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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., 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 © 2023 Elsevier Ltd. All rights reserved.)

Exposures to heavy metals play a role in the etiopathogenesis of diabetes. Epidemiological studies investigating a potential sex-specific linkage between manganese (Mn) exposures and glucose homeostasis are rare. We comprehensively estimated the associations of blood and urinary Mn levels with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homeostasis model assessment for insulin resistance (HOMA-IR), insulin, and estimated glomerular filtration rate (eGFR) among 1417 adults in the US National Health and Nutrition Examination Survey (NHANES) 2011-2016. We further examined the potential heterogeneities by sex and joint-effects of multiple metal exposures by the Bayesian kernel machine regression (BKMR). Among women, we found positive linear relationships between urinary Mn with FPG (P overall  = 0.003, P nonlinear  = 0.817) and HbA1c (P overall  = 0.023, P nonlinear  = 0.854). Among men, J-shaped relationships were observed between blood Mn with HOMA-IR (P nonlinear  = 0.042) and insulin (P nonlinear  = 0.014). For eGFR, positive linear relationships were obserned among women for blood Mn (P nonlinear  = 0.549) and among both men and women for urinary Mn levels. The joint-effects of urinary Mn with molybdenum (Mo) on FPG and HbA1c, urinary Mn with cadmium (Cd) and cesium (Cs) on eGFR, and blood Mn with Cd and lead (Pb) on eGFR were detected. In summary, blood and urinary Mn levels were independently associated with glucose levels, insulin resistance and kidney function with potential sex-dependent heterogeneities. These findings emphasize the probable role of Mn in the regulation of glucose metabolism and kidney function, and confirm the need for more studies on sex-specific risk of diabetes., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Associations between plasma elements and chronic kidney disease (CKD) among the elderly are poorly understood. In this cross-sectional study, we explored the associations between exposure to four plasma elements and CKD in elderly people aged ≥90 years in longevity areas in China. We measured plasma selenium, manganese, iron, and zinc levels and used logistic regression models to investigate associations between CKD and these four plasma elements after adjusting for confounding factors among 461 participants aged ≥90 years in the fifth wave of the Chinese Longitudinal Healthy Longevity Study (CLHLS) conducted in 2009. The median plasma selenium, manganese, iron, and zinc levels were 120.51 μg/L, 26.64 μg/L, 2880.52 μg/L, and 1882.42 μg/L in the CKD group and 108.76 μg/L, 31.55 μg/L, 4512.00 μg/L, and 2294.24 μg/L in the non-CKD group, respectively. Single- and multiple-element multivariable models showed that plasma manganese, iron, and zinc were negatively associated with CKD. In the multiple-element multivariable models, the adjusted odds ratios for CKD were 0.48 (95% confidence interval [CI]: 0.27-0.86) for the second highest quartile of manganese, 0.37 (95% CI: 0.21-0.68) and 0.36 (95% CI: 0.19-0.65) for the third highest and highest quartiles of iron, respectively, and 0.53 (95% CI: 0.29-0.94) for the highest quartile of zinc, compared with the lowest quartiles of these three elements. Plasma manganese, iron, and zinc levels protect against CKD in elderly people aged ≥90 years in longevity areas., Competing Interests: Declaration of competing interest We declare that we have no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Previous studies have shown that toxic metal exposure can have adverse effects on the nervous system of children, but the toxicology of metal co-exposure on neurodevelopment remains to be clarified. Brain derived neurotrophic factor (BDNF) plays an important role in nervous system development, but the possible effects of metal co-exposure on the serum BDNF concentrations of children remain unknown. A total of 561 children living in Taizhou City, China were recruited to participate in our cross-sectional multicenter survey. We measured their blood Pb, Hg, Al and Mn levels and serum BDNF concentrations as well as determined their associations in the total and within sex subgroups. The geometric means of the blood Pb, Hg, Al and Mn levels in all the participants were 67.18 μg/L, 1.01 μg/L, 52.03 μg/L and 18.26 μg/L, respectively. The serum BDNF concentration in children was 19.45 ng/mL. After adjusting for confounders, the blood Pb levels were significantly negatively associated with the serum BDNF concentrations in all the subjects and boys but not in girls. In addition, a significantly negative interaction between blood Pb and blood Hg and a positive interaction between blood Pb and blood Al on serum BDNF concentrations were also observed in boys but not in girls. Our findings highlight the toxic effects of metal co-exposure on serum BDNF levels in pre-school children and indicate that these effects might differ by gender, which suggest that special attention should be paid to the sex-specific effects of metal exposure., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Given the susceptibility of the fetus to toxicants, it is important to estimate their exposure. Approximately 2000 pregnant women were recruited in 2008-2011 from 10 cities across Canada. Cd, Pb, Mn and total Hg were measured in maternal blood from the 1st and 3rd trimesters, umbilical cord blood, and infant meconium. Nutrient intakes of vitamin D, iron, and calcium (Ca) were assessed using a food frequency questionnaire and a dietary supplement questionnaire. Median concentrations in 1st trimester maternal blood (n = 1938) were 0.20, 8.79 and 0.70 μg/L for Cd, Mn and Hg, respectively, and 0.60 μg/dL for Pb. While the median difference between the paired 1st and 3rd trimester concentrations of Cd was 0, there was a significant decrease in Pb (0.04 μg/dL) and Hg (0.12 μg/L) and an increase in Mn (3.30 μg/L) concentrations over the course of the pregnancy. While Cd was rarely detected in cord blood (19%) or meconium (3%), median Pb (0.77 μg/dL), Mn (31.87 μg/L) and Hg (0.80 μg/L) concentrations in cord blood were significantly higher than in maternal blood. Significant negative associations were observed between estimated Ca intake and maternal Cd, Pb, Mn and Hg, as well as cord blood Pb. Vitamin D intake was associated with lower maternal Cd, Pb, and Mn as well as Pb in cord blood. Even at current metal exposure levels, increasing dietary Ca and vitamin D intake during pregnancy may be associated with lower maternal blood Pb and Cd concentrations and lower Pb in cord blood., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

This study aimed to examine the potential association between low-level prenatal manganese (Mn) exposure and 1-year-old children's neurodevelopment quotient (DQ) by using the Gesell Developmental Inventory (GDI) (motor, adaptive, language, and social domains) and explored the role of brain-derived neurotrophic factor (BDNF) in Mn-induced cognitive impairments. A total of 377 mothers were recruited from a prospective birth cohort in rural northern China. Cord serum concentrations of Mn and BDNF were measured and children's DQ was evaluated. The median serum Mn concentration was 3.4 μg/L. After adjusting for confounding factors, Mn level was significantly associated with gross motor scores (β = -6.0, 95% CI: -11.8 to -0.2, p < 0.05) and personal-social scores (β = -4.2, 95% CI: -8.4 to 0.1, p < 0.05). BDNF level was positively correlated with personal-social score (β = 0.7, 95% CI: 0-1.4, p < 0.05). A significant correlation was found between Mn and BDNF (r = -0.13, 95% CI: -0.23 to -0.03, p < 0.01). Furthermore, the interaction between cord serum Mn and BDNF was significant (p < 0.001). In conclusion, elevated low-level prenatal Mn exposure impaired infant's neurodevelopment, and BDNF plays an important role in cognitive impairment, especially in the personal-social ability., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

While it is known that in utero exposure to environmental toxicants, namely heavy metals, can adversely affect the neonate, there remains a significant paucity of information on maternal biological changes specific to metal exposures during pregnancy. This study aims at identifying associations between maternal metal exposures and matrix metalloproteinases (MMPs) that are known to be engaged in pregnancy process. Third trimester maternal plasma (n = 1533) from a pregnancy cohort (Maternal-Infant Research on Environmental Chemicals Study, MIREC) were analyzed for MMP-1,-2,-7,-9 and -10 by affinity-based multiplex protein array analyses. Maternal metal concentrations (mercury, cadmium, lead, arsenic and manganese) in 1st and 3rd trimesters exhibited strong correlations (p < 0.05). Multivariate regression models were used to estimate odds ratio (OR) for the association between metal concentrations in quartiles and high (90%) and low (10%) maternal MMP levels. Significant (p < 0.05) metal exposure-related effects were observed with the different MMP isoform responses. MMP profiles were specific to the trimester at which the maternal blood metals were analyzed. Our findings suggest that the profiles of these MMP isoforms vary with the type of metal exposure, blood metal concentrations and the trimester at which metal levels were determined. These new findings on maternal metal-MMP relationships can guide future explorations on toxicity mechanisms relevant to metal exposure-mediated adverse birth outcomes., (Copyright © 2016. Published by Elsevier Ltd.)

This study aimed to investigate the distribution and factors influencing blood levels of Cadmium (Cd), Arsenic (As), and Manganese (Mn), and to determine their reference values in a sample of blood donors residing in Rio Branco, capital city of Acre State, Brazil. Blood samples were collected from all blood donors attending the Central Hemotherapic Unit in Rio Branco between 2010 and 2011. Among these, 1183 donors (98.9%) answered to a questionnaire on sociodemographic and lifestyle factors. Blood metal concentrations were determined by atomic spectrometry. Association between Cd, As and Mn levels and donors' characteristics was examined by linear regression analysis. Reference values were estimated as the upper limit of the 95% confidence interval of the 95th percentile of metal levels. References values were 0.87 μg L(-1) for Cd, 9.87 μg L(-1) for As, and 29.32 μg L(-1) for Mn. Reference values of Cd and As in smokers were 2.66 and 10.86 μg L(-1), respectively. Factors contributing to increase Cd levels were smoking, ethnicity (non-white), and lower education, whereas drinking tea and non-bottled water were associated with lower Cd. Lower levels of As were associated with higher household income, living near industrial facilities, working in a glass factory, a compost plant or in metal mining activities. Risk factors for Mn exposure were not identified. In general, blood Cd concentrations were in the range of exposure levels reported for other people from the general population, whereas levels of As and Mn were higher than in other non-occupationally exposed populations elsewhere., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Examine the relationship between blood lead concentration and children's intelligence quotient (IQ) in Chinese children 8-12 years old., Participants and Methods: This is a cross-sectional study, and participants included 446 children from three primary schools in Jiangsu, China. We collected environmental and genetic information from questionnaires. Blood lead (Pb), manganese (Mn), cadmium (Cd) and selenium (Se) concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). IQ was assessed using the Combined Raven's Test and then converted to a standard IQ score according to Chinese children's norm. Morning urine samples were collected to measure retinol binding protein (RBP)., Results: The average blood lead concentration was 33.13 μg L(-1) (geometric mean), and the blood lead concentration (BoxCox transform) was inversely and significantly associated with IQ (r=-0.11, p=0.02). The geometric mean of blood Mn, Cd and Se was 7.02 μg L(-1), 0.18 μg L(-1) and 94.77 μg L(-1), respectively. Blood Mn, Cd and Se showed no association with IQ, but all of them associated with urinary RBP. Urinary RBP was identified as a new factor associated with IQ (β=-6.49, p=0.011)., Conclusions: Urinary RBP was recognized as a new indicated factor associated with children's IQ. Mn, Cd and Se exposure might affect urinary RBP concentration and further IQ. Findings also support that blood lead concentrations in 8-12 years old children, even <44 μg L(-1), have a negative association with IQ., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Manganese (Mn) intoxication is most often regarded as an occupational manifestation and occurs in places such as manganese mines, dry cell battery plants and ceramic industries. In the present study, the influence of genetic polymorphism in cytochrome P450 2D6 (CYP2D6∗2), glutathione S-transferase M1 (GSTM1) and NAD(P)H quinone oxidoreductase 1 (NQO1) genes on blood manganese and plasma prolactin concentrations in manganese miners was investigated. Genotyping of CYP2D6∗2 C→T 2850 and NQO1 C→T 609 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) whereas the genotyping of GSTM1 was carried out by multiplex PCR using beta globin as an internal control. Manganese miners with CYP2D6∗2 C→T 2850 variant genotype had relatively low Mn concentration [GM: 21.4±8.9 μg L(-1)] than the subjects with wild (GM: 36.3±8.5 μg L(-1)) and heterozygous (GM: 34.4±6.9 μg L(-1)) genotypes. Miners with CYP2D6∗2 variant genotypes showed low prolactin levels (GM: 13.13±1.6 ng mL(-1)) compared to the wild (GM: 16.4.4±1.5 μg L(-1)) and heterozygous (GM: 18.7±1.6 ng mL(-1)) genotypes. Gene-gene interaction studies also revealed that the subjects with CYP2D6∗2 C→T 2850 variant genotypes had low levels of Mn and prolactin. Our new findings suggest that CYP2D6∗2 C→T 2850 variant genotypes can regulate plasma prolactin levels in manganese miners of Central India and could be involved in the fast metabolism of blood manganese, compared to wild and heterozygous genotypes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The effect of mercury and its interaction with zinc on the content of essential metals in tissues from neonate rats was investigated. Three-day-old Wistar rats were treated with saline or 27 mg kg(-1)d(-1) ZnCl2 (s.c.) for five consecutive days. From the 8th to the 12th day of life, the rats received one daily dose of saline or 5.0 mg kg(-1) HgCl2 (s.c). Twenty-four hours after the last injection liver, kidneys and blood were collected for metal quantification. The HgCl(2) exposure induced alterations on metal levels, such as increase of Fe, Hg and Zn in liver, decrease of Fe and Mg and increase of Cu and Hg contents in kidneys. The Hg exposure also increased Hg levels in the blood. The treatment with ZnCl2, administered previously to HgCl2, partially prevented the increase of Fe in the liver, and not only prevented the decrease of renal Mg but also increased it to levels higher than those found in control group. The Zn-Hg rats also presented higher renal Cu levels, and showed partially lower blood and hepatic Hg levels and higher renal Hg levels. The pre-administration of Zn caused no severe alterations in levels of essential metals (Cu, Fe, Mg and Mn). In short, Zn appears to be an alternative treatment of Hg poisoning in young animals in comparison to chelating drugs since these have low metal selectivity.