Metal Mixture Exposure Research Articles

Assessing the multi-dimensional effects of air pollution on maternal complications and birth outcomes: A structural equation modeling approach

ObjectiveThis cross-sectional study aims to investigate the direct and indirect relationships between exposure to a metal mixture in air and adverse pregnancy outcomes across gestational stages. MethodsWith 46,829 births in 2021 in two Florida counties and Air Quality System data, structural equation modeling was used to construct latent metal mixtures in PM2.5 and unravel their effects on pregnancy complications (preeclampsia and gestational diabetes) and birth outcomes (low birth weight and preterm birth risks). ResultsA latent variable featuring seven metals (Aluminum, Calcium, Iron, Magnesium, Manganese, Silicon, Vanadium) was identified through the measurement model. The latent metal mixture exposure had direct effects on gestational diabetes and preterm birth (1st trimester, 2nd trimester), low birth weight (1st trimester), and preeclampsia (2nd trimester). When considering total effects, the effects on low birth weight in the 1st trimester and on preeclampsia in 2nd trimester were masked, and the latent metal mixture increased the low-birth-weight risk in 2nd trimester by 2 % (OR = 1.02, 95 % CI = [1.00, 1.03]). ConclusionThis study reveals time-dependent associations between a metal mixture in PM2.5 exposure and adverse pregnancy outcomes, highlights the need to address dust in PM2.5, and provides additional evidence for understanding the pathway of the pollution effects on fetal health.

B-158 Association between multiple heavy metals exposure and blood lipid levels: evidence from a cross-sectional study of Korean adults

Abstract Background Metals are ubiquitous in our environment and enter human body via various pathways, such as air, soil, food, water, etc. Increasing studies have found that metals are important risk factors in developing dyslipidemia. However, there is no consensus regarding the effects of co-exposure to multiple metals on blood lipid levels. We investigated both the joint and individual effects of this metal mixture exposure on human blood lipid levels. Methods Blood concentrations of four human toxic metals (Pb, Cs, Hg, and Cd) in 2,798 general populations from Korea were simultaneously determined as a measure of exposure. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of four blood metals and metals mixture with lipid profiles, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Results The mean age of the overall study population was 41.2 ± 9.85 years, and 66.9% were men. The prevalence of overweight or obesity, diabetes, and hypertension in the population was 62.5, 6.8, and 13.9%, respectively. In the multivariable linear regression model, the blood Cs was positively associated with TC and LDL-C(p < 0.05, all), and the blood Pb was positively associated with serum TG (p < 0.05, all). Also, the blood Cd was positively associated with serum HDL-C (p < 0.05, all). We did not identify any other obvious interaction between metals on the lipid profiles using a bivariate exposure-response function in BKMR. Conclusions Our finding suggests that combined exposure to this metal mixture may affect human blood lipid levels. Therefore, reducing exposure to heavy metals, such as Cs and Pb, should be a priority for the general population. However, future studies with a larger number of heavy metals are still needed to focus on the detrimental effects of single metals on lipid profiles as well as to identify key components.

Exposure to Multiple Metal(loid)s and Hypertension in Chinese Older Adults.

Evidence about effects of metal(loid)s on hypertension among adults is insufficient. The aim of our study was to evaluate the individual and joint associations between seven selected metal(loid)s and hypertension, including lead (Pb), manganese (Mn), nickel (Ni), arsenic (As), cadmium (Cd), chromium (Cr), and vanadium (V)) in Chinese older adults. This study included 1009 older adults, and the blood concentrations of seven metal(loid)s were evaluated by inductively coupled plasma mass spectrometry (ICP-MS). The following conditions were considered as hypertension: (1) either systolic blood pressure ≥ 140mm Hg or diastolic blood pressure ≥ 90mm Hg, (2) a self-reported history of hypertension, or (3) currently taking antihypertensive medications. Logistic regression was utilized to investigate the association between individual metal(loid) and hypertension, while Bayesian kernel machine regression (BKMR) was employed to investigate the association of the metal(loid) mixture with hypertension. Adjusted single-metal(loid) model showed a significant positive association between Pb and hypertension (OR = 1.24, 95%CI = 1.03-1.50). This significant association still existed in multi-metal(loid) model (OR = 1.22, 95%CI = 1.01-1.47). BKMR further indicated a positive linear association of Pb with hypertension. The metal(loid) mixture was positively associated with hypertension in older adults, although not significant. Within the mixture, Pb had the highest posterior inclusion probabilities value (PIP = 0.9192). There were multiplicative interactions of Pb and Mn on hypertension. In addition, Pb and Mn had additive effects on the association of other blood metal(loid)s with hypertension. The associations of multiple metal(loid)s with hypertension are dependent on diabetes, areas, age, and BMI. The metal(loid) mixture exposure may contribute to hypertension in Chinese older adults, mainly driven by Pb and interactions of Pb and Mn. Reducing exposure to these metal(loid)s may prevent hypertension among older adults, which is especially true for those living with diabetes.

Early life metal mixture exposure and birth outcomes - PIPA Project - Brazil

Early life metal mixture exposure and birth outcomes - PIPA Project - Brazil

Association of Blood Metals and Metal Mixtures with the Myocardial Enzyme Profile: An Occupational Population-Based Study in China.

To investigate a cross-sectional association between blood metal mixture and myocardial enzyme profile, we quantified creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LD), α-hydroxybutyrate dehydrogenase (α-HBD), and aspartate transaminase (AST) levels among participants from the manganese-exposed workers healthy cohort (MEWHC) (n = 544). The levels of 22 metals in blood cells were determined using inductively coupled plasma mass spectrometry. The least absolute shrinkage and selection operator (LASSO) penalized regression model was utilized for screening metals. The exposure-response relationship between specific metal and myocardial enzyme profile was identified by general linear regression and restricted cubic spline analyses. The overall effect and interactions were evaluated using Bayesian kernel machine regression (BKMR). Manganese was linearly and positively associated with CK (Poverall = 0.019, Pnon-linearity = 0.307), dominating the positive overall effect of mixture exposure (manganese, arsenic, and rubidium) on CK level. Calcium and zinc were linearly and negatively associated with LD levels (Poverall < 0.05, Pnon-linearity > 0.05), and asserted dominance in the negative overall effect of metal mixtures (rubidium, molybdenum, zinc, nickel, cobalt, calcium, and magnesium) on LD level. Interestingly, we observed a U-shaped dose-response relationship of molybdenum with LD level (Poverall < 0.001, Pnon-linearity = 0.015), an interaction between age and calcium on LD level (Pinteration = 0.041), and an interaction between smoking and molybdenum on LD level (Pinteration = 0.035). Our study provides evidence that metal mixture exposure affects the myocardial enzyme profile. Additional investigation is required to confirm these associations, and to reveal the fundamental mechanisms involved.

Association of plasma metals with resting-state functional connectivity in ischemic stroke

BackgroundMetal exposure has long been considered a significant risk factor for ischemic stroke. However, existing data on the effects of metal exposure on brain function in ischemic stroke are limited. Therefore, this study aimed to explore the correlation between exposure to various metals and changes in resting-state functional connectivity (rs-FC) in ischemic stroke patients. MethodsThis study included 28 acute ischemic stroke patients with hemiplegia and 28 matched healthy controls (HCs). All participants underwent T1-weighted MRI and 3.0 T resting-state functional magnetic resonance imaging (fMRI). After MRI acquisition, the rs-FC between 137 cortical and subcortical regions was extracted and preprocessed. Plasma levels of 19 metals were measured using inductively coupled plasma mass spectrometry (ICP-MS). The Bayesian kernel machine regression (BKMR) model and the weighted quantile sum regression (WQS) model were used to assess the overall effect of metal mixture exposure. The severity of neurological deficits in each acute ischemic stroke patient was evaluated using the National Institutes of Health Stroke Scale (NIHSS). Additionally, the associations between exposure to various metals and modifications in brain functional connectivity were determined using Pearson or Spearman correlation analysis. ResultsBilateral brain connectivity was significantly decreased compared to controls and was associated with neurological impairment in ischemic stroke. In patients with ischemic stroke, the plasma concentrations of Cr (p < 0.001), Cu (p = 0.004), As (p = 0.010), Cs (p = 0.046), Rb (p = 0.041), and Sb (p = 0.001) were significantly higher than those in the HCs, whereas the plasma Tl concentrations (p = 0.022) were significantly lower. The results of the BKMR and WQS models showed that combined exposure to metal mixtures was linked to a higher risk of ischemic stroke. Cr was positively correlated with the rs-FC between the left Rolandic_Oper and the left Supp_Motor_Area (r = 0.414, p = 0.029), while negatively correlated with the rs-FC between the right Parietal_Inf and the left supramarginal (r = −0.398, p = 0.037). Cu was negatively correlated with the rs-FC between the left paracentral lobule and the left thalamus (r = −0.409, p = 0.031). Tl was positively correlated with the rs-FC between the right Parietal_Inf and the left supramarginal cortex (r = 0.590, p = 0.001). A negative correlation was observed between Cs and rs-FC between the right Cingulate_Mid and left Occipital_Sup (r = −0.429, p = 0.024). Sb was negatively correlated with the rs-FC between the left Parietal_Inf and the right SupraMarginal (r = −0.384, p = 0.044), the right Parietal_Inf and the left SupraMarginal (r = −0.583, p = 0.001), and the left SupraMarginal and the right SupraMarginal (r = −0.377, p = 0.048). ConclusionPlasma levels of Cr, Cu, Tl, Cs, and Sb were associated with altered rs-FC in brain regions related to motor control, sensory integration, executive function, language processing, and emotional regulation in ischemic stroke patients with basal ganglia infarction.

Serum metabolic changes link metal mixture exposures to vascular endothelial inflammation in residents living surrounding rivers near abandoned lead–zinc mines

Metal exposure is associated with vascular endothelial inflammation, an early pathological phenotype of atherosclerotic cardiovascular events. However, the underlying mechanism linking exposure, metabolic changes, and outcomes remains unclear. We aimed to investigate the metabolic changes underlying the associations of chronic exposure to metal mixtures with vascular endothelial inflammation. We recruited 960 adults aged 20–75 years from residential areas surrounding rivers near abandoned lead–zinc mine and classified them into river area and non-river area exposure groups. Urine levels of 25 metals, Framingham risk score (FRS), and serum concentrations of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as biomarkers of vascular endothelial inflammation, were assessed. A “meet-in-the-middle” approach was applied to identify causal intermediate metabolites and metabolic pathways linking metal exposure to vascular endothelial inflammation in representative metabolic samples from 64 participants. Compared to the non-river area exposure group, the river area exposure group had significantly greater urine concentrations of chromium, copper, cadmium, and lead; lower urine concentrations of selenium; elevated FRS; and increased concentrations of ICAM-1 and VCAM-1. In total, 38 differentially abundant metabolites were identified between the river area and non-river area exposure groups. Among them, 25 metabolites were significantly associated with FRS, 8 metabolites with ICAM-1 expression, and 10 metabolites with VCAM-1 expression. Furthermore, fructose, ornithine, alpha-ketoglutaric acid, urea, and cytidine monophosphate, are potential mediators of the relationship between metal exposure and vascular endothelial inflammation. Additionally, the metabolic changes underlying these effects included changes in arginine and proline metabolism, pyrimidine metabolism, starch and sucrose metabolism, galactose metabolism, arginine biosynthesis, and alanine, aspartate, and glutamate metabolism, suggesting the disturbance of amino acid metabolism, the tricarboxylic acid cycle, nucleotide metabolism, and glycolysis. Overall, our results reveal biomechanisms that may link chronic exposure to multiple metals with vascular endothelial inflammation and elevated cardiovascular risk.

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

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. 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 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. 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.

Metal mixture exposures and serum lipid levels in childhood: the Rhea mother-child cohort in Greece.

Growing evidence suggests that cardiovascular disease develops over the lifetime, often beginning in childhood. Metal exposures have been associated with cardiovascular disease and important risk factors, including dyslipidemia, but prior studies have largely focused on adult populations and single metal exposures. To investigate the individual and joint impacts of multiple metal exposures on lipid levels during childhood. This cross-sectional study included 291 4-year-old children from the Rhea Cohort Study in Heraklion, Greece. Seven metals (manganese, cobalt, selenium, molybdenum, cadmium, mercury, and lead) were measured in whole blood using inductively coupled plasma mass spectrometry. Serum lipid levels included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. To determine the joint and individual impacts of child metal exposures (log2-transformed) on lipid levels, Bayesian kernel machine regression (BKMR) was employed as the primary multi-pollutant approach. Potential effect modification by child sex and childhood environmental tobacco smoke exposure was also evaluated. BKMR identified a positive association between the metal mixture and both total and LDL cholesterol. Of the seven metals examined, selenium (median 90.6 [IQR = 83.6, 96.5] µg/L) was assigned the highest posterior inclusion probability for both total and LDL cholesterol. A difference in LDL cholesterol of 8.22 mg/dL (95% CI = 1.85, 14.59) was observed when blood selenium was set to its 75th versus 25th percentile, holding all other metals at their median values. In stratified analyses, the positive association between selenium and LDL cholesterol was only observed among boys or among children exposed to environmental tobacco smoke during childhood. Growing evidence indicates that cardiovascular events in adulthood are the consequence of the lifelong atherosclerotic process that begins in childhood. Therefore, public health interventions targeting childhood cardiovascular risk factors may have a particularly profound impact on reducing the burden of cardiovascular disease. Although growing evidence supports that both essential and nonessential metals contribute to cardiovascular disease and risk factors, such as dyslipidemia, prior studies have mainly focused on single metal exposures in adult populations. To address this research gap, the current study investigated the joint impacts of multiple metal exposures on lipid concentrations in early childhood.

Thyroid under siege: Unravelling the toxic impact of real-life metal mixture exposures in Wistar rats

This study explored the effect of a toxic metal(oid) mixture (cadmium, lead, arsenic, mercury, chromium, and nickel) on thyroid function in Wistar rats exposed for 28 or 90 days. Dose levels were determined based on prior human-biomonitoring investigation. The experiment included control (male/female rats, 28 and 90 days) and treated groups, reflecting the lower confidence limit of the Benchmark Dose (BMDL) for hormone levels (M1/F1, 28 and 90 days), median concentrations (M2/F2, 28 and 90 days), 95th percentile concentrations (M3/F3, 28 and 90 days) measured in a human study, and reference values for individual metals extracted from the literature (M4/F4, 28 days only). Blood and thyroid gland samples were collected at the experimental termination. Serum TSH, fT3, fT4, T3, and T4 levels were measured, and SPINA-GT and SPINA-GD parameters were calculated. In silico analysis, employing the Comparative Toxicogenomic Database and ToppGene Suite portal, aimed to reveal molecular mechanisms underlying the observed effects. Results showed greater sensitivity in the female rats, with significant effects observed at lower doses. Subacute exposure increased TSH, fT3, and T3 levels in females, while subchronic exposure in males decreased TSH and fT3 levels and increased fT4. Subacute exposure induced changes even at allegedly safe doses, emphasizing potential health risks. Histological abnormalities were observed in all the treated groups. In silico findings suggested that toxic metal exposure contributes to thyroid disorders via oxidative stress, disruption of micronutrients, interference with hormone synthesis, and gene expression dysregulation. These results indicate that seemingly safe doses in single-substance research can adversely affect thyroid structure and function when administered as a mixture. These findings highlight the complex impact of toxic metal exposure on thyroid health, emphasizing that adhering to accepted safety limits for single-substance research fails to account for adverse effects on thyroid structure and function upon exposures to metal mixtures.

Associations between maternal exposure to multiple metals and metalloids and blood pressure in preschool children: A mixture-based approach

BackgroundExposure to metals during pregnancy can potentially influence blood pressure (BP) in children, but few studies have examined the mixed effects of prenatal metal exposure on childhood BP. We aimed to assess the individual and combined effects of prenatal metal and metalloid exposure on BP in preschool children. MethodsA total of 217 mother–child pairs were selected from the Zhuang Birth Cohort in Guangxi, China. The maternal plasma concentrations of 20 metals [e.g. lead (Pb), rubidium (Rb), cesium (Cs), and zinc (Zn)] in early pregnancy were measured by inductively coupled plasmamass spectrometry. Childhood BP was measured in August 2021. The effects of prenatal metal exposure on childhood BP were explored by generalized linear models, restricted cubic spline and Bayesian kernel machine regression (BKMR) models. ResultsIn total children, each unit increase in the log10-transformed maternal Rb concentration was associated with a 10.82-mmHg decrease (95% CI: −19.40, −2.24) in childhood diastolic BP (DBP), and each unit increase in the log10-transformed maternal Cs and Zn concentrations was associated with a 9.67-mmHg (95% CI: −16.72, −2.61) and 4.37-mmHg (95% CI: −8.68, −0.062) decrease in childhood pulse pressure (PP), respectively. The log10-transformed Rb and Cs concentrations were linearly related to DBP (P nonlinear=0.603) and PP (P nonlinear=0.962), respectively. Furthermore, an inverse association was observed between the log10-transformed Cs concentration and PP (β =-12.18; 95% CI: −22.82, −1.54) in girls, and between the log10-transformed Rb concentration and DBP (β =-12.54; 95% CI: −23.87, −1.21) in boys, while there was an increasing association between the log10-transformed Pb concentration and DBP there was an increasing in boys (β =6.06; 95% CI: 0.36, 11.77). Additionally, a U-shaped relationship was observed between the log10-transformed Pb concentration and SBP (P nonlinear=0.015) and DBP (P nonlinear=0.041) in boys. Although there was no statistically signiffcant difference, there was an inverse trend in the combined effect of maternal metal mixture exposure on childhood BP among both the total children and girls in BKMR. ConclusionsPrenatal exposure to both individual and mixtures of metals and metalloids influences BP in preschool children, potentially leading to nonlinear and sex-specific effects.

Associations between maternal blood metal concentrations during the first trimester and spontaneous preterm birth: a nested case-control study

BackgroundFew studies have utilized whole blood samples to investigate the association between metal mixture exposure during early pregnancy and spontaneous preterm birth (SPB). We conduct this nested case–control study to investigate both the independent and joint effect of each metal, and identify critical metals in the metal mixture.ResultsA total of 120 pregnant women with SPB and 120 pregnant women with full-term delivery were selected from the prospective birth cohort. We measured 14 metal concentrations in maternal blood collected during 10–13 weeks gestation. Conditional logistic regression showed that high concentrations of vanadium (V), magnesium, and copper were positively associated with SPB (Adjusted OR = 5.76 (95% CI 2.46–13.53), 3.64 (95% CI 1.64–8.09), 2.88 (95% CI 1.29–6.41), respectively). Moderate manganese (Mn) concentration (50th–75th percentile) group had the lowest estimated OR (Adjusted OR = 0.32 (95% CI 0.13–0.76)). The high level of strontium (Sr) was negatively associated with SPB (Adjusted OR = 0.39 (95% CI 0.17–0.91)). The BKMR model showed a significant positive joint effect of metal mixture exposure on SPB, while V was the most important metal. The non-linear effects of V and lead (Pb) on SPB, and the interaction effects between V–Pb, Sr–Mn were also revealed.ConclusionsMaternal blood metal mixtures in the first trimester were found to be positively associated with SPB, with V exhibiting the strongest independent association. Mn had a potential U-shaped association with SPB. Elimination of metal contamination in the environment has a positive impact on maternal and child health.

Metal (loid) Exposure and Overweight and Obesity in 6–12-Year-Old Spanish Children

Epidemiological studies focusing on metal(oid) exposure and excess body weight among children show inconsistent results and the influence of metal(loid) mixtures has been little studied. We aimed to explore the effect of 10 metal(loid)s, individually and in combinations, on overweight and obesity among children aged 6–12. Urinary levels of these metal(oid)s from 92 controls and 51 cases with overweight and obesity were analyzed. Metal(loid) levels were log-transformed and categorized into tertiles according to the control group cutoff points. Two logistic regression models and weighted quantile sum regressions (WQS) were run: model 1 adjusting for age, sex, creatinine, energy intake and physical activity and model 2 additionally adjusting for maternal education, rice and fish consumption. In the single metal(oid) exposure model, there was a trend of significant negative association for urinary cobalt (Co), where children in the third tertile had lower odds of present overweight and obesity than those in the first (Odds Ratio, OR = 0.43; 95% Confidence Interval, CI = 0.20–0.93). Urinary chromium (Cr) levels were borderline-significant negatively associated with overweight and obesity (ORa = 1.70; 95% CI = 0.97–2.98). Molybdemun, Cr and Co had a major contribution to the inverse association between metal(loid) mixture and overweight and obesity as well as lead, cadmium and total arsenic in the positive relationship. Our findings in this explorative study suggested an inverse association of high urinary Co levels with overweight and obesity. Moreover, metal(loid) mixture exposure may have influence on overweight and obesity with an important contribution of Co in the potential negative effect.

Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting “no-threshold” concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies.

Impairments of Spatial Memory and N-methyl-d-aspartate Receptors and Their Postsynaptic Signaling Molecules in the Hippocampus of Developing Rats Induced by As, Pb, and Mn Mixture Exposure.

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development.

Preterm Birth and Metal Mixture Exposure among Pregnant Women from the Navajo Birth Cohort Study.

Preterm birth (PTB), defined as birth before 37 wk gestation, is associated with hypertension, diabetes, inadequate prenatal care, unemployment or poverty, and metal exposure. Indigenous individuals are more likely to have maternal risk factors associated with PTB compared with other populations in the United States; however, the role of environmental metals on PTB among pregnant Indigenous women remains uncertain. Previous research identified associations between PTB and individual metals, but there is limited investigation on metal mixtures and this birth outcome. We used a mixtures analysis framework to investigate the association between metal mixtures and PTB among pregnant Indigenous women from the Navajo Birth Cohort Study (NBCS). Maternal urine and blood samples were collected at the time of study enrollment and analyzed for metals by inductively coupled plasma dynamic reaction cell mass spectrometry. Bayesian Profile Regression was used to identify subgroups (clusters) of individuals with similar patterns of coexposure and to model association with PTB. Results indicated six subgroups of maternal participants with distinct exposure profiles, including one group with low exposure to all metals and one group with total arsenic, cadmium, lead, and uranium concentrations exceeding representative concentrations calculated from the National Health and Nutrition Examination Survey (NHANES). Compared with the reference group (i.e., the lowest exposure subgroup), the subgroup with the highest overall exposure had a relative risk of PTB of 2.9 times (95% credible interval: 1.1, 6.1). Exposures in this subgroup were also higher overall than NHANES median values for women 14-45 years of age. Given the wide range of exposures and elevated PTB risk for the most exposed subgroups in a relatively small study, follow-up investigation is recommended to evaluate associations between metal mixture profiles and other birth outcomes and to test hypothesized mechanisms of action for PTB and oxidative stress caused by environmental metals. https://doi.org/10.1289/EHP10361.

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 [β (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) [β (95%CI): − 0.82 (−1.38, −0.26), P = 0.004], and a positive association with tin (Sn) [β (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.

Hepato-renal toxicity of low dose metal(oid)s mixture in real-life risk simulation in rats: Effects on Nrf2/HO-1 signalling and redox status

The understanding that humans are exposed to a low level of toxic metals and metalloids in their lifetime has resulted in a shift in scientific and regulatory perspectives from the traditional evaluation of single metal toxicity to complex mixtures, relevant to real-life exposure. Therefore, the aim of this study was to examine the impact of real-life, 90-days exposure to mixture of toxic metal(oid)s, Cd, Pb, Ni, Cr, As and Hg, on the nuclear factor erythroid 2–related factor 2 and hemoxygenase-1 (Nrf2/HO-1) signalling and redox status by assessing total sulfhydryl groups (SH), glutathione (GSH), superoxide dismutase activity (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) in the liver and kidney of Wistar rats. Animals (20 males and 20 females) were randomized in 2 control and 6 treated groups that received by oral gavage mixture of metal(oid)s solutions in doses that reflect blood metal(oid) levels determined in previous human biomonitoring study as benchmark dose (F/M _BMD), median (F/M _MED), and 95th percentile (F/M _95). Our results have shown that metal(oid)s mixture impaired the activation of the Nrf2/HO-1 pathway in the kidney and liver of male rats and kidney of female rats, followed by depletion of GSH levels in males. Additionally, in males elevated levels of IMA in the liver were observed, while in both genders increased MDA levels were observed in the kidney. Interestingly, the effects were more pronounced in male than in female rats. This study is among the first that examined hepato-renal toxic mechanisms of real-life metal mixture exposure, while our results might be of immense importance for assessing the risk of exposure to mixtures of toxic substances.

Co-exposure to lead, mercury, and cadmium induces neurobehavioral impairments in mice by interfering with dopaminergic and serotonergic neurotransmission in the striatum.

Humans are exposed to lead (Pb), mercury (Hg), and cadmium (Cd) through various routes, including drinking water, and such exposure can lead to a range of toxicological effects. However, few studies have investigated the toxic effects of exposure to mixtures of metals, particularly in relation to neurotoxicity. In this study, 7-week-old male mice were exposed to Pb, Hg, and Cd individually or in combination through their drinking water for 28 days. The mice exposed to the metal mixture exhibited significantly reduced motor coordination and impaired learning and memory abilities compared to the control group and each of the single metal exposure groups, indicating a higher level of neurotoxicity of the metal mixture. The dopamine content in the striatum was significantly lower in the metal mixture exposure group than in the single metal exposure groups and the control group. Furthermore, compared to the control group, the metal mixture exposure group showed a significantly lower expression level of tyrosine hydroxylase (TH) and significantly higher expression levels of dopamine transporter (DAT), tryptophan hydroxylase 1 (TPH1), and serotonin reuptake transporter (SERT). Notably, there were no significant differences in SERT expression between the single metal exposure groups and the control group, but SERT expression was significantly higher in the metal mixture exposure group than in the single metal and control groups. These findings suggest that the key proteins involved in the synthesis and reuptake of dopamine (TH and DAT, respectively), as well as in the synthesis and reuptake of serotonin (TPH1 and SERT, respectively), play crucial roles in the neurotoxic effects associated with exposure to metal mixtures. In conclusion, this study demonstrates that simultaneous exposure to different metals can impact key enzymes involved in dopaminergic and serotonergic neurotransmission processes, leading to disruptions in dopamine and serotonin homeostasis and consequently a range of detrimental neurobehavioral effects.

Associations between parental and postnatal metal mixture exposure and developmental delays in a Taiwanese longitudinal birth cohort of preschool children.

Studies have evaluated the impact of environmental exposure to neurotoxic metals on developmental delays (DDs). However, comprehensive understanding regarding the associations between parental and postnatal exposure to metal mixtures and the occurrence of DDs in offspring is limited. In this study, we assessed the relationships between parental and postnatal exposure to three metals (arsenic [As], cadmium [Cd], and lead [Pb], levels of which were measured in toenails) and suspected DDs (SDDs) in preschool children within a Taiwanese longitudinal birth cohort. In total between 2017 and 2021, 154 pairs of parents and their children under the age of 6 years were recruited, and 462 toenail samples and 154 completed questionnaires were collected. Metal concentrations in toenails were quantified using inductively coupled plasma-mass spectrometry after acid digestion of the toenails. We applied multivariable logistic regression and Bayesian kernel machine regression to evaluate the overall effect and to identify key components of the metal mixture that were associated with the SDD risk. Higher concentrations of As, Cd, and Pb were found in the toenails of the parents of children with SDDs compared with the toenails of the parents of children without SDDs. Our examination of the combined effects of exposure to the metal mixture revealed that As concentration in the father's toenail and Cd concentration in the mother's toenail were positively correlated with the risk of SDDs in their offspring. Notably, the effect of exposure to the metal mixture on the risk of SDDs was stronger in boys than in girls. Our findings suggest that parents taking measures to minimize their exposure to metals might enhance their children's developmental outcomes.