Manganese Abstracts 8



Are current biomarkers suitable for the assessment of manganese exposure in individual workers
            (Apostoli et al., 2000) Download
BACKGROUND:  Whole blood and urinary manganese have been measured in occupational and environmental studies for the assessment of exposure. The aim of this study was to assess the relationship between the airborne concentrations of manganese and these biological indicators. METHODS:  Environmental and biological monitoring was performed in a group of 94 employees in a ferroalloy production, who were exposed to manganese (Mn) oxides (MnO(2) and Mn(3)O(4)). The results were compared with those from a control group of 87 subjects not exposed to Mn. RESULTS:  Mn exposure levels ranged between 5 and 740 micrograms/m(3), with arithmetic and geometric mean and median values being 202.6, 97.6, and 150 micrograms/m(3), respectively. Arithmetic and geometric means for Mn in total blood (MnB) were, respectively, 10.3+/-3.8 and 9.7 micrograms/L in the exposed and 5.9+/-1.7 and 5.7 micrograms/L in the controls. For urinary Mn (MnU), arithmetic and geometric means were, respectively, 4.9+/-3.6 and 3. 8 micrograms/L in the exposed and 1.2+/-1.4 and 0.7 micrograms/L in the controls. On a group comparison, a significant relationship was found between high and low exposed subgroups, identified according to Mn atmospheric concentrations (MnA), for both MnB (F value=38.0, P > 0.0001) and MnU (F value=36.1, P > 0.0001). On a linear relationship, a correlation was observed between MnA and MnB (r=0. 34; r(2)=0.112; P=0.001), whereas no association was found between MnA and MnU. A significant relationship emerged also between MnB and MnU (r=0.48, r(2)=0.23, P < 0.0001). No association was observed between an index of cumulative exposure and the biological indicators of exposure. CONCLUSIONS:  These results confirm that MnB and MnU can discriminate groups of occupationally exposed workers from groups of nonexposed subjects. MnB is also related to the intensity of external exposure on a linear relationship, but given a high variability, it is not suitable for individual biological monitoring. Therefore, further research should focus on more accurate biomarkers of Mn exposure.


Bone development in the albino rat on a low manganese diet
            (Barnes et al., 1941) Download
Summary We have not been able to demonstrate any abnormal tibia development in the albino rat raised on a diet low in manganese, provided the rat is normal at 21 days of age. In this respect the rat differs from the chick, at least in being much less sensitive to a low manganese diet. Only 2 cases of abnormal tibias have appeared in a total of 16 rats, born of females reared on a low manganese diet. Our limited data on rats from females reared on a low manganese diet suggest that the growth of the female is impaired, while that of the male …

Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders.
            (Bryan and Bowman, 2017) Download
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.


Association of Serum Manganese Levels with  Alzheimer's Disease and Mild Cognitive Impairment:  A Systematic Review and Meta-Analysis.
            (Du et al., 2017) Download
Manganese (Mn) is one of the most studied environmental heavy metals linked to Alzheimer's disease (AD). However, it remains unclear whether serum Mn levels are associated with AD and mild cognition impairment (MCI, a prodromal stage of AD). We conducted a metaanalysis to analyze the serum Mn levels in patients with AD and MCI. A systematic database search of PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) identified 17 studies, including 836 cases and 1254 health controls (HC). Random-effects meta-analysis showed that patients with AD had significantly reduced serum Mn levels compared with HC subjects (SMD = -0.39; 95% CI (-0.71, -0.08); p = 0.015). MCI individuals had a tendency toward reduced serum Mn levels compared with HC subjects (SMD = -0.31; 95% CI (-0.70, 0.08); p = 0.117). A significant decrease in serum Mn levels was found in patients with cognitive impairment (including both AD patients and MCI patients) (SMD = -0.37, 95% CI (-0.60; -0.13); p = 0.002). Finally, no significant differences were observed between AD and MCI patients in serum levels (SMD = 0.24; 95% CI (-0.23, 0.72); p = 0.310). Our findings show that the serum Mn levels are lower in AD patients, and Mn deficiency may be a risk factor for AD.

Insulin Sensitivity To Trace Metals (Chromium, Manganese) In Type 2 Diabetic Patients And Non Diabetic Individuals.
            (Hajra et al., 2016) Download
BACKGROUND:  Diabetes mellitus constitutes one of the most important problems in developing and non-developing countries. The purpose of the study to estimate the concentrations of Chromium and Manganese in diabetic and non-diabetic population of Hazara division. The cross sectional comparative study was carried out on one hundred blood samples of Type 2 Diabetic patients collected non-randomly from Ayub Teaching Hospital and one hundred normal healthy controls from Women Medical College Abbottabad from September 2014 to April 2015. METHODS:  The study included two hundred subjects. Among them 100 were diabetic and 100 non diabetic respectively. The blood samples were collected from Ayub Medical College, Abbottabad. The serum Chromium and Manganese levels were determined by Atomic Absorption spectrophotometer. RESULTS:  Serum Chromium and Manganese levels were decreased in diabetic and increased in non-diabetic patients. CONCLUSIONS:  Low serum level of Chromium and manganese were found in diabetic patients as compare to non-diabetic individuals.


Manganese Inhibits Viability of Prostate Cancer Cells.
            (Hernroth et al., 2018) Download
BACKGROUND/AIM:  Androgen deprivation therapy is usually in the initial phase a successful treatment for prostate cancer but eventually most patients develop androgen-independent metastatic disease. This study investigated if manganese (Mn) reduces viability of prostate cancer via induction of apoptosis. MATERIALS AND METHODS:  The prostate cancer cell lines PC3, DU145 and LNCaP underwent dose- and time-dependent screening of viability, analyzed by the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Flow cytometry was used for the cell-cycle and apoptosis analyses. Intracellular Mn concentration was measured using inductively coupled plasma-mass spectrometry. RESULTS:  At Mn concentrations of 200-1000 μM, the effect on viability was most pronounced in PC3 followed by LNCaP cells. These cell lines also showed higher intracellular concentration of Mn compared to DU145. In all cell lines, Mn increased the proportion of cells arrested in the G CONCLUSION:  To our knowledge, this is the first report demonstrating Mn as a potential agent in prostate cancer therapy.

Altered Metabolism of Blood Manganese Is Associated with Low Levels of Hemoglobin in Patients with Chronic Kidney Disease.
            (Kim et al., 2017) Download
Blood manganese (Mn) level has been reported to be higher in patients with anemia or iron deficiency. The purpose of this study was to analyze the relationship between blood Mn level and anemia in patients with chronic kidney disease (CKD). A total of 334 patients with CKD who were not treated with dialysis were included in this study. Blood Mn level and serum markers regarding anemia, renal function, and nutrition were measured and analyzed. Median blood Mn level was 8.30 (interquartile range(IQR): 5.27-11.63) μg/L. Univariate linear regression showed that blood Mn level was correlated with age (β = -0.049, p < 0.001), smoking (β = -1.588, p = 0.009), hypertension (β = -1.470, p = 0.006), serum total iron-binding capacity (TIBC) (β = 0.025, p < 0.001), serum transferrin (β = 0.029, p < 0.001), and estimated glomerular filtration rate (eGFR; β = 0.036, p < 0.001). Results of multiple linear regression analysis showed that beta coefficient of hemoglobin was 0.847 (p < 0.001) for blood Mn level in all participants after controlling for covariates, including gender, age, body mass index, smoking, diabetes, hypertension, and eGFR. Multivariate Poisson regression analysis with robust variance after adjusting for gender, age, smoking, hypertension, diabetes, eGFR, and nutritional markers showed that higher blood Mn level (per 1 μg/L increase) was associated with decreased prevalence of anemia (PR 0.974, 95% CI: 0.957 to 0.992, p = 0.005). Taken together, our results demonstrate that blood Mn level is positively associated with hemoglobin level in CKD patients. This might provide important information in the understanding of the pathogenesis of CKD-related anemia.


Magnesium, zinc, and chromium levels in children, adolescents, and young adults with type 1 diabetes.
            (Lin et al., 2016) Download
BACKGROUND & AIMS:  Several trace elements are involved in insulin signal transduction and glucose metabolism. Our aim for this present study was to determine the levels of three important elements-magnesium, chromium, and zinc-as well as one oxidative stress marker-malondialdehyde (MDA)-in young type 1 diabetic patients at different periods of their growth, and to realize the relationships between trace elements, oxidative stress, and growth stages. METHODS:  A total of 88 patients with type 1 diabetes mellitus in different growth stages and 76 gender- and age-matched healthy subjects were included in this study. The levels of MDA were measured through HPLC using a C-18 column. Zinc, magnesium, and chromium concentrations in serum were assessed using atomic absorption spectrophotometry. RESULTS:  We found higher levels of blood malondialdehyde (MDA; p < 0.001), significantly lower levels of magnesium (p < 0.001), and no differences in zinc and chromium levels (p = 0.153 and 0.515, respectively) in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% (3/88) of younger diabetic subjects exhibited hypomagnesemia; similar results were obtained when comparing different subgroups: children, adolescents, and adults. We also observed no differences in the levels of the three elements between the genders and among the growth stages (p > 0.05) of the diabetic subjects. There were no correlations between the three trace elements and HbA1C, diabetes duration, and insulin dose/BMI (all p > 0.05), but there was a significant difference between zinc levels and insulin dose/BMI (p = 0.043) in the diabetic patients. CONCLUSIONS:  We found elevated blood MDA, decreased magnesium, and no changes in zinc and chromium levels in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% of younger diabetic subjects exhibited hypomagnesemia. Whether magnesium supplementation is suitable for improving insulin sensitivity and decreasing oxidative stress and inflammation will require confirmation through additional studies.

Prolactin is a peripheral marker of manganese neurotoxicity.
            (Marreilha Dos Santos et al., 2011) Download
UNLABELLED:  Excessive exposure to Mn induces neurotoxicity, referred to as manganism. Exposure assessment relies on Mn blood and urine analyses, both of which show poor correlation to exposure. Accordingly, there is a critical need for better surrogate biomarkers of Mn exposure. The aim of this study was to examine the relationship between Mn exposure and early indicators of neurotoxicity, with particular emphasis on peripheral biomarkers. Male Wistar rats (180-200g) were injected intraperitoneally with 4 or 8 doses of Mn (10mg/kg). Mn exposure was evaluated by analysis of Mn levels in brain and blood along with biochemical end-points (see below). RESULTS:  Brain Mn levels were significantly increased both after 4 and 8 doses of Mn compared with controls (p<0.001). Blood levels failed to reflect a dose-dependent increase in brain Mn, with only the 8-dose-treated group showing significant differences (p<0.001). Brain glutathione (GSH) levels were significantly decreased in the 8-dose-treated animals (p<0.001). A significant and dose-dependent increase in prolactin levels was found for both treated groups (p<0.001) compared to controls. In addition, a decrease in motor activity was observed in the 8-dose-treated group compared to controls. CONCLUSIONS:  (1) The present study demonstrates that peripheral blood level is a poor indicator of Mn brain accumulation and exposure; (2) Mn reduces GSH brain levels, likely reflecting oxidative stress; (3) Mn increases blood prolactin levels, indicating changes in the integrity of the dopaminergic system. Taken together these results suggest that peripheral prolactin levels may serve as reliable predictive biomarkers of Mn neurotoxicity.

Multiple metals predict prolactin and thyrotropin (TSH) levels in men.
            (Meeker et al., 2009) Download
Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated with arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.


Manganese as a Possible Factor Influencing the Occurrence of Lameness in Pigs.
            (Miller and Keith, 1940) Download
Impairment of the normal movement of the legs frequently occurs in swine. This condition is variously termed lameness, stiffness, posterior paralysis or incoordination, depending on its severity and etiology. A characteristic stiffness occurs in rickets in pigs, a condition in which there is abnormal bone development. Incoordination occurs in pigs as the result of vitamin A deficiency, in which there are degenerative changes in the central nervous system. In addition, however, lameness of one type or another occurs in some instances in which …

U-Shaped Association between Plasma Manganese Levels and Type 2 Diabetes.
            (Shan et al., 2016) Download
BACKGROUND:  Manganese is both an essential element and a known toxicant, and it plays important roles in many mechanisms in relation to type 2 diabetes (T2D). However, epidemiological studies of this relationship are rare. OBJECTIVE:  We investigated the association between plasma manganese and newly diagnosed T2D as well as whether the association could be modified by manganese superoxide dismutase (MnSOD) polymorphisms. METHODS:  We conducted a case-control study of 3,228 participants in China: 1,614 T2D patients and 1,614 controls. Concentrations of plasma magnesium were measured, and all participants were genotyped for the MnSOD Val16Ala polymorphism (rs4880). RESULTS:  A U-shaped association was observed between plasma manganese and T2D, with increased odds ratios (ORs) in relation to either low or high plasma manganese levels. Compared with the middle tertile, the multivariate-adjusted ORs [95% confidence intervals (CIs)] of T2D associated with the lowest tertile and the highest tertile of plasma manganese were 1.89 (1.53, 2.33) and 1.56 (1.23, 1.97), respectively. In spline analysis, the U-shaped association was consistently indicated, with the lowest odds of T2D at the plasma manganese concentration of 4.95 μg/L. Minor allele frequencies (C allele) of the MnSOD Val16Ala polymorphism (rs4880) in the normal glucose tolerance (NGT) and the T2D groups were 13.57% and 14.50%, respectively. The MnSOD rs4880 polymorphism was not associated with T2D, and no interaction was found between plasma manganese and the MnSOD rs4880 polymorphism in relation to T2D. CONCLUSIONS:  Our results suggested a U-shaped association between plasma manganese and T2D; both low and high levels of plasma manganese were associated with higher odds of newly diagnosed T2D. The U-shaped association was not modified by the MnSOD rs4880 polymorphism. Citation: Shan Z, Chen S, Sun T, Luo C, Guo Y, Yu X, Yang W, Hu FB, Liu L. 2016. U-shaped association between plasma manganese levels and type 2 diabetes. Environ Health Perspect 124:1876-1881;


Redox dynamics of manganese as a mitochondrial life-death switch.
            (Smith et al., 2017) Download
Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca+2-dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause "manganism", a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H2O2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch.

The effect of deficiencies of manganese and copper on osteoinduction and on resorption of bone particles in rats.
            (Strause et al., 1987) Download
Subcutaneous implantation of devitalized demineralized bone powers (DBP) and mineral-containing bone particles (BP) into rats raised on either a control (C), low manganese and low copper (L), or manganese-deplete (D) diet, allowed the separate evaluation of bone formation and of bone resorption, respectively. DBP failed to induce chondrogenesis or osteogenesis in D rats. Cartilage formation was delayed in the L rats compared to C rats. There was significantly less resorption of BP by L and D rats than C rats. These results show multiple cellular effects of long-term manganese (Mn) and copper (Cu) deficiencies on bone metabolism including decreased osteogenesis and a decrease in osteoclast activity.


Association between urinary manganese and blood pressure: Results from National Health and Nutrition Examination Survey (NHANES), 2011-2014.
            (Wu et al., 2017) Download
Manganese is a trace mineral required for metabolism, growth and tissue formation, and reproduction. It is mainly obtained through food and water, as well as through occupational exposure. This study used data from National Health and Nutrition Examination Survey, combining the 2011-12 and 2013-14 cycles. We conducted linear regression analyses on urinary manganese and blood pressure. Significant negative associations (p<0.01) between urinary manganese and both systolic and diastolic blood pressure existed after adjusting for age, sex, body mass index, race/ethnicity, and status of taking antihypertensive medication. These results indicate that urinary manganese may play some role in blood pressure and protecting against hypertension, a major risk factor for cardiovascular disease.



Apostoli, P, R Lucchini, and L Alessio (2000), ‘Are current biomarkers suitable for the assessment of manganese exposure in individual workers’, Am J Ind Med, 37 (3), 283-90. PubMed: 10642418
Barnes, LRL, G Sperling, and LA Maynard (1941), ‘Bone development in the albino rat on a low manganese diet’, Proc Soc Exp Biol Med, 562. PubMed:
Bryan, MR and AB Bowman (2017), ‘Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders.’, Adv Neurobiol, 18 113-42. PubMed: 28889265
Du, K, et al. (2017), ‘Association of Serum Manganese Levels with  Alzheimer’s Disease and Mild Cognitive Impairment:  A Systematic Review and Meta-Analysis.’, Nutrients, 9 (3), PubMed: 28273828
Hajra, B, et al. (2016), ‘Insulin Sensitivity To Trace Metals (Chromium, Manganese) In Type 2 Diabetic Patients And Non Diabetic Individuals.’, J Ayub Med Coll Abbottabad, 28 (3), 534-36. PubMed: 28712229
Hernroth, B, et al. (2018), ‘Manganese Inhibits Viability of Prostate Cancer Cells.’, Anticancer Res, 38 (1), 137-45. PubMed: 29277766
Kim, M, et al. (2017), ‘Altered Metabolism of Blood Manganese Is Associated with Low Levels of Hemoglobin in Patients with Chronic Kidney Disease.’, Nutrients, 9 (11), PubMed: 29077007
Lin, CC, et al. (2016), ‘Magnesium, zinc, and chromium levels in children, adolescents, and young adults with type 1 diabetes.’, Clin Nutr, 35 (4), 880-84. PubMed: 26096861
Marreilha Dos Santos, AP, et al. (2011), ‘Prolactin is a peripheral marker of manganese neurotoxicity.’, Brain Res, 1382 282-90. PubMed: 21262206
Meeker, JD, et al. (2009), ‘Multiple metals predict prolactin and thyrotropin (TSH) levels in men.’, Environ Res, 109 (7), 869-73. PubMed: 19595304
Miller, RC and TB Keith (1940), ‘Manganese as a Possible Factor Influencing the Occurrence of Lameness in Pigs.’, Proc R Soc Med, 45 50. PubMed:
Shan, Z, et al. (2016), ‘U-Shaped Association between Plasma Manganese Levels and Type 2 Diabetes.’, Environ Health Perspect, 124 (12), 1876-81. PubMed: 27258818
Smith, MR, et al. (2017), ‘Redox dynamics of manganese as a mitochondrial life-death switch.’, Biochem Biophys Res Commun, 482 (3), 388-98. PubMed: 28212723
Strause, L, P Saltman, and J Glowacki (1987), ‘The effect of deficiencies of manganese and copper on osteoinduction and on resorption of bone particles in rats.’, Calcif Tissue Int, 41 (3), 145-50. PubMed: 3117341
Wu, C, JG Woo, and N Zhang (2017), ‘Association between urinary manganese and blood pressure: Results from National Health and Nutrition Examination Survey (NHANES), 2011-2014.’, PLoS One, 12 (11), e0188145. PubMed: 29141052