Early postnatal and concurrent exposure to metals and neurobehavioral outcomes at 5 years: Associations with individual environmental exposures and mixtures.

BACKGROUND: Little is known about the effect of postnatal exposure to heavy metals on children's behavior problems. This study aimed to investigate the association between metal exposure during different stages of postnatal life and neurobehavioral outcomes in preschool children. METHODS: Urinary concentrations of six metals (arsenic, cadmium, chromium, lead, manganese, and vanadium) were measured using inductively coupled plasma mass spectrometry in 220 participants at two time points: before 1 year and at 5 years of age. Mothers completed the Child Behavior Checklist when the children were 5 years old. Multivariable linear and logistic regression analyses were used to evaluate the association between metal concentrations and behavioral outcomes. We employed Bayesian kernel machine regression (BKMR) to assess possible joint effects and potential interactions between metal mixtures and behavioral outcomes. RESULTS: Concentrations of urinary arsenic (As) in infants were associated with higher scores for anxious/shy behavior problems (ß ranging from 0.03 to 0.23). Further analyses showed that As exposure increased the odds of scores falling into the borderline or clinical range on anxious/depressed, affective, and pervasive developmental problems (ORs: 2.45-3.40). Stratification by sex indicated significance in girls but not in boys. BKMR analysis showed that, among the metal mixtures, As displayed a major effect on behavior scores. Concentrations of urinary cadmium in infants were also associated with higher behavioral scores but did not increase the risk of clinical problems. A cross-sectional survey in 5-year-olds did not show a significant association between concurrent metal exposure and behavioral outcome. CONCLUSION: Our results showed that exposure to As and Cd during infancy was associated with emotional problems in children. The effect of arsenic exposure was more pronounced among female infants. We suggest reducing exposure to toxic metals during early postnatal life to prevent behavioral problems in children."

Associations of personal PM2.5-bound heavy metals and heavy metal mixture with lung function: Results from a panel study in Chinese urban residents.

BACKGROUND: There are a few reports on the associations between fine particulate matter (PM2.5)-bound heavy metals and lung function. OBJECTIVES: To evaluate the associations of single and mixed PM2.5-bound heavy metals with lung function. METHODS: This study included 316 observations of 224 Chinese adults from the Wuhan-Zhuhai cohort over two study periods, and measured participants' personal PM2.5-bound heavy metals and lung function. Three linear mixed models, including the single constituent model, the PM2.5-adjusted constituent model, and the constituent residual model were used to evaluate the association between single metal and lung function. Mixed exposure models including Bayesian kernel machine regression (BKMR) model, weighted quantile sum (WQS) model, and Explainable Machine Learning model were used to assess the relationship between PM2.5-bound heavy metal mixtures and lung function. RESULTS: In the single exposure analyses, significant negative associations of PM2.5-bound lead, antimony, and cadmium with peak expiratory flow (PEF) were observed. In the mixed exposure analyses, significant decreases in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), maximal mid-expiratory flow (MMF), and forced expiratory flow at 75% of the pulmonary volume (FEF75) were associated with the increased PM2.5-bound heavy metal mixture. The BKMR models suggested negative associations of PM2.5-bound lead and antimony with lung function. In addition, PM2.5-bound copper was positively associated with FEV1/FVC, MMF, and FEF75. The Explainable Machine Learning models suggested that FEV1/FVC, MMF, and FEF75 decreased with the elevated PM2.5-bound lead, manganese, and vanadium, and increased with the elevated PM2.5-bound copper. CONCLUSIONS: The negative relationships were detected between PM2.5-bound heavy metal mixture and FEV1/FVC, MMF, as well as FEF75. Among the PM2.5-bound heavy metal mixture, PM2.5-bound lead, antimony, manganese, and vanadium were negatively associated with FEV1/FVC, MMF, and FEF75, while PM2.5-bound copper was positively associated with FEV1/FVC, MMF, and FEF75.

Association between heavy metals exposure and persistent infections: the mediating role of immune function.

Introduction: Persistent infections caused by certain viruses and parasites have been associated with multiple diseases and substantial mortality. Heavy metals are ubiquitous environmental pollutants with immunosuppressive properties. This study aimed to determine whether heavy metals exposure suppress the immune system, thereby increasing the susceptibility to persistent infections. Methods: Using data from NHANES 1999-2016, we explored the associations between heavy metals exposure and persistent infections: Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV), Herpes Simplex Virus Type-1 (HSV-1), Toxoplasma gondii (T. gondii), and Toxocara canis and Toxocara cati (Toxocara spp.) by performing logistic regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models. Mediation analysis was used to determine the mediating role of host immune function in these associations. Results: Logistic regression analysis revealed positive associations between multiple heavy metals and the increased risk of persistent infections. In WQS models, the heavy metals mixture was associated with increased risks of several persistent infections: CMV (OR: 1.58; 95% CI: 1.17, 2.14), HCV (OR: 2.94; 95% CI: 1.68, 5.16), HSV-1 (OR: 1.25; 95% CI: 1.11, 1.42), T. gondii (OR: 1.97; 95% CI: 1.41, 2.76), and Toxocara spp. (OR: 1.76; 95% CI: 1.16, 2.66). BKMR models further confirmed the combined effects of heavy metals mixture and also identified the individual effect of arsenic, cadmium, and lead. On mediation analysis, the systemic immune inflammation index, which reflects the host's immune status, mediated 12.14% of the association of mixed heavy metals exposure with HSV-1 infection. Discussion: The findings of this study revealed that heavy metals exposure may increase susceptibility to persistent infections, with the host's immune status potentially mediating this relationship. Reducing exposure to heavy metals may have preventive implications for persistent infections, and further prospective studies are needed to confirm these findings.

Assessing the Risk of Heart Attack: A Bayesian Kernel Machine Regression Analysis of Heavy Metal Mixtures.

Background: The assessment of heavy metals' effects on human health is frequently limited to investigating one metal or a group of related metals. The effect of heavy metals mixture on heart attack is unknown. Methods: This study applied the Bayesian kernel machine regression model (BKMR) to the 2011-2016 National Health and Nutrition Examination Survey (NHANES) data to investigate the association between heavy metal mixture exposure with heart attack. 2972 participants over the age of 20 were included in the study. Results: Results indicate that heart attack patients have higher levels of cadmium and lead in the blood and cadmium, cobalt, and tin in the urine, while having lower levels of mercury, manganese, and selenium in the blood and manganese, barium, tungsten, and strontium in the urine. The estimated risk of heart attack showed a negative association of 0.0030 units when all the metals were at their 25th percentile compared to their 50th percentile and a positive association of 0.0285 units when all the metals were at their 75th percentile compared to their 50th percentile. The results suggest that heavy metal exposure, especially cadmium and lead, may increase the risk of heart attacks. Conclusions: This study suggests a possible association between heavy metal mixture exposure and heart attack and, additionally, demonstrates how the BKMR model can be used to investigate new combinations of exposures in future studies.

Interactions of binary mixtures of metals on rainbow trout (Oncorhynchus mykiss) heart mitochondrial H2O2 homeodynamics.

For continuous pumping of blood, the heart needs a constant supply of energy (ATP) that is primarily met via oxidative phosphorylation in the mitochondria of cardiomyocytes. However, sustained high rates of electron transport for energy conversion redox reactions predisposes the heart to the production of reactive oxygen species (ROS) and oxidative stress. Mitochondrial ROS are fundamental drivers of responses to environmental stressors including metals but knowledge of how combinations of metals alter mitochondrial ROS homeodynamics remains sparse. We explored the effects and interactions of binary mixtures of copper (Cu), cadmium (Cd), and zinc (Zn), metals that are common contaminants of aquatic systems, on ROS (hydrogen peroxide, H2O2) homeodynamics in rainbow trout (Oncorhynchus mykiss) heart mitochondria. Isolated mitochondria were energized with glutamate-malate or succinate and exposed to a range of concentrations of the metals singly and in equimolar binary concentrations. Speciation analysis revealed that Cu was highly complexed by glutamate or Tris resulting in Cu2+ concentrations in the picomolar to nanomolar range. The concentration of Cd2+ was 7.2-7.5 % of the total while Zn2+ was 15 % and 21 % of the total during glutamate-malate and succinate oxidation, respectively. The concentration-effect relationships for Cu and Cd on mitochondrial H2O2 emission depended on the substrate while those for Zn were similar during glutamate-malate and succinate oxidation. Cu + Zn and Cu + Cd mixtures exhibited antagonistic interactions wherein Cu reduced the effects of both Cd and Zn, suggesting that Cu can mitigate oxidative distress caused by Cd or Zn. Binary combinations of the metals acted additively to reduce the rate constant and increase the half-life of H2O2 consumption while concomitantly suppressing thioredoxin reductase and stimulating glutathione peroxidase activities. Collectively, our study indicates that binary mixtures of Cu, Zn, and Cd act additively or antagonistically to modulate H2O2 homeodynamics in heart mitochondria.

Plasma metals, genetic risk, and rapid kidney function decline among type 2 diabetes.

BACKGROUND: Rapid kidney function decline (RKFD) is a main clinical feature of early chronic kidney disease (CKD) in type 2 diabetes (T2D). Environmental and genetic factors influencing RKFD remain inadequately elucidated. OBJECTIVES: This study aimed to examine the associations of metals with RKFD among T2D and to further investigate the effect of metal mixtures on RKFD with the modifying effect of genetic susceptibility. METHODS: This study included 2209 people with T2D (1942 had genotyping data) free of CKD at baseline from the Dongfeng-Tongji cohort. We used inductively coupled plasma-mass spectrometry (ICP-MS) to measure 23 metals in baseline plasma. Using elastic net (ENET), multivariate logistic regression, and Bayesian kernel machine regression (BKMR) model, we examined independent associations of multiple metals with RKFD. We calculated the environmental risk score (ERS) to assess the effects of metal mixtures on RKFD and the genetic risk score (GRS) to assess genetic susceptibility. RKFD was defined as estimated glomerular filtration rate (eGFR) loss > 3 mL/min/1.73 m2/year. RESULTS: During a median of 9.8 years follow-up, 262 participants developed RKFD. Aluminum, vanadium, zinc, selenium, rubidium, tin, barium, and tungsten were screened from ENET. In multivariate logistic models, vanadium, selenium, and tungsten were negatively associated with RKFD, while zinc, tin, and rubidium were positively associated. The BKMR showed a nonlinear association of vanadium and rubidium with RKFD and interactions between metals (barium­vanadium, barium­rubidium). The ERS was positive associated with RKFD (per SD increase in ERS, OR = 1.94, 95% CI: 1.66, 2.27). No significant interaction between ERS and GRS was observed on RKFD, however, participants in the highest ERS and GRS group had the highest RKFD risk. CONCLUSION: Vanadium and rubidium were associated with RKFD in T2D. Metal mixtures was associated with an increased risk of RKFD in T2D, particularly in those at high genetic risk.

Comparative mathematical modeling of causal association between metal exposure and development of chronic kidney disease.

Background: Previous studies have identified several genetic and environmental risk factors for chronic kidney disease (CKD). However, little is known about the relationship between serum metals and CKD risk. Methods: We investigated associations between serum metals levels and CKD risk among 100 medical examiners and 443 CKD patients in the medical center of the First Hospital Affiliated to China Medical University. Serum metal concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). We analyzed factors influencing CKD, including abnormalities in Creatine and Cystatin C, using univariate and multiple analysis such as Lasso and Logistic regression. Metal levels among CKD patients at different stages were also explored. The study utilized machine learning and Bayesian Kernel Machine Regression (BKMR) to assess associations and predict CKD risk based on serum metals. A chained mediation model was applied to investigate how interventions with different heavy metals influence renal function indicators (creatinine and cystatin C) and their impact on diagnosing and treating renal impairment. Results: Serum potassium (K), sodium (Na), and calcium (Ca) showed positive trends with CKD, while selenium (Se) and molybdenum (Mo) showed negative trends. Metal mixtures had a significant negative effect on CKD when concentrations were all from 30th to 45th percentiles compared to the median, but the opposite was observed for the 55th to 60th percentiles. For example, a change in serum K concentration from the 25th to the 75th percentile was associated with a significant increase in CKD risk of 5.15(1.77,8.53), 13.62(8.91,18.33) and 31.81(14.03,49.58) when other metals were fixed at the 25th, 50th and 75th percentiles, respectively. Conclusions: Cumulative metal exposures, especially double-exposure to serum K and Se may impact CKD risk. Machine learning methods validated the external relevance of the metal factors. Our study highlights the importance of employing diverse methodologies to evaluate health effects of metal mixtures.

Manganese and Vanadium Co-Exposure Induces Severe Neurotoxicity in the Olfactory System: Relevance to Metal-Induced Parkinsonism.

Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl2, V2O5, and MnCl2-V2O5 co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl2 (252 µg) alone, V2O5 (182 µg) alone, or a mixture of MnCl2 (252 µg) and V2O5 (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.

Subchronic Exposure to Mixture of Cadmium, Copper, and Nickel Induces Neurobehavioral Deficits and Hippocampal Oxidative Stress of Wistar Rats.

The present study was aimed at evaluating the influence of the subchronic exposure of cadmium (Cd), copper (Cu), and nickel (Ni) mixtures on affective behaviors, memory impairment, and oxidative stress (OS) in the hippocampus. Thirty male Wistar rats were divided into 5 equal groups. Group 1 (control) received a saline solution (NaCl 0.9%). Groups 2, 3, and 4 received Cd (0.25 mg/kg), Cu (0.5 mg/kg), and Ni (0.25 mg/kg), respectively, while group 5 received a Cd, Cu, and Ni mixture through intraperitoneal injections for 2 months. After the exposure period, all rats were submitted to behavioral tests. Subsequently, OS markers and histological changes in the rats' hippocampi were assessed. Results showed that a 2-month exposure to the mixtures of metals (MM) has led to higher anxiety-like and depression-like behaviors and cognitive deficits in rats when compared to the control group and the individual metals. Furthermore, the MM induced heightened OS, evidenced by the rise in lipid peroxidation and nitric oxide levels. These effects were accompanied by a decrease in superoxide dismutase and catalase activities in the hippocampus. The histopathological analysis also supported that MM caused a neuronal loss in the CA3 sub-region. Overall, this study underscores that subchronic exposure to the Cd, Cu, and Ni mixture induces an OS status and histological changes in the hippocampus, with important affective and cognitive behavior variations in rats.

Cross-sectional and Longitudinal Associations Between Metal Mixtures and Serum C3, C4: Result from the Manganese­exposed Workers Healthy Cohort.

Exposure to metal mixtures compromises the immune system, with the complement system connecting innate and adaptive immunity. Herein, we sought to explore the relationships between blood cell metal mixtures and the third and fourth components of serum complement (C3, C4). A total of 538 participants were recruited in November 2017, and 289 participants were followed up in November 2021. We conducted a cross-sectional analysis at baseline and a longitudinal analysis over 4 years. Least Absolute Shrinkage and Selection Operator (LASSO) was employed to identify the primary metals related to serum C3, C4; generalized linear model (GLM) was further used to evaluate the cross-sectional associations of the selected metals and serum C3, C4. Furthermore, participants were categorized into three groups according to the percentage change in metal concentrations over 4 years. GLM was performed to assess the associations between changes in metal concentrations and changes in serum C3, C4 levels. At baseline, each 1-unit increase in log10-transformed in magnesium, manganese, copper, rubidium, and lead was significantly associated with a change in serum C3 of 0.226 (95% CI: 0.146, 0.307), 0.055 (95% CI: 0.022, 0.088), 0.113 (95% CI: 0.019, 0.206), - 0.173 (95% CI: - 0.262, - 0.083), and - 0.020 (95% CI: - 0.039, - 0.001), respectively. Longitudinally, decreased copper concentrations were negatively associated with an increment in serum C3 levels, while decreased lead concentrations were positively associated with an increment in serum C3 levels. However, no metal was found to be primarily associated with serum C4 in LASSO, so we did not further explore the relationship between them. Our research indicates that copper and lead may affect complement system homeostasis by influencing serum C3 levels. Further investigation is necessary to elucidate the underlying mechanisms.

Metal mixtures and oral health among children and adolescents in the National Health and Nutrition Examination Survey (NHANES), 2017-2020.

INTRODUCTION: Dental caries is the most common non-communicable human disease, yet little is known about the role of environmental metals, despite teeth consisting of a hard matrix of trace elements. We conducted a cross-sectional study of associations between environmental metals and objective assessment of dental caries and subjective assessments of oral health among a representative sample of U.S. children and adolescents. METHODS: Data were from the 2017-March 2020 pre-pandemic data file of the National Health and Nutrition Examination Survey (NHANES). To account for metal mixtures, we used weighted quantile sum (WQS) regression to estimate the joint impact of multiple trace elements assessed in blood and urine with oral disease outcomes. RESULTS: The blood metal mixture index was associated with a 32% (95% CI: 1.11, 1.56) increased risk of decayed surfaces while the urine metal mixture index was associated with a 106%, RR (95% CI = 2.06 (1.58, 2.70) increased caries risk. For both blood and urine, Mercury (Hg) had the largest contribution to the mixture index followed by Lead (Pb). The WQS blood metal mixture index was also significantly associated with poorer self-rated oral health, although the magnitude of the association was not as strong as for the objective oral disease measures, RR (95% CI) = 1.04 (1.02, 1.07). DISCUSSION: Increased exposure to a metal mixture was significantly related to poorer objective and subjective oral health outcomes among U.S. children and adolescents. These are among the first findings showing that metal mixtures are a significant contributor to poor oral health.

Genotoxicity responses of single and mixed exposure to heavy metals (cadmium, silver, and copper) as environmental pollutants in Drosophila melanogaster.

Heavy metals are now persistently present in living things' environments, in addition to their potential toxicity. Therefore, the aim of this study was to utilize D. melanogaster to determine the biological effects induced by different heavy metals including cadmium chloride (CdCl2), copper (II) sulfate pentahydrate (CuSO 4.5 H2O), and silver nitrate (AgNO3). In vivo experiments were conducted utilizing three low and environmentally relevant concentrations from 0.01 to 0.5 mM under single and combined exposure scenarios on D. melanogaster larvae. The endpoints measured included viability, reactive oxygen species (ROS) generation and genotoxic effects using Comet assay and the wing-spot test. Results indicated that tested heavy metals were not toxic in the egg-to adult viability. However, combined exposure (CdCl2+AgNO3 and CdCl2+AgNO3+CuSO 4.5 H2O) resulted in significant genotoxic and unfavorable consequences, as well as antagonistic and/or synergistic effects on oxidative damage and genetic damage.

Prenatal exposure to metal mixtures and childhood temporal processing in the PROGRESS Birth Cohort Study: Modification by childhood obesity.

Children are frequently exposed to various biological trace metals, some essential for their development, while others can be potent neurotoxicants. Furthermore, the inflammatory and metabolic conditions associated with obesity may interact with and amplify the impact of metal exposure on neurodevelopment. However, few studies have assessed the potential modification effect of body mass index (BMI). As a result, we investigated the role of child BMI phenotype on the relationship between prenatal exposure to metal mixtures and temporal processing. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 563) aged 6-9 years completed a Temporal Response Differentiation (TRD) task where they had to hold a lever down for 10-14 s. Blood and urinary metal (As, Pb, Cd, and Mn) measurements were collected from mothers in the 2nd and 3rd trimesters. Child BMI z-scores were dichotomized to normal (between -2 and +0.99) and high (≥1.00). Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate and examine the combined effect of metal biomarkers (i.e., blood and urine) on TRD measures. Effect modification by the child's BMI was evaluated using 2-way interaction terms. Children with a high BMI and greater exposure to the metal mixture during prenatal development exhibited significant temporal processing deficits compared to children with a normal BMI. Notably, children with increased exposure to the metal mixture and higher BMI had a decrease in the percent of tasks completed (ß = -10.13; 95 % CI: -19.84, -0.42), number of average holds (ß = -2.15; 95 % CI: -3.88, -0.41), longer latency (ß = 0.78; 95 % CI: 0.13, 1.44), and greater variability in the standard deviation of the total hold time (ß = 2.08; 95 % CI: 0.34, 3.82) compared to normal BMI children. These findings implicate that high BMI may amplify the effect of metals on children's temporal processing. Understanding the relationship between metal exposures, temporal processing, and childhood obesity can provide valuable insights for developing targeted environmental interventions.

Assessment of sources and health risks of heavy metals in metropolitan household dust among preschool children: The LEAPP-HIT study.

The most common construction material used in Taiwan is concrete, potentially contaminated by geologic heavy metals (HMs). Younger children spend much time indoors, increasing HM exposure risks from household dust owing to their behaviors. We evaluated arsenic (As), cadmium (Cd), and lead (Pb) concentrations in fingernails among 280 preschoolers between 2017 and 2023. We also analyzed HM concentrations, including As, Cd, Pb, chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn), in 90 household dust and 50 road dust samples from a residential area where children lived between 2019 and 2021 to deepen the understanding of sources and health risks of exposure to HMs from household dust. The average As, Cd, and Pb concentrations in fingernails were 0.12 ± 0.06, 0.05 ± 0.05, and 0.95 ± 0.77 µg/g, respectively. Soil parent materials, indoor construction activities, vehicle emissions, and mixed indoor combustion were the pollution sources of HMs in household dust. Higher Cr and Pb levels in household dust may pose non-carcinogenic risks to preschoolers. Addressing indoor construction and soil parent materials sources is vital for children's health. The finding of the present survey can be used for indoor environmental management to reduce the risks of HM exposure and avoid potential adverse health effects for younger children.

Exploring the association between two groups of metals with potentially opposing renal effects and renal function in middle-aged and older adults: Evidence from an explainable machine learning method.

BACKGROUND: Machine learning models have promising applications in capturing the complex relationship between mixtures of exposures and outcomes. OBJECTIVE: Our study aimed at introducing an explainable machine learning (EML) model to assess the association between metal mixtures with potentially opposing renal effects and renal function in middle-aged and older adults. METHODS: This study extracted data from two cycle years of the National Health and Nutrition Examination Survey (NHANES). Participants aged 45 years or older with complete data on six metals (lead, cadmium, manganese, mercury, and selenium) and related covariates were enrolled. The EML model was developed by the optimized machine learning model together with Shapley Additive exPlanations (SHAP) to assess the chronic kidney disease (CKD) risk with metal mixtures. The results from EML were further compared in detail with multiple logistic regression (MLR) and Bayesian kernel machine regression (BKMR). RESULTS: After adjusting for included covariates, MLR pointed out the lead and arsenic were generally positively associated with CKD, but manganese had a negative association. In the BKMR analysis, each metal was found to have a non-linear association with the risk of CKD, and interactions can exist between metals, especially for arsenic and lead. The EML ranked the feature importance: lead, manganese, arsenic and selenium were close behind in importance after gender, age or BMI for participants with CKD. Strong interactions between mercury and lead, manganese and cadmium and arsenic and manganese were identified by partial dependence plot (PDP) of SHAP and bivariate exposure-response effect plots of BKMR. The EML model determined the "trigger point" at which the risk of CKD abruptly changed. CONCLUSION: Co-exposure to metals with different nephrotoxicity could have different joint association with renal function, and EML can be a powerful method for studying complex exposure mixtures.

Association between Mediterranean diet and metal mixtures concentrations in pregnant people from the New Hampshire Birth Cohort Study.

Diet is a primary source of nutrients but also toxic metal exposure. In pregnancy, balancing essential metal exposure while reducing non-essential ones is vital for fetal and maternal health. However, the effect of metal mixtures from diets like the Mediterranean, known for health benefits, remains unclear. This study aimed to explore the association between Mediterranean diet adherence and metals exposure, both individually and as mixtures. The study involved 907 pregnant participants from the New Hampshire Birth Cohort Study. We calculated the relative Mediterranean diet score (rMED) through a validated food frequency questionnaire, which includes 8 traditional Mediterranean dietary components. Also, at ~24-28 weeks of gestation, we used ICP-MS to measure speciation of Al, Cd, Co, Cu, Fe, Hg, Mo, Ni, Sb, Se, Sn, Zn, and As in urine, as well as Pb, Hg, As, Ni, and Se in toenails. We used multiple linear regression and Weighted Quantile Sum regression to analyze the association between rMED and metal mixtures. The models were adjusted for age, pre-pregnancy BMI, smoking during pregnancy, and educational level. High adherence to the Mediterranean diet was associated with increased urinary Al (® = 0.26 (95 % confidence interval (CI) = 0.05; 0.46)), Cd (ß = 0.12 (95%CI = 0.00; 0.24)), Mo (ß = 0.10 (95%CI = 0.00; 0.20)), and AsB (ß = 0.88 (95%CI = 0.49; 1.27)) as well as toenail Hg (ß = 0.44 (95%CI = 0.22; 0.65)), Ni (ß = 0.37 (95%CI = 0.06; 0.67)), and Pb (ß = 0.22 (95%CI = 0.03; 0.40)) compared to those with low adherence. The intake of fruits and nuts, fish and seafood, legumes, cereals, meat, and olive oil were found to be related to the metal biomarkers within the rMED. In conclusion, the Mediterranean diet enhances essential metal intake but may also increase exposure to harmful ones.

Exposure to metal mixtures and adverse pregnancy and birth outcomes: A systematic review.

BACKGROUND: Prenatal exposure to metal mixtures is associated with adverse pregnancy and birth outcomes like low birth weight, preterm birth, and small for gestational age. However, prior studies have used individual metal analysis, lacking real-life exposure scenarios. OBJECTIVES: This systematic review aims to evaluate the strength and consistency of the association between metal mixtures and pregnancy and birth outcomes, identify research gaps, and inform future studies and policies in this area. METHODS: The review adhered to the updated Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist, along with the guidelines for conducting systematic reviews and meta-analyses of observational studies of etiology (COSMOS-E). Our data collection involved searching the PubMed, MEDLINE, and SCOPUS databases. We utilized inclusion criteria to identify relevant studies. These chosen studies underwent thorough screening and data extraction procedures. Methodological quality evaluations were conducted using the NOS framework for cohort and case-control studies, and the AXIS tool for cross-sectional studies. RESULTS: The review included 34 epidemiological studies, half of which focused on birth weight, and the others investigated neonate size, preterm birth, small for gestational age, miscarriage, and placental characteristics. The findings revealed significant associations between metal mixtures (including mercury (Hg), nickel (Ni), arsenic (As), cadmium (Cd), manganese (Mn), cobalt (Co), lead (Pb), zinc (Zn), barium (Ba), cesium (Cs), copper (Cu), selenium (Se), and chromium (Cr)) and adverse pregnancy and birth outcomes, demonstrating diverse effects and potential interactions. CONCLUSION: In conclusion, this review consistently establishes connections between metal exposure during pregnancy and adverse consequences for birth weight, gestational age, and other vital birth-related metrics. This review further demonstrates the need to apply mixture methods with caution but also shows that they can be superior to traditional approaches. Further research is warranted to deeper understand the underlying mechanisms and to develop effective strategies for mitigating the potential risks associated with metal mixture exposure during pregnancy.

Exposure to metal mixtures and young children's growth and development: A biomonitoring-based study in Eastern China.

Exposure to metal mixtures may affect children's health but the conclusions are controversial. We aimed to investigate the associations of metal mixture exposure with children's physical and behavioral development. 15 metals were detected in the urine samples of 278 preschoolers aged 3-6 years from eastern China. Multiple linear models and restricted cubic splines were used to evaluate dose-response relationships between single metal and children's physical and behavioral development. The Bayesian Kernel Machine Regression (BKMR) models, the weighted quantile sum (WQS) models and Quantile G-Computation were applied to evaluate the joint effects of metal mixtures. The results showed that arsenic (As) was negatively associated with z score of height for age (HAZ) in individual-metal models [ß (95%CI): - 0.22 (-0.38, -0.06), P = 0.006]. Concerning children's behavioral development, multiple-metal models demonstrated a negative association with strontium (Sr) [ß (95%CI): - 0.82 (-1.38, -0.26), P = 0.004], and a positive association with tin (Sn) [ß (95%CI): 0.69 (0.16, 1.21), P = 0.010]. Notably, these associations remained significant or suggestive even after adjustments for multiple tests, sensitivity analyses, and application of different statistical models, including BKMR, WQS, and Quantile G-Computation. Furthermore, the study identified a negative joint effect of the metal mixture on HAZ, as demonstrated by BKMR and Quantile G-Computation models, with As playing an irreplaceable role in this observed impact. In summary, exposure to As appears to have adverse effects on HAZ, while exposure to Sn may hinder children's behavioral development. Conversely, exposure to Sr may have a protective effect on children's behavioral development. Additionally, the combined impact of metal mixtures is implicated in potentially impairing children's physical development, particularly in terms of HAZ.

Assessing the effects of single and binary exposures of copper and lead on Mytilus galloprovincialis: Physiological and genotoxic approaches.

It is becoming increasingly recognised that contaminants are not isolated in their threats to the aquatic environment, with recent shifts towards studying the effects of chemical mixtures. In this study, adult marine mussels (Mytilus galloprovincialis) were exposed to two aqueous concentrations of the essential trace metal, Cu (5 and 32 µg L-1), and the non-essential metal, Pb (5 and 25 µg L-1), both individually and in binary mixtures. After a 14-day exposure, metal accumulation was determined in the digestive gland, gill and mantle tissues by inductively coupled plasma-mass spectrometry following acid digestion, and a number of biochemical, neurotoxic and physiological markers were assessed. These included measurements of DNA damage using comet assay, total glutathione concentration, acetylcholinesterase (AChE) activity and clearance rate. Metal accumulation was greater in the digestive gland and gill than in the mantle, and based on computed free ion concentrations, was greater for Pb than for Cu. Copper exhibited an inhibitory effect on Pb accumulation but Pb did not appear to affect Cu accumulation. Comet assay results revealed DNA damage (i.e., genotoxic effects) in all treatments but differences between the exposures were not significant (p > 0.05), and there were no significant differences in AChE activities between treatments. The most distinctive impacts were a reduction in clearance rate resulting from the higher concentration of Cu, with and without Pb, and an increase in glutathione in the gill resulting from the higher concentration of Cu without Pb. Multivariate analysis facilitated the development of a conceptual model based on the current findings and previously published data on the toxicity and intracellular behaviour of Cu and Pb that will assist in the advancement of regulations and guidelines regarding multiple metal contaminants in the environment.

Sex-specific associations between nine metal mixtures in urine and urine flow rate in US adults: NHANES 2009-2018.

Background: The urinary system serves as a crucial pathway for eliminating metallic substances from the body, making it susceptible to the effects of metal exposure. However, limited research has explored the association between metal mixtures and bladder function. This study aims to investigate the relationship between urinary metal mixtures (specifically barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten) and urine flow rate (UFR) in the general population, utilizing multiple mixture analysis models. Methods: This study utilizes data obtained from the National Health and Nutrition Examination Survey. After adjusting for relevant covariates, we assessed the correlations between metal mixtures and UFR using three distinct analysis models: weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). Additionally, a gender-stratified analysis was conducted. Finally, we also performed sensitivity analyses. Results: A total of 7,733 subjects were included in this study, with 49% being male. The WQS regression model, when fitted in the positive direction, did not yield any significant correlations in the overall population or in the male and female subgroups. However, when analyzed in the negative direction, the WQS index exhibited a negative correlation with UFR in the overall group (ß = -0.078; 95% CI: -0.111, -0.045). Additionally, a significant negative correlation between the WQS index and UFR was observed in the female group (ß = -0.108; 95% CI: -0.158, -0.059), while no significant correlation was found in the male group. The results obtained from the qgcomp regression model were consistent with those of the WQS regression model. Similarly, the BKMR regression model revealed a significant negative correlation trend between metal mixtures and UFR, with cadmium and antimony potentially playing key roles. Conclusion: Our study revealed a significant negative correlation between urinary metal mixture exposure and mean UFR in US adults, with notable gender differences. Specifically, higher urinary levels of cadmium and antimony were identified as potential key factors contributing to the decrease in mean UFR. These findings significantly contribute to the existing knowledge on the impact of metal mixtures on bladder function and provide valuable insights for safeguarding bladder health and preventing impaired bladder function.