The relationship between serum manganese concentration with all-cause and cause-specific mortality: a retrospective and population-based cross-sectional study.

BACKGROUND: The study aimed to explore the association between manganese concentration and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality in the general population of the United States. METHODS: We integrated the data from the National Health and Nutrition Examination Survey from 2011 to 2018. A total of 9,207 subjects were selected based on the inclusion and exclusion criteria. The relationship between manganese concentration and all-cause, CVD-related, and cancer-related mortality was analyzed by constructing a Cox proportional hazard regression model and a restricted cubic spline (RCS) plot. Additionally, subgroup analyses stratified by age, sex, race/ethnicity, hypertension, diabetes mellitus (DM), chronic heart disease, chronic heart failure, angina pectoris, heart attack, stroke, and BMI were further performed. RESULTS: In the full adjusted model, compared with the lowest quartile, the adjusted hazard ratios with 95% confidence intervals (CIs) for all-cause, CVD-related, and cancer-related mortality across manganese quartiles were (1.11 (0.87,1.41), 0.96 (0.74, 1.23), and 1.23 (0.96, 1.59); P-value for trend =0.041), (0.86 (0.54, 1.37), 0.87 (0.55, 1.40), and 1.07 (0.67, 1.72); P-value for trend =0.906), and (1.45 (0.92, 2.29), 1.14 (0.70, 1.88), and 1.26 (0.75, 2.11); P-value for trend =0.526), respectively. The RCS curve shown a U-shaped association between manganese concentration and all-cause mortality and CVD-related mortality (P-value for nonlinear <0.05). However, there was an increase and then a decrease in the link between manganese concentration and cancer-related mortality (P-value for nonlinear <0.05). Manganese exposure was positively correlated with sex (correlation coefficient, r =0.19, P-value <0.001) and negatively correlated with age (correlation coefficient, r =-0.11, P-value <0.001) and serum creatinine (correlation coefficient, r =-0.12, P-value <0.001), respectively. CONCLUSIONS: Our findings suggest that elevated serum manganese concentrations are associated with all-cause and CVD-related mortality in the U.S. population and that maintenance of serum manganese between 8.67-9.23 µg/L may promote public health.

Associations of plasma manganese with adverse pregnancy outcomes: Nested case-control studies in a Chinese birth cohort.

Both insufficient and excessive manganese exposure are associated with adverse pregnancy outcomes. However, no systematic research has established a standardized reference range for manganese levels with the consideration of the associated health risks during pregnancy. To verify the associations of prenatal manganese exposure with adverse outcomes and to identify a proper reference range for manganese based on health risks, we designed three nested case-control studies on three adverse outcomes including hypertensive disorders of pregnancy (HDP), preterm birth (PTB), and low birth weight (LBW) to investigate the associations with manganese levels. Plasma manganese concentrations in early pregnancy were measured. Conditional logistic regression analyses were used to estimate the associations of manganese levels with adverse outcomes. Restricted cubic spline (RCS) models were used to characterize the dose-response relationship of manganese and each outcome. Nonlinear associations were observed for manganese and adverse outcomes. Compared with women in the middle tertile of plasma manganese, we found that those in the highest tertile had a significantly higher risk of HDP (OR = 1.72, 95% CI: 1.02 to 2.89), that women in the lowest tertile had almost a tripled risk of delivering LBW infants (OR = 2.93, 95% CI: 1.67 to 5.17), and that women both in the lowest and the highest tertiles had significantly higher risks of PTB [OR = 1.83 (95% CI: 1.14 to 2.95); OR = 1.70 (95% CI: 1.05 to 2.76)]. U-shaped associations were found between plasma manganese and risk of PTB and infant LBW. Based on the results of RCS models, we identified a proper plasma manganese range of 1.72-3.18 µg/L, with relatively lower risks of adverse pregnancy outcomes. In conclusion, our study found U-shaped associations between manganese exposure and adverse pregnancy outcomes, and provided an optimal range of manganese concentration for pregnant women, based on health risk considerations.

The effect of mask fit test on the association between the concentration of metals in biological samples and the results of time-weighted average personal exposure: A study on Japanese male welders.

OBJECTIVES: The mask fit test confirms whether the wearing condition of the wearer's face and the facepiece of the respirators are used appropriately. This study aimed to examine whether the results of the mask fit test affect the association between the concentration of metals related to welding fumes in biological samples and the results of time-weighted average (TWA) personal exposures. METHODS: A total of 94 male welders were recruited. Blood and urine samples were obtained from all participants to measure the metal exposure levels. Using personal exposure measurements, the 8-h TWA (8 h-TWA) of respirable dust, TWA of respirable Mn, and 8-h TWA of respirable Mn were calculated. The mask fit test was performed using the quantitative method specified in the Japanese Industrial Standard T8150:2021. RESULTS: Fifty-four participants (57%) passed the mask fit test. Only in the Fail group of the mask fit test, it was observed that blood Mn concentrations be positively associated with the results of TWA personal exposure after adjusting for multivariate factors (8-h TWA of respirable dust; coefficient, 0.066; standard error (SE), 0.028; P = 0.018, TWA of respirable Mn: coefficient, 0.048; SE, 0.020; P = 0.019, 8 h-TWA of respirable Mn: coefficient, 0.041; SE, 0.020; P = 0.041). CONCLUSIONS: The results clarify that welders with high concentrations of welding fumes in their breathing air zone are exposed to dust and Mn if there is leaking air owing to the lack of fitness between respirators and the wearer's face when using human samples in Japan.

Manganese and thyroid function in the national health and nutrition examination survey, 2011-2012.

CONTEXT: Manganese (Mn) exposure is prevalent, as it is found naturally as ionized trace elements and released into the environment as a byproduct of manufacturing and waste disposal. Animal and human studies have suggested variable effects on thyroid function, but the association of Mn exposure with thyroid function has not been evaluated in a national sample. OBJECTIVE: To investigate the associations between serum and urinary Mn levels and serum thyroid hormone concentrations in a nationally representative sample. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: This was a cross-sectional analysis of data from the 2011-2012 National Health and Nutrition Examination Survey among 1360 participants. MAIN OUTCOME MEASURES: Serum thyroid stimulating hormone (TSH), total triiodothyronine (T3), total thyroxine (T4), free T3, and free T4. RESULTS: Serum Mn levels were positively associated with increasing total T4, free T3, and total T3 in the whole cohort (p < 0.01). Urinary Mn levels were not associated with thyroid hormone levels. When subgroup analyses were performed by gender, only males had total T4 associated with serum Mn [ß = 0.01, p < 0.01, confidence interval (CI): 0.004-0.018]. In individuals under 22 years old, serum Mn was significantly associated with total T4 (ß = 0.02, p = 0.002, CI: 0.008-0.029). Serum Mn was positively associated with Free T3 in both genders (ß = 0.07, p < 0.001). CONCLUSION: While our findings do not suggest clinical thyroid dysfunction, there is an association between serum Mn and subclinical changes in thyroid function that warrant further studies. Regulatory action should be considered as Mn-based organometallic compounds are being considered as replacements for lead in gasoline and may pose future risks to human health.

Blood cadmium, lead, manganese, mercury, and selenium levels in American Indian populations: The Strong Heart Study.

BACKGROUND: Many American Indian (AI) communities are in areas affected by environmental contamination, such as toxic metals. However, studies assessing exposures in AI communities are limited. We measured blood metals in AI communities to assess historical exposure and identify participant characteristics associated with these levels in the Strong Heart Study (SHS) cohort. METHOD: Archived blood specimens collected from participants (n = 2014, all participants were 50 years of age and older) in Arizona, Oklahoma, and North and South Dakota during SHS Phase-III (1998-1999) were analyzed for cadmium, lead, manganese, mercury, and selenium using inductively coupled plasma triple quadrupole mass spectrometry. We conducted descriptive analyses for the entire cohort and stratified by selected subgroups, including selected demographics, health behaviors, income, waist circumference, and body mass index. Bivariate associations were conducted to examine associations between blood metal levels and selected socio-demographic and behavioral covariates. Finally, multivariate regression models were used to assess the best model fit that predicted blood metal levels. FINDINGS: All elements were detected in 100% of study participants, with the exception of mercury (detected in 73% of participants). The SHS population had higher levels of blood cadmium and manganese than the general U.S. population 50 years and older. The median blood mercury in the SHS cohort was at about 30% of the U.S. reference population, potentially due to low fish consumption. Participants in North Dakota and South Dakota had the highest blood cadmium, lead, manganese, and selenium, and the lowest total mercury levels, even after adjusting for covariates. In addition, each of the blood metals was associated with selected demographic, behavioral, income, and/or weight-related factors in multivariate models. These findings will help guide the tribes to develop education, outreach, and strategies to reduce harmful exposures and increase beneficial nutrient intake in these AI communities.

Respiratory health disorders among workers in some Egyptian welding enterprises.

Welding fumes contain a complex mixture of metallic oxides that pose a risk to welders' respiratory systems. This study aimed to evaluate respiratory health disorders among workers in some Egyptian welding enterprises and their relationship to the workplace environment. This research was performed from January 1st, 2019 to February 28th, 2021 in welding enterprises in Birket El-Sabaa, a randomly selected district of Menoufia governorate, Egypt. A cross-sectional comparative study was conducted on 110 welders and 110 non-occupationally exposed subjects. Environmental studies were carried out for total welding fumes, respirable dust, and manganese air levels. Spirometric measures and manganese levels in whole blood were applied. Analysis of the personal air samples revealed that the mean values of welding fumes, respirable dust, and manganese air levels were higher than the international permissible levels. Welders had a higher significant prevalence of respiratory manifestations (rhinitis, cough, expectoration, wheezes, dyspnea, and chronic bronchitis) as well as decreased spirometric measures (FVC%, FEV1%, FEV1/FVC%, and FEF25-75%) than controls. The mean value of whole blood manganese level was statistically significantly higher among welders than that of the controls (3.35 ± 0.5 and 1.81 ± 0.79 ng/mL; respectively). A significant relationship was reported between longer work time and the prevalence of respiratory manifestations and decreased spirometric measurements. The use of masks/respirators was associated with a reduced prevalence of respiratory manifestations. Finally, welders that are exposed to welding fumes at concentrations higher than the permissible levels in welding establishments suffer from adverse respiratory problems, as shown by increased prevalence of respiratory manifestations and lower spirometric measurements. Regular use of high-quality personal protective equipment, especially masks, as well as periodic medical examinations for welders, is highly urged.

Prenatal metal mixture concentrations and reward motivation in children.

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6-8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

Cord Blood Manganese Concentrations in Relation to Birth Outcomes and Childhood Physical Growth: A Prospective Birth Cohort Study.

Gestational exposure to manganese (Mn), an essential trace element, is associated with fetal and childhood physical growth. However, it is unclear which period of growth is more significantly affected by prenatal Mn exposure. The current study was conducted to assess the associations of umbilical cord-blood Mn levels with birth outcomes and childhood continuous physical development. The umbilical cord-blood Mn concentrations of 1179 mother-infant pairs in the Sheyang mini birth cohort were measured by graphite furnace atomic absorption spectrometry (GFAAS). The association of cord-blood Mn concentrations with birth outcomes, and the BMI z-score at 1, 2, 3, 6, 7 and 8 years old, were estimated separately using generalized linear models. The relationship between prenatal Mn exposure and BMI z-score trajectory was assessed with generalized estimating equation models. The median of cord-blood Mn concentration was 29.25 µg/L. Significantly positive associations were observed between Mn exposure and ponderal index (ß, regression coefficient = 0.065, 95% CI, confidence interval: 0.021, 0.109; p = 0.004). Mn exposure was negatively associated with the BMI z-score of children aged 1, 2, and 3 years (ß = -0.383 to -0.249, p < 0.05), while no significant relationships were found between Mn exposure and the BMI z-score of children at the age of 6, 7, and 8 years. Prenatal Mn exposure was related to the childhood BMI z-score trajectory (ß = -0.218, 95% CI: -0.416, -0.021; p = 0.030). These results indicated that prenatal Mn exposure was positively related to the ponderal index (PI), and negatively related to physical growth in childhood, which seemed most significant at an early stage.

Associations between welding fume exposure and blood hemostatic parameters among workers exposed to welding fumes in confined space in Chonburi, Thailand.

BACKGROUND: Occupational welding fumes contain varieties of toxic metal particles and may affect cardiovascular system like the Particulate Matters (PM). Few studies have focused on the effects of toxic metals on the hemodynamic balance; however, the reporting results were not consistent. This study aimed to investigate the association between toxic metals exposure (Chromium (Cr), Manganese (Mn) and Lead (Pb)) and blood hemostatic parameters status after a 3-week exposure cessation among workers exposed to welding fumes. METHODOLOGY: Structured interviews and biological samplings were conducted for 86 male workers without a history of Anemia and Cardiovascular diseases (CVDs) and working in a confined space to construct crude oil tanks. Metal levels of Cr, Mn and Pb in urine were measured during the working days using Inductively Coupled Plasma Mass Spectrometer (ICP-MS) method. The concentrations of hemostatic proteins in blood (White blood cell counts (WBC), Lymphocytes, Monocyte, Eosinophil, Neutrophil, Hematocrit (Hct) were assessed after a 3 weeks exposure cessation. Workers were divided into groups based on occupation type (welder group and non-welder group), and based on metal levels (high and low exposure groups) for comparison. Linear regression models were used to explore the association between metal exposure and multiple blood hemostatic parameters adjusted for age, Body Mass Index (BMI), and smoking status. RESULTS: Urine Mn and Cr level of the welder group was significantly higher than the non-welder group (Mn: 0.96 VS 0.22 ug/g creatinine, p < 0.001; Cr: 0.63 VS 0.22 ug/g creatinine, p < 0.01). The mean value of Hct in the welder group was 44.58 ± 2.84 vol%, significantly higher than the non-welder group (43.07 ± 3.31 vol%, p = 0.026). The median value of WBC in the high Mn-exposed group (6.93 ± 1.59 X 106 Cell/ml) was significantly lower than the low Mn-exposed group (7.90 ± 2.13 X 106 Cell/ml, p = 0.018). The linear regression analyses showed that there was a significantly negative association between log transformed WBC value and the Mn exposure groups (high and low) after adjusting for age, BMI, and smoking status (ß = - 0.049, p = 0.045), but no significant result was found between WBC and occupation types (welder and non-welder) (p > 0.05). Multiple linear regression analysis also showed positive association between Hct and occupational types (welder and non-welders) (ß = 0.014, p = 0.055). The other hemostatic parameters were not different from controls when divided by occupation type or metal level groups. CONCLUSIONS: Our results showed that welders were exposed to about 3 to 4 times higher Mn and Cr concentrations than non-welders. Moreover, one third of the non-welders were exposed to high-exposure groups of Mn and Cr metals. Regression models revealed a significant association of the WBC counts with the Mn exposure group. Therefore, we infer that Mn exposure may play a significant role on the blood hemostatic parameters of workers in the confined space. Hazard identification for non-welders should also be conducted in the confined space.

The Content of Minerals in the PCOS Group and the Correlation with the Parameters of Metabolism.

Polycystic ovary syndrome (PCOS) is a common disease in women of childbearing age. It is characterized by excessive androgen production, ovulation disorders, and developing metabolic syndrome. The aim of the study was to check whether selected minerals were related to the pathophysiological mechanisms of PCOS. The concentrations of minerals were determined using an inductively coupled atomic plasma-emission spectrometer (ICP-AES Jobin Yvon JY-24). Blood samples from PCOS and control women were collected, processed, and digested with a microwave system in women with PCOS with and without insulin resistance and in the control group. It was found: zinc (Zn)-10.14 ± 2.11, 9.89 ± 1.44 and 10.30 ± 1.67; nickel (Ni) 0.001 ± 0.0009, 0.001 ± 0.0006 and 0.002 ± 0.00001; iron (Fe) 868.0 ± 155.8, 835.3 ± 156.4 and 833.0 ± 94.6; manganese (Mn) 0.017 ± 0.006, 0.017 ± 0.008 and 0.020 ± 0.009; copper (Cu) 0.714 ± 0.129, 0.713 ± 0.114 and 0.761 ± 0.146; magnesium (Mg) 48.4 ± 8.3, 50.0 ± 8.4 and 45.3 ± 10.7; sodium (Na) 374.3 ± 84.3, 396.3 ± 66.6 and 367.9 ± 88.9; potassium (K) 2541.8 ± 330.9, 2409.6 ± 347.1 and 2336.9 ± 211.4 (µg/g). Some micronutrient deficiencies may have a negative effect on the lipid profile in PCOS patients (Ni, Na). Further studies are needed to better understand dependencies.

GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms.

Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

Hepatic oxidative damage and Nrf2 pathway protein changes in rats following long-term manganese exposure.

This study investigated hepatic oxidative damage in rats following long-term manganese (Mn) exposure and clarified the underlying mechanisms. Forty-eight rats (SPF, male) were randomly assigned to receive low (10 mg/kg, n = 16) or high doses of Mn (50 mg/kg, n = 16) or sterilized distilled water (control group, n = 16). Rats were euthanized after 12 months, and liver Mn levels and histopathological changes were determined. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA), glutathione peroxidase (GSH-PX), nuclear factor E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinine oxidoreductase-1 (NQO1) levels were also determined. The Mn concentration and relative liver weights were significantly higher in the high-dose Mn group than in the control and low-dose Mn exposure groups. Low-dose Mn exposure resulted in mild expansion of hepatic sinuses and intact nuclei, whereas high-dose exposure led to pathological alterations in hepatocytes. High-dose Mn treatment significantly increased AST, ALT, and MDA activities and decreased GSH-PX activity. Additionally, liver Nrf2, HO-1, and NQO1 protein expression were markedly reduced by Mn exposure. Under the study conditions, long-term low-dose Mn exposure resulted in slight pathological changes in liver structure, but high-dose Mn exposure affected both liver structure and function, which might be related to the inhibition of Nrf2 expression, suppression of the transcription of its underlying antioxidant genes, and down regulation of the corresponding proteins. Consequently, the antioxidant capacity in the rat liver was weakened.

Manganese and copper levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

The liver and the biliary tree form the main excretory route of manganese (Mn) and copper (Cu). Cholestasis, can lead to the accumulation of these trace elements in the organism, resulting in toxicity to the basal ganglia of the central nervous system. The aim of our study was to reveal the influence of long-term cholestasis on the Mn and Cu levels in the blood of patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We recruited patients with PBC (n = 20) and PSC (n = 32). A control group (n = 40) was also set up. We also examined serum bile acid concentrations and liver enzyme activities. We did not observe any significant differences in any of these parameters between the PBC and PSC groups. The Mn and Cu levels in the PBC and PSC patients differed significantly from the that in the control group (p < 0.0001 and p < .021, respectively). Patients in whom the laboratory cholestasis markers normalized during ursodeoxycholic acid treatment (18/52;35%) presented with significantly lower levels of Mn and Cu (p = .015 and p = .012, respectively). Ten PSC patients showed normal levels of Mn and Cu six months after liver transplantation. Fine tremors, rigidity, dysarthria, and hypomimia were reported in nine (23%), eight (20%), four (10%), and eight (20%) patients, respectively. In addition to monitoring the cholestasis levels, liver function, and Mn and Cu levels during the long-term treatment of PBC and PSC patients, it is important to also regularly monitor the occurrence and development of extrapyramidal symptoms of Parkinson's-like syndromes.

Interaction of Blood Manganese Concentrations with GSTT1 in Relation to Autism Spectrum Disorder in Jamaican Children.

Using data from 266 age- and sex-matched pairs of Jamaican children with autism spectrum disorder (ASD) and typically developing (TD) controls (2-8 years), we investigated whether glutathione S-transferase theta 1 (GSTT1) modifies the association between blood manganese concentrations (BMC) and ASD. After adjusting conditional logistic regression models for socioeconomic status and the interaction between GSTT1 and GSTP1 (glutathione S-transferase pi 1), using a recessive genetic model for GSTT1 and either a co-dominant or dominant model for GSTP1, the interaction between GSTT1 and BMC was significant (P = 0.02, P = 0.01, respectively). Compared to controls, ASD cases with GSTT1-DD genotype had 4.33 and 4.34 times higher odds of BMC > 12 vs. ≤ 8.3 µg/L, respectively. Replication in other populations is warranted.

Correlations between Basal Trace Minerals and Hormones in Middle and Long-Distance High-Level Male Runners.

Several essential trace minerals play an important role in the endocrine system; however, toxic trace minerals have a disruptive effect. The aim of this research was to determine basal concentrations and the possible correlations between trace minerals in plasma and several plasma hormones in runners. Sixty high-level male endurance runners (21 ± 3 years; 1.77 ± 0.05 m; 64.97 ± 7.36 kg) participated in the present study. Plasma hormones were analyzed using an enzyme-linked immunosorbent assay (ELISA) and plasma trace minerals were analyzed with inductively coupled plasma mass spectrometry (ICP-MS). Correlations and simple linear regression were used to assess the association between trace minerals and hormones. Plasma testosterone concentrations were inversely correlated with manganese (r = -0.543; ß = -0.410; p < 0.01), selenium (r = -0.292; ß = -0.024; p < 0.05), vanadium (r = -0.406; ß = -1.278; p < 0.01), arsenic (r = -0.336; ß = -0.142; p < 0.05), and lead (r = -0.385; ß = -0.418; p < 0.01). Plasma luteinizing hormone (LH) levels were positively correlated with arsenic (r = 0.298; ß = 0.327; p < 0.05) and cesium (r = 0.305; ß = 2.272; p < 0.05), and negatively correlated with vanadium (r = -0.303; ß = -2.467; p < 0.05). Moreover, cortisol concentrations showed significant positive correlations with cadmium (r = 0.291; ß = 209.01; p < 0.05). Finally, insulin concentrations were inversely related to vanadium (r = -0.359; ß = -3.982; p < 0.05). In conclusion, endurance runners living in areas with high environmental levels of toxic minerals should check their concentrations of anabolic hormones.

Hypermanganesemia Induced Chorea and Cognitive Decline in a Tea Seller.

Background: Manganese associated neurotoxicity and neurodegeneration is quite rare yet established neurological disorder. This neurotoxic element has predilection for depositing in basal ganglia structures, manifesting mainly as parkinsonian and dystonic movement disorders with behavioral abnormalities. Case report: We report a 40-year-old man who presented with a subacute onset bilateral, asymmetric hyperkinetic movement disorder (predominantly left sided chorea) with multi-domain cognitive impairment, dysarthria, and generalized rigidity. Clinical history and examination yielded multiple differential diagnoses including deposition and metabolic disorders, autoimmune and paraneoplastic encephalitis involving basal ganglia, and neurodegenerative disorders with chorea and cognitive impairment. However, magnetic resonance imaging was suggestive of paramagnetic substance deposition, which came out to be manganese after laboratory investigations. History, clinical examinations, and investigation results pointed towards a diagnosis of acquired hypermanganesemia due to over-ingestion of manganese containing substance (i.e., black tea). He was treated symptomatically and with chelation therapy (calcium disodium edetate). At the sixth month of follow-up, complete resolution of chorea, dysarthria and partial amelioration of rigidity were observed. His cognitive decline and behavioral abnormalities improved. Discussion: This is probably the first reported case of acquired hypermanganesemia that presented as a combination of asymmetric chorea and cognitive dysfunction with atypical imaging characteristics. The clinical picture mimicked that of Huntington's disease. We highlight the potential deleterious effects of an apparently "benign" non-alcoholic beverage (i.e., black tea) on cerebral metabolism.

Essential trace elements in Norwegian obese patients before and 12 months after Roux-en-Y gastric bypass surgery: Copper, manganese, selenium and zinc.

OBJECTIVES: The objective of the present study was to assess trace element status in morbidly obese subjects before and one year after Roux-en-Y gastric bypass (RYGB) in order to identify possible deficiencies. METHODS: The study population included 46 patients in the age range 27-59 years, the majority (85 %) were women. The enrolled patients attended an eight week course on lifestyle changes before bariatric surgery. After RYGB they were recommended daily micronutrient supplements with a commonly used multivitamin-mineral tablet in addition to intramuscular vitamin B12 injections (1 mg) every third month for 12 months. Whole blood concentrations of Cu, Mn, Se and Zn were determined using high resolution inductively coupled plasma mass spectrometry. RESULTS: During the 12 months follow up after bariatric surgery, the patients had lost mean 32.3 kg and median whole blood concentrations of Cu (-16 %) were reduced, Mn (+14 %) and Zn (+6%) were increased, while the Se values were essentially unchanged. Compared with reference ranges, median postoperative concentrations of all essential trace elements were either below (Zn) or in the lower reference range (Cu, Mn, Se). CONCLUSION: Essential trace elements were below or in the lower reference range twelve months after RYGB. Our results indicate a need for updated guidelines in Nordic countries for trace metal monitoring and supplements in patients after bariatric surgery, especially when gastric bypass surgery is used. Further studies are required to explore and prevent trace element deficiency related to obesity and bariatric surgery.

Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease.

ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic SNPs identified in GWAS; A391T has associations with an increased risk of schizophrenia, obesity, Crohn's disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knockin (KI) to generate a mouse model of ZIP8 A391T (Zip8 393T-KI mice). Recapitulating the SNP association with blood Mn, blood Mn was reduced in Zip8 393T-KI mice. There was restricted abnormal tissue Mn homeostasis, with decreases in liver and kidney Mn and a reciprocal increase in biliary Mn, providing in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemically induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of patients with Crohn's disease. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in complex human disease.

The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation.

A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.