain directly by this route.”

“The fuel additive MMT, which increases octane and reduces deposit accumulation in internal combustion engines, meeting the same objective that tetraethyl Pb (lead) addressed, is primarily converted during internal combustion of gasoline to manganese phosphate and sulfate, which are released from the exhaust system into environmental air.”

Summary statements: “In summary, there is very good evidence that transporters mediate the influx of [several species of manganese] into the brain. Results suggest that diffusion mediates brain Mn efflux. In light of transporter-mediated brain influx, but not efflux, it would be anticipated that repeated, excessive Mn exposure might result in brain Mn accumulation over time. This has been observed in animals. Similarly, the human brain Mn concentration rose in humans from infancy to adulthood and the highest Mn concentrations were in the basal ganglia, the site of Mn-induced neurotoxicity.”

 

JAN 2006 – Harvard School of Public Health, Boston, MA

The Influence of High Iron Diet on Rat Lung Manganese Absorption

“Individuals chronically exposed to manganese are at high risk for neurotoxic effects of this metal.”

“High dietary iron levels inversely affect intestinal uptake of manganese, and a major goal of this study was to determine if dietary iron loading could increase lung non-heme iron levels and alter manganese absorption.”

Summary statement: “These data demonstrate that manganese absorption from the lungs to the blood can be modified by iron status and the route of administration.”

 

MAY 2006 – Wake Forest University Health Sciences, Winston Salem, NC, Norwegian University of Science and Technology, Trondheim, Norway, and Vanderbilt University, Nashville, TN

A Manganese-Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat

“Neonates accumulate more Mn than adults due to enhanced Mn absorption (70% vs. 3% respectively), an incomplete blood-brain barrier, and little to no biliary excretion until weaning.”

“The current results demonstrate that developing rats undergo alterations in the transport and distribution of essential metals translating to neurochemical perturbations after maternal exposure to a diet supplemented with excess levels of Mn.”

Summary statements: “In humans, nonhuman primates and rodents, there is an association between high dietary Mn and cognitive deficits. Adverse neurological effects (learning or behavioral impairment, intellectual function) were observed in children (10-13 years) exposed to excess Mn in the drinking water and in food produced on land fertilized with sewage water. Despite the increased vulnerability of immature animals, developmental effects of Mn are not yet adequately studied.”

 

AUG 2006 – Wake Forest University Health Sciences, Winston Salem, NC

A Manganese-Enhanced Diet Alters Brain Metals and Transporters in the Developing Rat

“Manganese neurotoxicity in adults can result in psychological and neurological disturbances similar to Parkinson’s disease, including extrapyramidal motor system defects and altered behaviors. However, virtually nothing is known regarding excess Mn accumulation during central nervous system development.”

“Mn-exposed pups showed an increase in brain Mn, chromium and zinc concurrent with a decrease in brain Fe.”

“Neurochemical changes were observed as an increase in GABA and the ratio of GABA to glutamate, indicating enhanced inhibitory transmission to the brain.”

Summary statement: “The results of this study demonstrate that developing rats undergo alterations in the transport and distribution of essential metals translating to neurochemical perturbations after maternal exposure to a diet supplemented with excess levels of Mn.”

 

SEP 2006 – University of North Carolina, Greensboro, NC, Harvard School of Public Health, Boston, MA & Vanderbilt University Medical Center, Nashville, TN

Manganese Neurotoxicity: A Focus on the Neonate

“While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable.”

“Mn deposition in the brain has potentially important implications for long-term neurodevelopmental outcome in exposed infants.”

“Research projects that examine…mechanisms of Mn neurotoxicity in the neonatal brain are scant.”

“It is known that increases in blood and brain Mn levels have been reported in persons with liver disease, and data suggest that iron deficiency may be a risk factor for Mn neurotoxicity.”

“The plasma and transmembrane transport of Fe and Mn are thought to share common mechanisms.”

“The most important source of Mn for the population at large is diet, with most daily intakes falling below 5 mg Mn/kg. Adult dietary intake of Mn is estimated to be between 0.9 to 10 mg Mn/day.”

“Levels of Mn in excess of 30 mg/kg can be found in certain foods, such as grains, rice and nuts.”

“Another important source of dietary Mn intake is Mn-containing dietary supplements. Many of these contain Mn levels of 5-20 mg.”

“Human milk is generally low in Mn content (1.8-27.5 micrograms per liter), however, Mn concentrations in infant formulas can vary dramatically (33-330 micrograms per liter). It has been suggested that consumption of soy-based infant formulas is a potential area of concern for human infants, as levels of 200-300 micrograms per liter are common.”

Summary statement: “We briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in the underreported area of neurotoxicity. No data are available in terms of assessing the neurological effects of Mn-exposure during early life and long term consequences of this exposure.”

 

SEP 2006 – Thomas Jefferson University, Philadelphia, PA, Norwegian University of Science and Technology, Trondheim, Norway, and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Effects of Chronic Manganese Exposure on cognitive and Motor Functioning in Non-Human Primates

“Acute exposure to manganese is associated with complex behavioral/ psychiatric signs that may include Parkinsonian motor features. However, little is known about the behavioral consequences of chronic manganese exposures.”

“Excess manganese intake can occur from excessive dietary intake as well as occupational and environmental exposures. Excess dietary intake most typically occurs in infants fed soy-based formulas that contain higher levels of manganese than breast milk or cow’s milk-based formulas.”

“Neurological deficits in humans…are usually found following high level acute exposures or following long-term or chronic exposures. However, there is relatively little known about the threshold exposure necessary for inducing such deficits.”

“Manganese sulfate was used in this study since it is one of the main combustion products of MMT, an antiknock additive to unleaded fuel that contributes to environmental deposition of manganese and in consideration of the enhanced awareness that manganese may play a role in neurologic diseases.”

Summary statement: “In summary, chronic manganese exposure in macaque monkeys led to behavioral alterations consisting of compulsive-like behaviors, decreased activity levels, problems in fine motor functioning and variable sensitivity to cognitive deficits such as impaired spatial working memory. Additional work is necessary to understand the long-term effects of different doses and dosing regimens of manganese on cognitive and motor functioning in non-human primates.”

 

NOV 2006 – Columbia University, New York, NY

Gene Expression Profiling of Human Primary Astrocytes Exposed to Manganese Chloride Indicates Selective Effects on Several Functions of the Cells

“Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity.”

“It is estimated that over 3,700 tons of Mn are released into the atmosphere every year (2001), particularly from the gasoline additive MMT.”

“In the brain, astrocytes are a “sink” for Mn, with concentrations 10-50-fold higher than in neurons. Mn transport to astrocytes is significantly affected by Fe status. Also, evidence suggests that Mn transport involves multiple pathways that may be competitive or synergistic with iron transport.”

Summary statement: “In summary, our studies using a combination of genomic, biochemical and toxicological approaches uncovered several note-worthy characteristics of the effects of Mn on primary human astrocytes. Our findings provide a molecular basis for further investigation of the mechanisms underlying Mn neurotoxicity and perhaps even other neurodegenerative diseases.”

 

2007 – Crinella, FM, Ericson, JE, et al, University of California, Irvine, CA

Prenatal Manganese Levels Linked to Childhood Behavioral Disinhibition

“[F]ood is the major source of absorbed Mn in the general population, and certain groups, such as neonates and infants, are more vulnerable than adults to Mn via intestinal absorption. In the young rodent, intestinal absorption of Mn is on the order of 70%, compared to the 1-2% in the adult rat; further, Mn enters the neonatal brain at a much higher rate than in adult animals.”

“With respect to prenatal exposure, Mn concentrations in umbilical cord blood have been found to be 33% to 50% higher than in maternal blood, suggesting not only an active transport system, but also a concentrating mechanism.”

“These findings suggest that prenatal accretion of Mn, as reflected in tooth enamel deposits dating to the 20th gestation week, is significantly associated with childhood behavioral outcomes. Children with higher levels of prenatal manganese were more impulsive, inattentive, aggressive, defiant, disobedient, destructive and hyperactive.”

Summary statement: “The significance of this study is that it suggests a link between fetal Mn exposure and later behavioral disinhibition. The fact that several statistically significant associations have been shown, all in a direction consistent with existing literature on behavioral effects of Mn exposure, supports the potential importance of this method and points to a need for prospective studies of larger populations.”

 

JAN 2007 – Wake Forest University Health Sciences, Winston Salem, NC

Iron Deficient and Manganese Supplemented Diets alter Metals and Transporters in the Developing Rat Brain

“Manganese neurotoxicity in adults can result in psychological and neurological disturbances similar to Parkinson’s disease, including extrapyramidal motor system defects and altered behaviors.”

“Iron deficiency is one of the most prevalent nutritional disorders in the world, affecting approximately 2 billion people, especially pregnant and lactating women, infants, toddlers and adolescents. Iron deficiency can enhance brain Mn accumulation even in the absence of excess Mn in the environment or the diet.”

Summary statement: “The results of this study confirm that there is homeostatic relationship among several essential metals in the brain [including that] between Fe and Mn.”

 

FEB 2007 – University of North Carolina, Greensboro, NC, Harvard School of Public Health, Boston, MA & Vanderbilt University Medical Center, Nashville, TN

Manganese Neurotoxicity: A Focus on the Neonate

“Mn is used in numerous industries including steel production, formulating gasoline anti-knock additives (MMT), mining, welding, battery assembly and glass and ceramics manufacturing.”

“Mn deposition in the brain has potentially important implications for long-term neuro-developmental outcome in exposed infants.”

“Overall, it appears that the striatum is a vulnerable brain region in terms of Mn neurotoxicity in the neonate.”

“It is known that increases in blood and brain Mn levels have been reported in persons with liver disease and data suggests that iron (Fe) deficiency may be a risk factor for Mn neurotoxicity. This point is especially relevant considering the prevalency of Fe deficiency throughout the world (approximately 2 billion people are affected).”

“The plasma and transmembrane transport of Fe and Mn are thought to share common mechanisms.”

“Analysis conducted by the National Water-Quality Assessment Program of the U.S. Geological Survey, suggests that roughly 6% of domestic wells contain high levels of Mn in drinking water in the range of 300 micrograms per liter. This level of Mn exposure has recently been associated with reduced Full-Scale, Performance and Verbal raw scores in children in Bangladesh.”

“Human milk is generally low in Mn content (1.8-27.5 micrograms per liter, however, Mn concentration in infant formulas can vary dramatically (33-300 micrograms per liter).”

“It has been suggested that consumption of soy-based infant formulas is a potential area of concern for human infants as levels of 200-300 micrograms per liter are common.”

“It is known that changes in Mn-containing proteins have been observed in many neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinsonian-like syndrome, as well, neurobehavioral deficits are associated with Mn exposure.”

Summary statement: “Therefore, longitudinal studies that examine both markers of oxidative stress and neurotransmitter biology in subjects who have a history of Mn exposure during critical neurodevelopmental periods are necessary.”

 

MAR 2007 – Neurotoxicol Teratol, Ericson JE, Crinella FM

Prenatal Manganese Levels Linked to Childhood Behavioral Disinhibition

“Animal research suggests that exposure to high levels of manganese during infancy may deplete dopamine in areas of a child’s brain that are linked to impulsivity and ADHD.”

Summary statements:Iron deficiency in the mother during pregnancy can cause over-exposure to manganese in the infant. Also, soy infant formula may be a source of over-exposure after birth. Soy formula can contain 80 times the amount of manganese that normally occurs in breast milk.”

 

MAR 2007 – Vanderbilt University, Nashville, TN, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, Thomas Jefferson University, Philadelphia, PA & Purdue University, West Lafayette, IN

Manganese: Recent Advances in Understanding its Transport and Neurotoxicity

“Despite its essentiality, Mn has been known to be a neurotoxicant for at least 150 years. Exposure to excessive amounts of Mn is associated with a variety of psychiatric and motor disturbances. Cognitive deficits such as memory impairment, reduced learning capacity, decreased mental flexibility, cognitive slowing and difficulty with visuomotor and visuospatial information processing have also been reported.”

“Severely intoxicated patients have difficulty simply coping with daily life.”

“A body of evidence suggests that Mn-induced neurotoxicities appear to be associated with altered Fe metabolism at both systemic and cellular levels.”

“Searching for a reliable biological indicator for early Mn exposure has become a daunting task in the clinical investigation of Mn neurotoxicity.”

“Because of the intracellular distribution and relatively short half life of Mn in the blood compartment, blood Mn in general does not serve as a reliable indicator of the total body burden of Mn or of the overall disease status”

“Compared to blood Mn, urine Mn is even less likely to be a clinical indicator for Mn toxicity, because the primary route of Mn excretion (>95%) is via the bile to feces.”

Summary statement: “Finally, it is clear that additional studies are necessary in order to identify potential efficacious treatments for Mn intoxication along with reliable biomarkers of exposure, representing fruitful area for future research.”

 

JUL 2007 – National Taiwan University College of Medicine, Taipei, Taiwan

In Utero Exposure to Manganese and Psychomotor Development at the Age of Six Months

“In the present study, we examined the effect of exposure to manganese in utero on psychomotor development in children at six months of age and found that the higher the manganese levels, the lower the DQ [developmental quotients] in the fine-motor subdomain, including basic hand use and visual-motor coordination. It is suggested that the adverse effects of exposure to excessive manganese levels on vulnerable children could be detected at the early age of six months.”

“Because manganese can increase the dopamine oxidation associated with the formation of free radicals, too high manganese levels in susceptible mitochondrial DNA may induce higher oxidative injury and oxidant damage. Such mechanism might be able to explain why infants with higher manganese exposure had lower fine-motor DQ.”

“Our study’s subjects were from the general population, and exposed to manganese from the environment. In general, environmental sources of manganese are water, air, pesticides, and diet such as grains, nuts and tea.”

Summary statement: “In the present study, we found that fetuses may be vulnerable to low level exposure of environmental manganese, particularly in motor performance. However, there could be some residual confounding we did not exclude. Thus, our findings still need further research to be verified. Nonetheless, to prevent the risk of poorer psychomotor development, we advise pregnant women to avoid exposure to excessive manganese in ordinary life during pregnancy.”

 

FEB 2009 – Department of Biology, King College, Bristol, TN

A Chronic Iron-Deficient/High-Manganese Diet in Rodents Results in Increased Brain Oxidative Stress and Behavioral Deficits in the Morris Water Maze

“Iron deficiency is especially common in pregnant women and may even persist following childbirth. This is of concern in light of reports demonstrating that iron deficiency may be sufficient to produce homeostatic dysregulation of other metals, including manganese.”

Summary statement: “Taken together, our data suggest that vulnerable iron-deficient populations exposed to high levels of manganese may indeed be at risk of potentially dangerous alterations in brain metal levels which could also lead to behavioral deficits.”

 

OCT 2009 – Vanderbilt University School of Medicine, Nashville, TN, Murray State University Breathitt Veterinary Center, Hopkinsville, KY, and Dept. of Pharmacology and Kennedy Center for Research on Human Development, Nashville, TN

Oxidative Damage and Neurodegeneration in Manganese-Induced Neurotoxicity

“Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors including oxidative injury, mitochondrial dysfunction and neuroinflammation.”

Summary statement: “The present study provides a potential direct link between oxidative stress, mitochondrial dysfunction, inflammation and neurodegeneration due to Mn neurotoxicity.”

 

DEC 2009 – Laboratory of Toxicology, Federal University of Bahia, Bahia, Brazil, National School of Public Health, Rio de Janeiro, Brazil and University of Quebec, Montreal, Quebec, Canada

Manganese Exposure and the Neuropsychological Effect on Children and Adolescents: A Review

“The vast majority of studies on neurotoxic effects of Mn were conducted in occupational settings where exposure occurs mainly through inhalation of airborne particulates.”

“Few studies have investigated possible over-exposure of children to Mn. The literature on possible adverse effects of exposure to Mn on children’s health is relatively sparse, despite the fact that Mn is acknowledged to be a neurotoxin.”

Summary statement: “Although limited by poor study design and difficulties in exposure assessment, the evidence of adverse effects from Mn environmental exposure on children is compelling enough to warrant further research. Finally, it is of paramount importance that epidemiologic studies include a comprehensive environmental assessment in order not only to better understand the exposure pathways, but also to provide reliable data for risk assessment, which can be used later to design efficient interventions to abate exposure.”

 

APR 2010 – University of Lisbon, Lisbon, Portugal

Rat Brain Endothelial Cells are a Target of Manganese Toxicity

Information on Mn’s effects on endothelial cells of the blood-brain barrier (BBB) is lacking. Accordingly, we tested the hypothesis that BBB endothelial cells are a primary target for Mn-induced neurotoxicity.”

“We suggest that direct Mn-induced injury to mitochondria and the ensuing impairment in their energy metabolism can modify the properties of the BBB and lead to changes in its permeability, which may facilitate the entrance into the brain parenchyma of endogenous and exogenous macro and micro-molecules, resulting in brain toxicity.”

Summary statement: “We conclude that Mn induces direct injury to mitochondria in RBE4 [rat brain endothelial] cells. The ensuing impairment in energy metabolism and redox status may modify the restrictive properties of the blood-brain barrier, compromising its function.”

 

NOV 2010 – Office of Environmental Health Hazard Assessment (OEHHA), Dept. of California State EPA

Manganese: Potential Designated Chemical

“Manganese toxicity is currently one of the most active areas of metal toxicology research in human populations.”

“For the general population, exposure to manganese occurs mainly through food intake. However, manganese in drinking water or air has been shown in some circumstances to result in significant exposure.”

“Recent studies have also shown that manganese is associated with developmental neurotoxicity.”

“Risk of manganese neurotoxicity is potentially higher prior to maturation of blood brain barrier and manganese homeostasis. In the fetus and neonate, an incompletely formed blood brain barrier results in a greater permeability to manganese.”

“Several studies have found cord-blood levels to be approximately twice as high as maternal levels.”

“Manganese intakes in formula-fed infants can be 10 to 50 times higher than breast-fed infants.”

“Neonatal humans do not excrete manganese for the first two to three weeks of life. The intestinal barrier to manganese absorption is also immature in premature and neonatal infants.”

“A number of studies have reported correlations between early life exposure to excessive manganese and symptoms of impaired neurodevelopment as revealed on neurobehavioral tests and in poorer academic performance.”

Summary statement: “Manganese is an essential nutrient, yet excessive exposure to manganese can cause neurotoxicity, including developmental neurotoxicity. While industrial exposures have been identified and monitored, the potential for excessive exposures to the general population and to sensitive subpopulations has not been well-characterized. Biomonitoring manganese will help the state to assess the extent of exposure to California residents.”