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Groundwater poisoning by heavy metals has caused serious health hazards in the exposed population globally. Manganese (Mn) poisoning causing human health hazards is very meagerly reported worldwide. The present research elucidates for the first time the catastrophic effect of manganese causing cancer in the Gangetic plains of Bihar (India). The blood samples of n = 1146 cancer patients were voluntarily obtained for the study, after their consent. Their household water samples were also collected for the study. All the samples were analysed for Mn contamination by Atomic Absorption Spectrophotometer. The study indicates high Mn contamination in the cancer patient blood samples with highest content as 6022 µg/L. Moreover, the cancer patient's household handpump water samples also contained elevated Mn contamination. The correlation coefficient study finds significant association between Mn contamination in blood of cancer patients and their handpump water. The carcinoma group of cancer patients mostly in Stage III & IV had significant Mn contamination in their blood (above WHO/BIS permissible limit). The geospatial study depicts Mn contamination in handpump water in the state of Bihar in correlation with cancer patient's blood samples. This novel finding is being reported in India for the first time, which correlates cancer with handpump drinking water. The long-term Mn exposure could be one of the causative agents for elevating cancer incidences. However, other confounding risk factors cannot be denied., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Occupational exposure to manganese (Mn) primarily occurs through the inhalation of manganese-containing fumes and dust, with welding environments being significant sources of such exposure. Elevated levels of Mn in welding fumes can lead to a neurological syndrome known as manganism. A 28-yr-old male welder with 14 yr of experience, is presenting with complaints of forgetfulness, reasoning disorder, and decreased mental functions persisting for 10 yr. Three months ago, when he started working at the new workplace, he underwent employment screening conducted by the workplace physician. During this screening process, the physician identified a high whole blood Mn level of 25.9 µg/l. The diagnosis of manganism in this patient was established based on exposure to Mn and its compounds, high levels of Mn detected in the whole blood, hyperactive patellar reflexes observed during the physical examination, cranial Magnetic Resonance Imaging (MRI) findings consistent with manganism and complaints reported by the patient that are characteristic of manganism. In this report, the aim is to emphasize the significance of taking a comprehensive occupational history and to draw attention the potential health hazards associated with Mn and its compounds.

Purpose: Welders are more likely to develop neurobehavioral disorders because of their exposure to neurotoxic metals such as manganese. This study aimed to measure the neurobehavioral performance of welders occupationally exposed to manganese at welding enterprises and its relationship with the workplace environment., Methods: It is a comparative cross-sectional study carried out on 130 welders working at 50 welding enterprises in Menoufia governorate, Egypt, compared to 130 non-occupationally exposed controls., Results: It was found that the environments of the studied welding enterprises had levels of respirable dust, manganese, and total welding fumes that exceeded internationally permissible limits. In addition, the mean blood manganese levels were significantly higher among welders (4.16 ± 0.61) than the controls (1.72 ± 0.41). Welders had a significantly higher prevalence of neurological manifestations and lower performance of neurobehavioral tests. Lower neurobehavioral performance among welders was significantly correlated with increased work duration and blood levels in some tests., Conclusion: To lessen the fumes in the breathing zone of workers, it is therefore strongly recommended to regularly wear high-quality personal protective equipment, especially masks, and to ensure proper ventilation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Manganese (Mn) is a heavy metal that occurs widely in nature and has a vital physiological role in growth and development. However, excessive exposure to Mn can cause neurological damage, especially cognitive dysfunction, such as learning disability and memory loss. Numerous studies on the mechanisms of Mn-induced nervous system damage found that this metal targets a variety of metabolic pathways, for example, endoplasmic reticulum stress, apoptosis, neuroinflammation, cellular signaling pathway changes, and neurotransmitter metabolism interference. This article reviews the latest research progress on multiple signaling pathways related to Mn-induced neurological dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metals have been proved to be one of risk factors for chronic kidney disease (CKD) and diabetes, but the effect of mixed metal co-exposure and potential interaction between metals are still unclear. We assessed the urine and whole blood levels of cadmium (Cd), manganese (Mn), lead (Pb), mercury (Hg), and renal function in 3080 adults from National Health and Nutrition Survey (NHANES) (2011-2018) to explore the effect of mixed metal exposure on CKD especially in people with type 2 diabetes mellitus (T2DM). Weighted quantile sum regression model and Bayesian Kernel Machine Regression model were used to evaluate the overall exposure impact of metal mixture and potential interaction between metals. The results showed that the exposure to mixed metals was significantly associated with an increased risk of CKD in blood glucose stratification, with the risk of CKD being 1.58 (1.26,1.99) times in urine and 1.67 (1.19,2.34) times in whole blood higher in individuals exposed to high concentrations of the metal mixture compared to those exposed to low concentrations. The effect of urine metal mixture was elevated magnitude in stratified analysis. There were interactions between urine Pb and Cd, Pb and Mn, Pb and Hg, Cd and Mn, Cd and Hg, and blood Pb and Hg, Mn and Cd, Mn and Pb, Mn and Hg on the risk of CKD in patients with T2DM and no significant interaction between metals was observed in non-diabetics. In summary, mixed metal exposure increased the risk of CKD in patients with T2DM, and there were complex interactions between metals. More in-depth studies are needed to explore the mechanism and demonstrate the causal relationship., (© 2024. The Author(s).)

Competing Interests: None declared.

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 [Ca 4 Mn(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 Ca 4 Mn(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 Ca 4 Mn(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 Ca 4 Mn(DPDP) 5 . The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca 4 Mn(DPDP) 5 may be explained by redox interactions between Pt 2+ and Mn 2+ and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt 2+ presumably leads to oxidation of the Mn 2+ from Ca 4 Mn(DPDP) 5 as well as from Mn 2+ in MnSOD and other endogenous sources. Thereafter, Mn 3+ may be oxidized by peroxynitrite (ONOO - ) into Mn 4+ , 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 (O 2 •- ) 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 Pt 2+ -associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca 4 Mn(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 Pt 2+ -associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt 2+ outcompetes Mn 2+ and endogenous Zn 2+ 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 Pt 2+ by DPDP, which in turn suggests that Mn 2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

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., Competing Interests: Declaration of competing interest The authors report no conflicts., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s).)

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 (β = -0.02 mm; 95% confidence interval [CI], -0.05 to -0.01) and occipital cortices (β = -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 (β = 772.4 mm 3 , 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., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

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.

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.

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 β (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., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

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 (β (95% CI) = -0.76 (-1.19 to -0.33); p = 0.003), while the inverse relationship with the composite score trended towards significance (β (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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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: β = -0.79 (95%CI = -1.51, -0.08) and β = -0.29 (95%CI = -0.62, -0.03), respectively, for each tenfold increase in exposure. MnB was positively associated with FT4 (β = 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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 PM 2.5 -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 PM 2.5 -Mn at a long-term fixed site in Meyerton was 203 ng/m 3 and 10 ng/m 3 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest Both authors declare no competing financial and non-financial interests., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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/m 3 ; reference WHO guideline = 150 ng/m 3 ). 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., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 MnCl 2 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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 PM 2.5 -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 PM 2.5 -Mn concentration was 203 ng/m 3 at a long-term fixed site in Meyerton and 10 ng/m 3 in Ethembalethu., Conclusion: Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

Background: Recent research has uncovered the potential for excess manganese (Mn) intakes causing significant neurotoxic effects for early brain development., Methods: We identified the Mn tolerable intakes (TI) published by the U.S. Institute of Medicine (IOM), World Health Organization (WHO), Agence nationale de sécurité sanitaire (ANSES), and U.S. Environmental Protection Agency (US EPA) and examined the primary studies on which regulatory TIs are based. We converted the TIs to μg of Mn/kg/day using standard assumptions specific to each agency. We estimated μg of Mn/kg/day intakes due to formulas. Using our estimates for formula intakes, weights, and kcal content, we converted regulatory maxima and minima from μg of Mn/100 kcals to estimates of μg of Mn/kg/day., Results: Except for the proposed ANSES TI for drinking water, none of the primary studies on which Mn intake guidelines and regulations are based measured health outcomes. Some infant formulas may exceed the regulatory TIs, especially if prepared with water containing considerable concentrations of Mn (e.g. 250 μg/L), even while meeting national and international regulatory standards or guidelines., Conclusions: Infant formula regulations must be revised to reduce the potential for excess manganese intakes and the practice of manganese supplementation of infant formulas should be ceased., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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.

Scope: Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration., Methods and Results: Chronic co-exposure of C. elegans to Mn and Zn increases metal uptake, exceeding levels of single metal exposures. Supplementation with Mn and/or Zn also leads to an age-dependent increase in metal content, a decline in overall mRNA expression, and metal co-supplementation induced expression of target genes involved in Mn and Zn homeostasis, in particular metallothionein 1 (mtl-1). Studies in transgenic worms reveal that mtl-1 played a prominent role in mediating age- and diet-dependent alterations in metal homeostasis. Metal dyshomeostasis is further induced in parkin-deficient nematodes (Parkinson's disease (PD) model), but this did not accelerate the age-dependent dopaminergic neurodegeneration., Conclusions: A nutritive overdose of Mn and Zn can alter interactions between essential metals in an aging organism, and metallothionein 1 acts as a potential protective modulator in regulating homeostasis., (© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

A review of published articles examining the effects of manganese exposure to workers and community residents shows adverse neurologic outcomes. Innovative biomarkers, including those from neuroimaging, were incorporated into many of these studies to assess both manganese exposure and neurologic outcomes. A variety of health effects were evaluated, including cognitive and motor impairments. Studies of community participants residing near manganese point sources show variability in outcomes, reflecting the complexities of exposure measurement, individual absorption, and assessment of neurologic effects. The aging population provides insight into the impacts of chronic exposure in younger populations., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although prior studies showed a correlation between environmental manganese (Mn) exposure and neurodevelopmental disorders in children, the results have been inconclusive. There has yet been no consistent biomarker of environmental Mn exposure. Here, we summarized studies that investigated associations between manganese in biomarkers and childhood neurodevelopment and suggest a reliable biomarker., Methods: We searched PubMed and Web of Science for potentially relevant articles published until December 31th 2019 in English. We also conducted a meta-analysis to quantify the effects of manganese exposure on Intelligence Quotient (IQ) and the correlations of manganese in different indicators., Results: Of 1754 citations identified, 55 studies with 13,388 subjects were included. Evidence from cohort studies found that higher manganese exposure had a negative effect on neurodevelopment, mostly influencing cognitive and motor skills in children under 6 years of age, as indicated by various metrics. Results from cross-sectional studies revealed that elevated Mn in hair (H-Mn) and drinking water (W-Mn), but not blood (B-Mn) or teeth (T-Mn), were associated with poorer cognitive and behavioral performance in children aged 6-18 years old. Of these cross-sectional studies, most papers reported that the mean of H-Mn was more than 0.55 μg/g. The meta-analysis concerning H-Mn suggested that a 10-fold increase in hair manganese was associated with a decrease of 2.51 points (95% confidence interval (CI), - 4.58, - 0.45) in Full Scale IQ, while the meta-analysis of B-Mn and W-Mn generated no such significant effects. The pooled correlation analysis revealed that H-Mn showed a more consistent correlation with W-Mn than B-Mn. Results regarding sex differences of manganese associations were inconsistent, although the preliminary meta-analysis found that higher W-Mn was associated with better Performance IQ only in boys, at a relatively low water manganese concentrations (most below 50 μg/L)., Conclusions: Higher manganese exposure is adversely associated with childhood neurodevelopment. Hair is the most reliable indicator of manganese exposure for children at 6-18 years of age. Analysis of the publications demonstrated sex differences in neurodevelopment upon manganese exposure, although a clear pattern has not yet been elucidated for this facet of our study.

Objective: To understand the neurotoxic effects of manganese (Mn) exposure on monoaminergic function, utilizing [C]dihydrotetrabenazine (DTBZ) positron emission tomography (PET) to measure vesicular monoamine transporter 2 (VMAT2)., Methods: Basal ganglia and thalamic DTBZ binding potentials (BPND) were calculated on 56 PETs from 41 Mn-exposed workers. Associations between cumulative Mn exposure, regional BPND, and parkinsonism were examined by mixed linear regression., Results: Thalamic DTBZ BPND was inversely associated with exposure in workers with less than 3 mg Mn/m-yrs, but subsequently remained stable. Pallidal DTBZ binding increased in workers with less than 2 mg Mn/m-yrs of exposure, but decreased thereafter. Thalamic DTBZ binding was inversely associated with parkinsonism (P = 0.003)., Conclusion: Mn-dose-dependent associations with thalamic and pallidal DTBZ binding indicate direct effects on monoaminergic VMAT2. Thalamic DTBZ binding was also associated with parkinsonism, suggesting potential as an early biomarker of Mn neurotoxicity.

Background: Manganese, an essential micronutrient, has been found in lower concentrations among women with preeclampsia in cross-sectional and case-control studies without establishment of a temporal relationship., Methods: We evaluated the prospective association of manganese (in red blood cells) in first trimester of pregnancy with incidence of preeclampsia (ascertained by reviewing medical records) among 1,312 women in eastern Massachusetts (Project Viva, 1999-2002). We used log-binomial regression to examine the manganese-preeclampsia relationship, adjusting for maternal age, race/ethnicity, parity, prepregnancy body mass index, blood pressure, and hematocrit., Results: The median (25th, 75th percentile) manganese concentrationin red blood cells was 16.2 ng/g (13.1, 20.4) and 48 (4%) women developed preeclampsia. We observed an inverse dose-response relationship between manganese and preeclampsia. Compared with women in the lowest tertile, women in the middle manganese tertile had 0.81 times the risk of preeclampsia (95% CI: 0.43, 1.5) and those in the highest tertile had 0.50 (95% CI: 0.25, 0.99) times the risk., Conclusions: Our results provide insight into a potentially modifiable way to prevent preeclampsia.

Background: We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4-6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects., Methods: We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n = 571). McCarthy Scales of Children's Abilities were measured at 4-6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex., Results: No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother's with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother's with low ferritin (-2.41 (-5.28, 0.47), interaction P value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed., Conclusions: Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.

Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Elevated exposure to manganese (Mn) could induce cardiovascular dysfunction. However, limited research is available on the effects of occupational Mn exposure on myocardial enzymes. We aimed to evaluate the relationships between Mn exposure and myocardial enzyme elevation among Mn-exposed workers., Methods: Data were from a follow-up investigation of a Mn-exposed workers healthy cohort in 2017. A total of 744 workers were divided into low-exposure and high-exposure groups according to Mn time-weighted average (Mn-TWA) of less than or equal to 0.15 mg/m 3 or greater than 0.15 mg/m 3 , respectively. Serum levels of myocardial enzymes, including creatine kinase (CK) and creatine kinase-MB (CK-MB), lactic dehydrogenase, α-hydroxybutyrate dehydrogenase, and aspartate transaminase, were assessed, as well as airborne Mn exposure levels., Results: After adjustment for sex, body mass index, seniority, education, current smoking status, current drinking status, and hypertension, Mn-TWA levels were positively associated with the risk of CK elevation (odds ratio [OR] = 1.47 (95% confidence interval [CI]: 1.18-1.83) per interquartile range [IQR] increase), and risk of CK-MB elevation [OR = 1.57 (95% CI: 1.03-2.38) per IQR increase]. In a stratified analysis, Mn-TWA levels were positively correlated with CK elevation in workers of seniority greater than 19 years, male workers, current smokers, and drinkers., Conclusion: Our results suggest that occupational exposure to Mn is associated with increased risk of CK and CK-MB elevation. The potential mechanisms of the associations between airborne exposure to Mn and increased risk of these myocardial enzyme elevations warrant further investigation., (© 2020 Wiley Periodicals, Inc.)

Background: Manganese (Mn) ions play a crucial role in the immune response. The immunotoxicity of Mn is rarely reported compared with the neurotoxicity of Mn., Objectives: The purpose of this study was to investigate the associations between chronic Mn exposure and immunological parameters in occupational Mn-exposed workers., Methods: A total of 538 workers were selected from the follow-up of manganese-exposed workers healthy cohort (MEWHC) in 2017. We divided the workers into the low-exposure group and the high-exposure group by the cutoff of the manganese-time weighted average (Mn-TWA) setting at 0.15 mg/m 3 . We examined serum immunological parameters by the immunoturbidimetric method and leukocyte counts and ratios in blood routine. Then we used the generalized linear model analyses and spline analyses to explore the associations between external exposure of Mn and multiple immunological parameters adjusted for variables. Based on the epidemiological analyses, we used Elisa (enzyme-linked immune sorbent assay) to detect plasma complement C3 of Mn-exposed rats., Results: In male workers, the mean value of complement C3 was 1.20 ± 0.16 g/L in the high-exposure group, which was significantly lower as compared to the low-exposure group (1.25 ± 0.18 g/L, P = 0.023). The generalize linear models' analyses showed that complement C3 value had a significantly negative association with external exposure of Mn included adjustment for variables (β = -0.04, P = 0.035). Moreover, in male rats, the high-exposure group also had a lower level of complement C3 compared with the low-exposure group (P < 0.001). None significant association was observed in immunological parameters among female workers and rats (all P > 0.05)., Conclusions: Mn exposure from inhalable dust was associated with decreased complement C3 among occupationally Mn-exposed male individuals but not in female workers, which was further confirmed by the rat model. Further research into the possible mechanism of C3 reduction is needed in the future., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Objective: Ambient exposure to fine particles is associated with increased cardiovascular morbidity and mortality. Associations between occupational particulate matter (PM) exposure and cardiovascular disease have been studied less. The objective of this study was to examine associations between PM exposure and endothelial function among workers in Norwegian smelters., Methods: We examined endothelial function with Endo-PAT equipment after a working day (WD) and on a day off (DO) in 59 furnace workers recruited from three metal smelters in Norway. The difference in baseline pulse amplitude (BPA) and reactive hyperemia index (RHI) between the 2 days was analysed in relation to individual exposure to PM < 250 nm (PM 250 ) or the respirable aerosol fraction of particles, and adjusted for relevant covariates., Results: The exposure to PM 250 ranged from 0.004 to 5.7 mg/m 3 . The mean BPA was significantly higher on WD relative to DO (772 vs. 535, p = 0.001). This difference was associated with PM concentrations among participants ≥ 34 years, but not among the younger workers. Reactive hyperemia was significantly lower on workdays relative to days off (1.70 vs. 1.84, p = 0.05). This difference was observed only among participants above the age 34. No associations with PM exposure were observed., Conclusions: PM exposure was associated with higher BPA among participants older than 34 years. BPA reflects microvessel pulsatility. Our results may indicate an age-dependent cardiovascular susceptibility to PM exposure. Endothelial function measured by RHI was reduced on WD among participants 34 years and older, but we found no associations between PM exposure and RHI.

Air pollution has been linked to poor olfactory function in human adults. Among pollutants, particulate matter (PM) is especially relevant, as it may contain toxic metal ions that can reach the brain via olfactory pathways. Our purpose was to investigate the relation between atmospheric PM and olfactory identification performance in children. Using a validated method, we tested the olfactory identification performance of 120 children, 6-12 years old, from two locations in Mexico City: a focal group (n = 60) from a region with high PM levels and a control group of equal size and similar socioeconomic level from a region with markedly lower PM concentrations. Groups were matched for age and sex. Concentrations of manganese and lead in the hair of participants were determined as biomarkers of exposure. Daily outdoor PM levels were obtained from official records, and indoor PM levels were measured in the children's classrooms. Official records confirmed higher levels of outdoor PM in the focal region during the days of testing. We also found higher classroom PM concentrations at the focal site. Children from the focal site had on average significantly lower olfactory identification scores than controls, and hair analysis showed significantly higher levels of manganese for the focal children but no difference in lead. Children appear to be vulnerable to the effects of air pollution on olfactory identification performance, and metal-containing particles likely play a role in this. Olfactory tests provide a sensitive, noninvasive means to assess central nervous function in populations facing poor air quality., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Exposure to high levels of manganese (Mn) in children has recently been associated with adverse neurodevelopmental effects. Current infant formula regulations for Mn content were set between 1981 (United States), 2006 (European Union, France), and 2007 (Codex Alimentarius) prior to the publication of much of the growing body of research on the developmental neurotoxicity of Mn. In this study, we sought to measure the concentrations of Mn in some infant formulas and young child nutritional beverages available on the United States (US) and French markets using ion beam analysis by particle induced X-ray emission (PIXE) spectrometry and then compare the analytical results to concentrations reported in the literature for breast milk and applicable infant formula regulations and guidelines. We were particularly interested in measuring Mn concentrations in product types for which there is very little data from previous surveys, especially soy-based, rice-based, goat-milk based, chocolate-flavored, and nutritional beverages for young children that are not regulated as infant or follow-on formulas (e.g. "toddler formulas" and "toddler powders"). We purchased 44 infant formulas and young child nutritional beverage products in the US and France with varying protein sources (cow-milk, goat-milk, soy, rice) labelled for birth to 3 years. We selected these samples using maximum variation sampling to explore market extremes to facilitate comparisons to regulatory limits. Since this sampling method is non-probabilistic, other inferences cannot be made beyond this set of samples to the overall markets. We used ion beam analysis to measure the concentrations of Mn in each product. The range of measured Mn concentrations in the products is 160-2,800 μg/L, substantially higher than the 3-6 μg/L mean Mn concentration reported in human breast milk. All products satisfied national and Codex Alimentarius Commission (CAC) international standards for minimum Mn content in infant formulas; however, 7/25 of the products purchased in the US exceeded the CAC Guidance Upper Level of 100 μg Mn/kcal for infant formula., Competing Interests: EJM’s affiliation is with Better Life Laboratories, a nonprofit organization that conducts scientific research and provides technical expertise, equipment, and training to help needy people around the world. Better Life Laboratories received no specific funding for this project from any donors. Donors to Better Life Laboratories provided no input in choosing the subject matter of this project, the hypotheses that were tested, the individual samples that were analyzed, the method of analysis, the research findings, or the manner of disseminating the results. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Manganese (Mn) is an essential nutrient for cellular function, but in high concentrations, it is neurotoxic. Environmental exposure to Mn has been associated with cognitive effects in children. This study aimed to assess the effect of environmental exposure to Mn on verbal memory and learning in schoolchildren residents from two municipalities in the state of Hidalgo, Mexico. Cross-sectional studies were conducted in 2006 and 2013 with a total of 265 schoolchildren of 7 to 11 years old. Children's Auditory Verbal Learning Test-2 (CAVLT-2) was used to assess verbal memory and learning. Mn exposure tertiles were defined according to hair manganese (MnH) levels determined by atomic absorption spectrophotometry. Linear regression models were used to estimate the association between MnH levels and CAVLT-2 scores. The models were adjusted by potential confounders. The lowest and highest exposure tertiles were defined below and above MnH levels of ≤ 0.72 and ≥ 3.96 μg/g, respectively. Mn exposure was significantly associated with an average of 5- to 9-point decrease in learning curves and summary CAVLT-2 scores in the highest tertile. This study adds to the evidence of decreased verbal memory and learning in schoolchildren environmentally exposed to manganese.

Objective: To investigate the current status of the occupational hazards of welding fume, manganese, and manganese compounds in the welding environment of a large container manufacturing enterprise, as well as the status of occupational health examination of workers, and to provide a basis for improving the welding environment of this enterprise. Methods: In August 2016, July 2017, and August 2018, convenience sampling was used to perform an on-site occupational hygiene survey of the welding workshop for three consecutive years, and welding fume, manganese and, manganese compounds (counted as manganese dioxide) were measured for their workplace exposure concentrations and exposure levels in workers. A comprehensive analysis was performed for the results of occupational health examination. Results: Welding fume, manganese, and manganese compounds in the welding environment gradually increased from 2016 to 2018 (χ(2)(trend)=5.14 and 5.54, P <0.05). The maximum over-standard rate of concentration-short term exposure limit was 43.3% (13/30) for welding fume and 40.0% (12/30) for manganese and its compounds, and the maximum over-standard rate of time-weighted average concentration was 26.7% (8/30) for welding fume and 23.3% (7/30) for manganese and its compounds. Abnormalities were observed in the occupational health examination of welding workers in 2016-2018, among which respiratory system abnormalities (cough, expectoration, and wheezing), nervous system abnormalities (dizziness, fatigue, sleep disorders, amnesia, hyperhidrosis, and palpitations), and electrocardiogram abnormalities (bundle conduction block) had an incidence rate of above 10.0%, and the incidence rate of abnormalities on posterior-anterior X-ray high-kV chest radiograph was close to 8.9% (30/336) . Conclusion: There is severe exposure to welding fume, manganese, and manganese compounds among workers in this enterprise, which cause great hazards to the health of workers. It is necessary to strengthen occupational health management, take measures to improve the welding environment, and enhance occupational disease prevention.

Coridius chinensis (C. chinensis) is a traditional Chinese medicine that has been used to treat pain, erectile dysfunction, and other diseases. Our previous study demonstrated that manganese-induced reproductive damage was partially rescued by a medium dose of C. chinensis treatment in rat. However, the underlying mechanism is unknown. In this study, we found that the weight of reproductive organs and the sperm count in manganese-exposed rat were partially rescued by C. chinensis extracts (CcE) treatment. The number of apoptotic cells was significantly decreased and the expression of malondialdehyde, cytochrome c, and caspase-3 in manganese-exposed rats was significantly decreased after high dose of CcE treatment. Further studies revealed that the activity of superoxide dismutase, total antioxidant capacity, and glutathione peroxidase enzymes was significantly increased in testis tissues and serum of manganese-exposed rats with high dose of CcE treatment. Taken together, the results of this study suggest that CcE inhibits the Mn 2+ -induced apoptosis in testes by inducing the activity of antioxidants., (© 2019 The Authors. Environmental Toxicology published by Wiley Periodicals, Inc.)

In this study, two cyanobacterial strains (morphologically identified as Microcystis novacekii BA005 and Nostoc paludosum BA033) were exposed to different Mn concentrations: 7.0, 10.5, 15.7, 23.6 and 35.4 mg L -1 for BA005; and 15.0, 22.5, 33.7, 50.6, and 76.0 mg L -1 for BA033. Manganese toxicity was assessed by growth rate inhibition (EC 50 ), chlorophyll a content, quantification of Mn accumulation in biomass and monitoring morphological and ultrastructural effects. The Mn EC 50 values were 16 mg L -1 for BA005 and 39 mg L -1 for BA033, respectively. Reduction of chlorophyll a contents and ultrastructural changes were observed in cells exposed to Mn concentrations greater than 23.6 and 33.7 mg L -1 for BA005 and BA033. Damage to intrathylakoid spaces, increased amounts of polyphosphate granules and an increased number of carboxysomes were observed in both strains. In the context of the potential application of these strains in bioremediation approaches, BA005 was able to remove Mn almost completely from aqueous medium after 96 h exposure to an initial concentration of 10.5 mg L -1 , and BA033 was capable of removing 38% when exposed to initial Mn concentration of 22.5 mg L -1 . Our data shed light on how these cyanobacterial strains respond to Mn stress, as well as supporting their utility as organisms for monitoring Mn toxicity in industrial wastes and potential bioremediation application.

Background: Sodium para-aminosalicylic acid (PAS-Na), an anti-tuberculosis drug, has been demonstrated its function in facilitating the Mn elimination in manganism patients and Mn-exposed models in vivo and improving the symptoms of Mn poisoning. But whether it can improve the growth retardation and inflammatory responses induced by Mn have not been reported., Objectives: This study was designed to investigate the preventive effects of PAS-Na on the development of retardation and inflammatory responses in Mn-exposed rats., Methods: Male Sprague Dawley (SD) rats (8 weeks old, weighing 180 ± 20 g) were randomly divided into normal control group and Mn-exposed group in the 4 weeks experiment observation and normal control group, Mn-exposed group, PAS-Na preventive group and PAS-Na control group in the 8 weeks experiment observation. The Mn-exposed group received an intraperitoneal injection (i.p.) of 15 mg/kg MnCl 2 and the normal control group i.p. physiological Saline in the same volume once a day for 4 or 8 weeks, 5 days per week. The PAS-Na preventive group i.p. 15 mg/kg MnCl 2 along with back subcutaneous (s.c.) injection of 240 mg/kg PAS-Na once a day for 8 weeks, 5 days per week. PAS-Na control group received s.c. injection of 240 mg/kg PAS-Na along with i.p. injection of saline once daily. The body weight was determined once a week until the end of the experiment. The manganese contents in the blood were detected by graphite furnace atomic absorption spectrometry. The inflammatory factor levels (TNF-α, IL-1β, IL-6, and PGE2) in the blood were detected by using enzyme-linked immunosorbent assay (Elisa) and each organ taking from rats were weighed and recorded., Results: Mn exposure significantly suppressed the growth in rats and increased heart, liver, spleen and kidney coefficients as compared with the control group. The whole blood Mn level and serum levels of IL-1β, IL-6, PGE2, and TNF-α in sub-chronic Mn-exposure group were markedly higher than those in the control group. However, preventive treatment with PAS-Na obviously reduced the whole blood Mn level, the spleen and liver coefficients of the Mn-exposed rats. And serum levels of IL-1β and TNF-α were significantly reduced by 33.9% and 14.7% respectively in PAS-Na prevention group., Conclusions: PAS-Na could improve the growth retardation and alleviate inflammatory responses in Mn-exposed rats., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The aim of this study was to analyse the published literature on the potential effects of manganese exposure from drinking water on school-age children, with emphasis on cognitive, and neurodevelopment and behavioural effects. A systematic review of up-to-date scientific evidence published from 2006 to 2017 was conducted using Science Direct. A further search was carried out using PubMed and Web of Science. A total of 21 studies were reviewed and categorised into 12 cognitive and 9 neurodevelopment and behavioural effects. The most utilised cognitive test was the Wechsler Intelligence Scale for Children (WISC) or some subtests from it. 10 of the 12 studies on cognitive effects reported an adverse effect of manganese exposure from drinking water on children. 3 out of the 9 studies on neurodevelopment and behavioural effects reported that manganese exposure from drinking water was associated with poorer neurobehavioural performances in school children. 4 others implied the presence of some sex-specific associations with manganese exposure. 1 study suggested that children suffering from attention deficit hyperactivity disorder (ADHD) may be more susceptible to manganese exposure. Another study suggested that manganese was a beneficial nutrient as well as a neurotoxicant. Regardless of the limitations of the studies analysed, the adverse effects of manganese exposure from drinking water on school-aged children is sufficiently demonstrated. Further investigation into the subject to address inconsistencies in existing studies is recommended., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Lead (Pb) and manganese (Mn) are confirmed neurotoxins but it is unclear to what extent low-level exposure produces a unique behavioral signature. The objective of this study was to investigate latent cognitive profiles among children (6-8 years) from Montevideo, Uruguay co-exposed to these metals., Method: Among 345 children, blood Pb and hair Mn were measured using atomic absorption spectroscopy and ICP-MS, respectively. Sixteen measures, reflecting multiple domains of cognitive functioning were gathered: (1) three tests from Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-Extra Dimensional Shift (IED), Spatial Span (SSP) and Stockings of Cambridge (SOC), (2) ten tasks from Woodcock-Muñoz Achievement Battery, Revised (WM): Visual-Motor Integration, Verbal Comprehension (Vocabulary, Synonyms, Antonyms, Analogies), Visual-Auditory Comprehension, Concept Formation, Visual Spatial Thinking, Number Inversion and Spatial Relations, (3) Bender Gestalt task, and (4) Weschler block design task. Scores were modeled using latent profile analysis (LPA). Association between blood Pb and hair Mn on performance profiles was assessed using ordinal regression, controlling for confounders. An interaction between Pb and Mn was tested., Results: Mean ± SD of blood Pb was 4.1 ± 2.1 μg/dL and 35% of children had blood Pb ≥ 5 μg/dL. Median [5%, 95%] hair Mn level was 0.8 [0.3, 4.1] ppb. Three latent cognitive performance profiles were identified: high (n = 46, 13%), average (n = 209, 61%) and low (n = 90, 26%). Each one-unit increase in blood Pb was associated with a 28% greater likelihood of belonging to a poorer-performing profile. The association was non-linear, with the effect of Pb on profile membership strongest at lower levels of exposure. There was no meaningful interaction between Pb and Mn., Conclusions: A behavioral signature for low-level Pb & Mn exposure was not identified, but the likelihood of membership in low-performing profile was higher at lowest levels of blood Pb. There was no effect measure modification between Pb and Mn. Future research should address how complex environments created by chemical exposures and the social context relate to cognitive performance in young children., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Neurotoxic effects of high-level occupational exposure to manganese (Mn) are well established; however, whether lower-level environmental exposure to Mn in early life causes neurodevelopmental toxicity in children is unclear., Methods: A systematic literature review was conducted to identify and evaluate epidemiologic studies of specific Mn biomarkers assessed during gestation, childhood, or adolescence in association with neurodevelopmental outcomes, focusing on quantitative exposure-response estimates with specific endpoints that were assessed in multiple independent study populations. Study quality was evaluated using the revised RTI item bank and the Cochrane Risk of Bias tool, and the overall weight of epidemiologic evidence for causality was evaluated according to the Bradford Hill considerations., Results: Twenty-two epidemiologic studies were identified that estimated associations between early-life Mn biomarkers and neurodevelopmental outcomes. Seven of these studies provided adjusted estimates for the association with child intelligence assessed using versions of the Wechsler Intelligence Scales for Children; no other specific neurodevelopmental endpoints were assessed in more than three independent study populations each. Among the studies of child intelligence, five studies in four independent populations measured blood Mn, three studies measured hair Mn, and one measured dentin Mn. Overall, cross-sectional associations between Mn biomarkers and measures of child intelligence were mostly statistically nonsignificant but in a negative direction; however, the lone prospective cohort study found mostly null results, with some positive (favorable) associations between dentin Mn and child intelligence. Studies were methodologically limited by their cross-sectional design and potential for confounding and selection bias, as well as unaddressed questions on exposure assessment validity and biological plausibility., Conclusions: The statistical associations reported in the few studies of specific Mn biomarkers and specific neurodevelopmental endpoints do not establish causal effects based on the Bradford Hill considerations. Additional prospective cohort studies of Mn biomarkers and validated neurodevelopmental outcomes, and a better understanding of the etiologic relevance of Mn biomarkers, are needed to shed light on whether environmental exposure to Mn causes adverse neurodevelopmental effects in children., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)