Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP.

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO-) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•-) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

Positive association between dietary manganese intake and new-onset hypertension: A nationwide cohort study in China.

BACKGROUND AND AIM: To date, few studies have investigated the association between dietary manganese intake and the risk of hypertension, so the prospective relationship of dietary manganese intake and new-onset hypertension remains uncertain. We aimed to investigate the association between dietary manganese intake and the risk of new-onset hypertension in the general Chinese population. METHODS AND RESULTS: This prospective cohort study included 12,177 participants who were free of hypertension at baseline from China Health and Nutrition Survey (CHNS). Dietary intake was measured by 3 consecutive 24-h dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by a physician or under antihypertensive treatment during the follow-up. During a median follow-up duration of 6.1 years, 4269 (44.9 per 1000 person-years) participants developed new-onset hypertension. Overall, there was a positive association between dietary manganese intake and new-onset hypertension. The adjusted HRs (95%CIs) of new-onset hypertension were 1.00 (reference), 0.97 (0.87, 1.08), 1.24 (1.10, 1.39) and 1.75 (1.52, 2.01) across the quartiles of dietary manganese intake, respectively. Accordingly, a significantly higher risk of new-onset hypertension (HR, 1.38; 95%CI: 1.27, 1.50) was found in participants in quartiles 3-4 of dietary manganese intake (≥6.0 mg/day), compared with those in quartiles 1-2 (<6.0 mg/day). CONCLUSIONS: In the general Chinese population, dietary manganese intake was positively associated with the risk of new hypertension, independent of sodium intake and other important covariates.

Blood manganese and non-alcoholic fatty liver disease in a high manganese exposure area in China.

BACKGROUND AND AIMS: Manganese (Mn) deficiency and intoxication may affect nonalcoholic fatty liver disease (NAFLD) risk differently. We aimed to explore the association between blood Mn and NAFLD in an area with high Mn exposure in drinking water. METHODS: We conducted a case-control study among 1407 patients with NAFLD and 1774 sex- and age-matched healthy controls in a physical examination population in Zhoushan hospital, Zhejiang province in China. We used the restricted cubic splines method to investigate the dose-response relationship. Logistic regression models were applied to determine the risk of NAFLD, and severity of NAFLD. RESULTS: The blood Mn concentration was higher in the NAFLD group than in the control group in women (16.1 ± 6.2 µg/L vs. 14.7 ± 6.4 µg/L, P = 0.022) and men (14.5 ± 6.3 µg/L vs. 13.6 ± 6.8 µg/L, P < 0.001). We found an inverted L shape relationship between blood Mn and NAFLD in both women and men. Compared to the lowest quartile, the adjusted odds ratio (OR) and 95% confidence interval (CI) of NAFLD for the highest quartile group was 1.646(1.222,2.217), 1.494(1.082,2.061), and 3.146(1.285,7.701) for the total population, men, and women. The positive relationship was only observed in those with fibrosis-4 score < 1.30 and normal alanine transaminase. Stratified analysis showed an interaction between smoking (P = 0.073), alcohol drinking (P = 0.013), and Mn, with a more prominent effect on the NAFLD in the never-smokers (OR = 2.153, 95% CI 1.408-3.290) and drinkers (OR = 2.596, 95% CI 1.608-4.191). CONCLUSION: Higher blood Mn is associated with an elevated NAFLD risk in the high Mn exposure areas, especially in nonsmokers and drinkers. Further studies are needed to verify this result in the areas with high Mn exposure.

Associations of ambient manganese exposure with brain gray matter thickness and white matter hyperintensities.

Manganese (Mn) exposure is associated with increased risks of dementia and cerebrovascular disease. However, evidence regarding the impact of ambient Mn exposure on brain imaging markers is scarce. We aimed to investigate the association between ambient Mn exposure and brain imaging markers representing neurodegeneration and cerebrovascular lesions. We recruited a total of 936 adults (442 men and 494 women) without dementia, movement disorders, or stroke from the Republic of Korea. Ambient Mn concentrations were predicted at each participant's residential address using spatial modeling. Neurodegeneration-related brain imaging markers, such as the regional cortical thickness, were estimated using 3 T brain magnetic resonance images. White matter hyperintensity volume (an indicator of cerebrovascular lesions) was also obtained from a certain number of participants (n = 397). Linear regression analyses were conducted after adjusting for potential confounders. A log-transformed ambient Mn concentration was associated with thinner parietal (ß = -0.02 mm; 95% confidence interval [CI], -0.05 to -0.01) and occipital cortices (ß = -0.03 mm; 95% CI, -0.04 to -0.01) after correcting for multiple comparisons. These associations remained statistically significant in men. An increase in the ambient Mn concentration was also associated with a greater volume of deep white matter hyperintensity in men (ß = 772.4 mm3, 95% CI: 36.9 to 1508.0). None of the associations were significant in women. Our findings suggest that ambient Mn exposure may induce cortical atrophy in the general adult population.

Dietary Manganese Intake and Risk of Liver Cancer in Japanese Men and Women: The JACC Study.

We explored the association between dietary manganese intake and the risk of liver cancer in 14,517 men and 21,583 women who participated in the Japan Collaborative Cohort Study for Cancer Risk Assessment. We assessed dietary manganese intake using a food frequency questionnaire and incident liver cancer by reviewing cancer registries. According to manganese intake, we estimated the liver cancer risk by Cox regression analyses. During the 513,657 person-year follow-ups within a median of 17.9 years of 36,100 participants, there were 239 incident cases of liver cancer. The multivariable hazard ratio (HR) (95% confidence interval [CI]; P-trend) for liver cancer risk in the highest vs. the lowest quintiles of dietary manganese intake was 0.56 (0.32-0.99; 0.04) in men and 1.16 (0.56-2.40; 0.79) in women; P-interaction = 0.06. The history of liver disease modified the observed association in men (P-interaction = 0.02), in which the multivariable HR (95%CI) of liver cancer risk comparing the highest vs. lowest quintiles of dietary manganese intake was 0.32 (0.14-0.74) in Japanese men without a history of liver disease, while it was 1.54 (0.62-3.79) in men with a history of liver disease. In conclusion, a higher dietary manganese intake was associated with a lower risk of liver cancer in men without a history of liver disease.

Welder's lung and brain MRI findings in manganese-exposed welders.

BACKGROUND: Biomarkers of manganese (Mn) exposure and manganism are poorly understood. Blood Mn levels are often used to assess exposure, while brain Mn accumulation may be demonstrated by pallidal hyperintensity at magnetic resonance imaging (MRI). Mn-containing electrodes used in manual metal arc welding may be associated with the welder's lungs. METHODS: A cross-sectional study was set up to compare T1 intensity in basal ganglia at MRI and Mn blood levels in subjects with or without pneumoconiosis. Clinical, radiological, pulmonary function and laboratory parameters were assessed among 154 welders referred to our hospital for suspected pulmonary pathology. RESULTS: The study group included 123 male welders with pneumoconiosis (79.9%) and 31 welders without pulmonary damage (20.1%). The cases without pneumoconiosis were younger (38.5±6.6 vs 42.1±7.1, p=0.012). Cases with pneumoconiosis had blood lower Mn levels [13.5 (10-21)] as compared to those without pneumoconiosis [18.5 (7.8- 34)], p=0.035. In the same groups, the cases with high blood Mn levels were 49 (39.8%) and 18 (58.1%) p= 0.052, respectively. Brain MRI hyperintensity was found in 86 (55.8%) subjects with welder's lung 63 (51.2) but also in 23 (74.2) individuals without welder's lung. MRI hyperintensity in basal ganglia was significantly related to high blood Mn (p<0.005). CONCLUSION: This is the first study evaluating blood Mn levels of welders and their correlation with pulmonary and neurological effects. Poor working conditions may be associated with exposure to Mn and fibrogenic fumes leading to chronic lung diseases and hyperintensity in brain MRI suggesting Mn accumulation.

Interaction between manganese and SLC6A3 genetic polymorphisms in relation to dyslexia.

BACKGROUND: Excessive exposure to manganese is harmful for neurodevelopment, causing intellectual disability, decreased cognitive ability and diminished language quotients. However, little is known about the link between manganese, genetic susceptibility and the risk of dyslexia. We aim to examine the association between manganese exposure and dyslexia and to test whether the SLC6A3 gene would modify this relationship. METHODS: A case-control study was conducted among 239 dyslexic children and 230 controls in China. Urinary manganese concentrations were assessed by inductively coupled plasma mass spectrometry (ICP-MS). Two single nucleotide polymorphisms (rs2975226 and rs27072) in the SLC6A3 gene were selected. RESULTS: The rs2975226 polymorphism was associated with dyslexia within the recessive model (OR = 1.74, 95 % CI = 1.06-2.86) and the additive model (OR = 1.69, 95 % CI = 1.10-2.61) after multivariate adjustment. Modification effects on the relationship of manganese levels in urine with the risk of dyslexia were suggested in rs27072 (P-value for interaction = 0.003). Furthermore, the highest quartile of urinary manganese was found to have a 3.87-fold (95 % CI = 1.39-10.74) elevated dyslexia risk compared with the lowest quartile among the rs27072 mutation carriers. CONCLUSIONS: The rs2975226 polymorphism was associated with dyslexia and manganese exposure could interact with the rs27072 mutation to increase the risk of dyslexia.

HIF-1α upregulation exerts the antagonistic effect against angiogenesis inhibition in manganese deficiency-induced tibial dyschondroplasia of broiler chicks.

Manganese (Mn) is an essential microelement for broiler breeding and its deficiency causes tibial dyschondroplasia (TD). Tibial growth plate (TGP) development and metaphyseal vascularization are crucial for tibia growth in fast-growing broiler chickens, but their roles in Mn deficiency-induced TD in chicks remain unclear. This study was designed to clarify this issue. A total of 36 one-day-old broilers were divided into the control group and Mn-deficiency (Mn-D) group, which were fed with a standard diet (60 mg Mn/kg) and Mn deficiency diet (22 mg Mn/kg) for 42 days, respectively. TGP and proximal tibial metaphysis were collected to perform the related assays. This study found that Mn deficiency decreased the tibia length and TGP thickness in the TD model. Also, Mn deficiency increased the irregular and white tibial dyschondroplasia lesions (TDL) region under the TGP, and reduced the expression levels of vascular endothelial growth factor (VEGF) and macrophage migration inhibitory factor (MIF). Combined with histological assessment, it was suggested that Manganese deficiency inhibited angiogenesis in the proximal tibial metaphysis. Meanwhile, Mn deficiency enhanced the expression levels of hypoxia-inducible factor-1 α (HIF-1α), autophagy-related protein 5 (ATG5), and microtubule-associated protein 1 light chain 3 ß (LC3-II) in TGP, but decreased the expression level of SQSTM1 (P62), which suggested that autophagy was activated during this process. Collectively, these data indicate that HIF-1α up-regulation and concurrent autophagy activation exert a protective effect against Mn deficiency-induced angiogenesis inhibition, which may provide useful guidance to prevent TD in broilers.

Gray matter microstructural alterations in manganese-exposed welders: a preliminary neuroimaging study.

OBJECTIVES: Chronic occupational manganese (Mn) exposure is characterized by motor and cognitive dysfunction. This study aimed to investigate structural abnormalities in Mn-exposed welders compared to healthy controls (HCs). METHODS: Thirty-five HCs and forty Mn-exposed welders underwent magnetic resonance imaging (MRI) scans in this study. Based on T1-weighted MRI, the voxel-based morphometry (VBM), structural covariance, and receiver operating characteristic (ROC) curve were applied to examine whole-brain structural changes in Mn-exposed welders. RESULTS: Compared to HCs, Mn-exposed welders had altered gray matter volume (GMV) mainly in the medial prefrontal cortex, lentiform nucleus, hippocampus, and parahippocampus. ROC analysis indicated the potential highest classification power of the hippocampus/parahippocampus. Moreover, distinct structural covariance patterns in the two groups were associated with regions, mainly including the thalamus, insula, amygdala, sensorimotor area, and middle temporal gyrus. No significant relationships were found between the findings and clinical characteristics. CONCLUSIONS: Our findings showed Mn-exposed welders had changed GMV and structural covariance patterns in some regions, which implicated in motivative response, cognitive control, and emotional regulation. These results might provide preliminary evidence for understanding the pathophysiology of Mn overexposure. KEY POINTS: • Chronic Mn exposure might be related to abnormal brain structural neural mechanisms. • Mn-exposed welders had morphological changes in brain regions implicated in emotional modulation, cognitive control, and motor-related response. • Altered gray matter volume in the hippocampus/parahippocampus and putamen might serve as potential biomarkers for Mn overexposure.

Elevated whole blood manganese is associated with impaired cognition in older adults, NHANES 2013-2014 cycle.

Manganese (Mn) is found in many commonly consumed foods and therefore its deficiency is rare. However, excessive exposure to Mn from contaminated drinking water as well as occupational exposure can result in toxic accumulation in the brain, which has been associated with impaired neurological function. The objective of this study was to examine the NHANES 2013 - 2014 cycle focusing on the relationship between whole blood Mn concentrations and cognitive tests including working memory, word recall and sustained attention in elderly adults (aged 60 years and older). The different cognitive function test scores were used in principal component analysis to develop a composite score. The relationship between blood Mn concentration and cognitive function (principal component score and Digit Symbol Substitution Test (DSST)) were investigated using regression analysis. Median (95% CI) concentrations of blood Mn, serum copper, and serum iron were 8.76 (8.5, 9.1) µg/L, 114.9 µg/dL (110.3, 118.1), and 80 (78, 83) µg/dL, respectively. We found that among individuals in the highest quartile of blood Mn concentration (>11.18 µg/L), there was an inverse association between blood Mn and cognitive function as assessed using DSST (ß (95% CI) = -0.76 (-1.19 to -0.33); p = 0.003), while the inverse relationship with the composite score trended towards significance (ß (95% CI) = -0.04 (-0.08 to 0.00); p = 0.053). These findings suggest that having elevated blood Mn ay be associated with cognitive decline in aging and warrants further studies on how the different sources of Mn may contribute to this outcome.

Environmental manganese exposure and cognitive control in a South African population.

OBJECTIVE: To characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population. METHODS: We administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PM2.5-Mn to confirm community exposure differences. RESULTS: Compared to Ethembalethu residents, Meyerton residents' test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton <10 years. Mean PM2.5-Mn at a long-term fixed site in Meyerton was 203 ng/m3 and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Exposure to common-use pesticides, manganese, lead, and thyroid function among pregnant women from the Infants' Environmental Health (ISA) study, Costa Rica.

BACKGROUND: Pesticides and metals may disrupt thyroid function, which is key to fetal brain development. OBJECTIVES: To evaluate if current-use pesticide exposures, lead and excess manganese alter free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) concentrations in pregnant women from the Infants' Environmental Health Study (ISA). METHODS: At enrollment, we determined women's (n = 400) specific-gravity corrected urinary pesticide (µg/L) metabolite concentrations of mancozeb (ethylene thiourea (ETU)), pyrimethanil, thiabendazole, chlorpyrifos, synthetic pyrethroids, and 2,4-D. We also measured manganese hair (MnH) (µg/g) and blood (MnB) (µg/L), and blood lead (PbB) (µg/L) concentrations. To detect an immediate and late effect on thyroid homeostasis, we determined TSH, FT4 and FT3 in serum obtained at the same visit (n = 400), and about ten weeks afterwards (n = 245). We assessed associations between exposures and outcomes with linear regression and general additive models, Bayesian multivariate linear regression, and Bayesian kernel machine regression. RESULTS: About 80%, 94%, and 100% of the women had TSH, FT4, and FT3 within clinical reference ranges, respectively. Women with higher urinary ETU, and pyrimethanil-metabolites, had lower FT4: ß = -0.79 (95%CI = -1.51, -0.08) and ß = -0.29 (95%CI = -0.62, -0.03), respectively, for each tenfold increase in exposure. MnB was positively associated with FT4 (ß = 0.04 (95%CI = 0.00, 0.07 per 1 µg/L increase), and women with high urinary pyrethroid-metabolite concentrations had decreased TSH (non-linear effects). For the late-effect analysis, metabolites of pyrethroids and chlorpyrifos, as well as MnH, and PbB were associated decreased TSH, or increased FT4 and/or FT3. DISCUSSION: Mancozeb (ETU) and pyrimethanil may inhibit FT4 secretion (hypothyroidism-like effect), while chlorpyrifos, pyrethroids, MnB, MnH, PbB and Mn showed hyperthyroidism-like effects. Some effects on thyroid homeostasis seemed to be immediate (mancozeb (ETU), pyrimethanil, MnB), others delayed (chlorpyrifos, MnH, PbB), or both (pyrethroids), possibly reflecting different mechanisms of action.

Manganese transport in mammals by zinc transporter family proteins, ZNT and ZIP.

Manganese (Mn) is an essential trace element required for various biological processes. However, excess Mn causes serious side effects in humans, including parkinsonism. Thus, elucidation of Mn homeostasis at the systemic, cellular, and molecular levels is important. Many metal transporters and channels can be involved in the transport and homeostasis of Mn, and an increasing body of evidence shows that several zinc (Zn) transporters belonging to the ZIP and ZNT families, specifically, ZNT10, ZIP8, and ZIP14, play pivotal roles in Mn metabolism. Mutations in the genes encoding these transporter proteins are associated with congenital disorders related to dysregulated Mn homeostasis in humans. Moreover, single nucleotide polymorphisms of ZIP8 are associated with multiple clinical phenotypes. In this review, we discuss the recent literature on the structural and biochemical features of ZNT10, ZIP8, and ZIP14, including transport mechanisms, regulation of expression, and pathophysiological functions. Because a disturbance in Mn homeostasis is closely associated with a variety of phenotypes and risk of human diseases, these transporters constitute a significant target for drug development. An understanding of the roles of these key transporters in Mn metabolism should provide new insights into pharmacological applications of their inhibitors and enhancers in human diseases.

Biomonitoring and bioaccessibility of environmental airborne manganese in relation to motor function in a healthy adult population.

BACKGROUND/AIM: Santander, the capital of Cantabria, Spain (172,000 inhabitants) is 7 km from an industrial emission source (IES) of Mn located in a 10,000 inhabitants town (Maliaño) (annual air Mn arithmetic mean = 231.8 ng/m3; reference WHO guideline = 150 ng/m3). Our objective was to compare the motor function of adult healthy volunteers living in both places. METHODS: Cross-sectional study analyzing 130 consecutive participants. Exposure to Mn was assessed in terms of source distance from the IES, by Personal Environmental Monitors (PEMs) carried for 24 h by participants consisting of a portable impactor connected to a personal pump, and by biomarkers (blood, hair and fingernails). The impactor allowed the separation of fine (PM2.5) and coarse (PM10-2.5) particles and for each particle size in-vitro bioaccessibility tests with biologically active fluids were performed to separate the soluble (bioaccessible) from the insoluble (non-bioaccessible) fraction. Mean Differences (MDs) adjusted for age, sex, and study level, were obtained for motor function tests results. RESULTS: Regarding Grooved Pegboard, overall mean time to complete the test was 59.31 and 65.27 seconds (Standard Deviation = 10.11 and 11.69) for dominant and nondominant hands respectively. Statistically significant higher times (indicating worse function) were observed when living near the IES in both hands but MDs of only 1.22 and 2.05 seconds were obtained after adjusting for the predefined confounders (p = 0.373 and 0.221 respectively). Regarding Mn levels in their PEMs (in both bioaccessible and non-bioaccessible coarse&fine fractions) higher times were computed in participants with higher levels for the bioaccessible-fine fraction, with a MD that diminished but still yielded statistical significance after controlling for confounding: adjusted MD = 3.01 more seconds; 95%CI (0.44-5.38), p = 0.022. Poorer results were also observed for fingernails levels. Regarding Finger Tapping Test, no statistically significant differences were found with the exception of Mn fingernails levels. CONCLUSIONS: Our results suggest poorer motor function as assessed by Grooved Pegboard test in relation to "proximity to IES", "bioaccessible-fine fraction as determined by PEMs and "Mn fingernails levels". However, our findings were affected by confounding, and only the adjusted MD for the Mn bioaccessible-fine fraction remained of sufficient magnitude to maintain statistical significance.

Rodent hair is a Poor biomarker for internal manganese exposure.

Hair is used as a biomarker of manganese (Mn) exposure, yet there is limited evidence to support its utility to quantify internal vs external Mn exposure. C57BL/6 J mice and Sprague-Dawley rats were exposed in two blocks of 3 subcutaneous injections every 3 days starting on day 0 or 20. The control group received two blocks of saline (vehicle); Treatment A received the first block as Mn (50 mg/kg MnCl2 tetrahydrate), with the second block as either methylmercury (MeHg at 2.6 or 1.3 mg/kg) for mice or vehicle for rats; and Treatment B received Mn for both blocks. Hair was collected on days 0 and 60 from all treatment groups and Mn quantified by inductively coupled plasma-mass spectrometry (ICP-MS) and total Hg by Direct Mercury Analyzer (DMA). No correlation between internal Mn dose and hair Mn was observed, whereas hair Hg was significantly elevated in MeHg exposed vs non-exposed mice. Whole body Mn content at day 60 was quantified postmortem by neutron activation analysis, which detected significantly elevated Mn for Treatment B in mice and rats. Overall, we find no evidence to support the use of hair as a valid biomarker for internal exposure to Mn at a neurotoxic level.

Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.

Multibiomarker approach to assess the magnitude of occupational exposure and effects induced by a mixture of metals.

Metals and metalloids including lead (Pb), arsenic (As) and manganese (Mn) can occur as mixtures in occupational contexts, such as mines. These chemicals are all known to be neurotoxic and provoke changes in heme metabolism also known to induce neurotoxicity. The objective of this work was to propose a multi-biomarker (BM) methodology to screen subjects exposed to the mixture of Pb, As and Mn and assess the severity of their exposure/effects, in an individual basis. The urinary levels of the metals, dela-aminolevulinic acid (ALA) and porphyrins were determined in Portuguese miners and in a control group. The combination of Pb and As urinary levels had the highest capability to identify subjects occupationally exposed to this mixture in mines, as evaluated through Receiver Operating Characteristic (ROC) (A = 98.2%; p < 0.05), allowing that 94.2% of 86 studied subjects were properly identified and the generation of an equation indicating the odd of a subject be considered as exposed to the metal mixture. The combination of urinary ALA and porphyrins revealed to be best one to be applied in the assessment of subjects with high, intermediate, and low magnitudes of exposure/effects, with 95.7% of 46 miners classified correctly according to their severity sub-group and allowing to generate equations, which can be applied in new subjects. The proposed methodology showed a satisfactory performance, evaluating in an integrated manner the magnitude of exposure/effects of the exposed workers, may contributing to improve the control of their health.

Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14-/- Mice.

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14-/- mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14-/- mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.

Depression and anxiety in a manganese-exposed community.

OBJECTIVE: To characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. METHODS: We administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. RESULTS: Meyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. CONCLUSION: Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

Evaluating the risk of manganese-induced neurotoxicity of parenteral nutrition: review of the current literature.

INTRODUCTION: Several diseases and clinical conditions can affect enteral nutrition and adequate gastrointestinal uptake. In this respect, parenteral nutrition (PN) is necessary for the provision of deficient trace elements. However, some essential elements, such as manganese (Mn) may be toxic to children and adults when parenterally administered in excess, leading to toxic, especially neurotoxic effects. AREAS COVERED: Here, we briefly provide an overview on Mn, addressing its sources of exposure, the role of Mn in the etiology of neurodegenerative diseases, and focusing on potential mechanisms associated with Mn-induced neurotoxicity. In addition, we discuss the potential consequences of overexposure to Mn inherent to PN. EXPERT OPINION: In this critical review, we suggest that additional research is required to safely set Mn levels in PN, and that eliminating Mn as an additive should be considered by physicians and nutritionists on a case by case basis in the meantime to avoid the greater risk of neurotoxicity by its presence. There is a need to better define clinical biomarkers for Mn toxicity by PN, as well as identify new effective agents to treat Mn-neurotoxicity. Moreover, we highlight the importance of the development of new guidelines and practice safeguards to protect patients from excessive Mn exposure and neurotoxicity upon PN administration.