Search

Background: Evidence suggests that prenatal per- and polyfluoroalkyl substances (PFAS) and metals, two classes of chemicals found ubiquitously in human populations, influence immune system development and response., Objective: We evaluated whether first trimester blood PFAS and metals were associated with antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion., Methods: We measured six PFAS, as well as six nonessential and four essential metals, in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, recruited between 1999 and 2000 in eastern Massachusetts. We measured antigen- or mitogen-stimulated cord blood mononuclear cell proliferation responses (n = 269-314) and cytokine secretion (n = 217-302). We used covariate-adjusted least absolute shrinkage and selection operator (LASSO) for variable selection and multivariable regression to estimate associations with the immune markers., Results: Each ng/mL of MeFOSAA was associated with a 3.6% (1.4, 5.8) higher lymphocyte proliferation response after stimulation with egg antigen, as well as 0.8 (0.7, 1.0) reduced odds of having IFN-γ detected in response to dust mite. Each ng/g increment of cesium was associated with 27.8% (-45.1, -4.9) lower IL-10 levels in response to dust mite. Each ng/g increment of mercury was associated with 12.0% (1.3, 23.8) higher IL-13 levels in response to mitogen PHA. Each ng/g increment of selenium and zinc was associated with 0.2% (0.01, 0.4) and 0.01% (0.002, 0.02) higher TNF-α in response to mitogen PHA, respectively., Conclusions: Prenatal metals and PFAS influence cord blood lymphocyte proliferation and cytokine secretion in ways that may increase risk for atopic disease in childhood., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Metal exposures can adversely impact olfactory function. Few studies have examined this association in children. Further, metal exposure occurs as a mixture, yet previous studies of metal-associated olfactory dysfunction only examined individual metals. Preventing olfactory dysfunctions can improve quality of life and prevent neurodegenerative diseases with long-term health implications., Objective: We aimed to test the association between exposure to a mixture of 12 metals measured in environmental sources and olfactory function among children and adolescents residing in the industrialized province of Brescia, Italy., Methods: We enrolled 130 children between 6 and 13 years old (51.5% females) and used the "Sniffin' Sticks" test to measure olfactory performance in identifying smells. We used a portable X-ray fluorescence instrument to determine concentrations of metals (arsenic (As), calcium, cadmium (Cd), chromium, copper, iron, manganese, lead (Pb), antimony, titanium, vanadium and zinc) in outdoor and indoor deposited dust and soil samples collected from participants' households. We used an extension of weighted quantile sum (WQS) regression to test the association between exposure to metal mixtures in multiple environmental media and olfactory function adjusting for age, sex, socio-economic status, intelligence quotient and parents' smoking status., Results: A higher multi-source mixture was significantly associated with a reduced Sniffin' Sticks identification score (β = -0.228; 95% CI -0.433, -0.020). Indoor dust concentrations of Pb, Cd and As provided the strongest contributions to this association (13.8%, 13.3% and 10.1%, respectively). The metal mixture in indoor dust contributed more (for 8 metals out of 12) to the association between metals and olfactory function compared to soil or outdoor dust., Impact Statement: Among a mixture of 12 metals measured in three different environmental sources (soil, outdoor and indoor dust), we identified Pb, Cd and As measured in indoor dust as the main contributors to reduced olfactory function in children and adolescents residing in an industrialized area. Exposure to indoor pollution can be effectively reduced through individual and public health interventions allowing to prevent the deterioration of olfactory functions. Moreover, the identification of the factors that can deteriorate olfactory functions can be a helpful instrument to improve quality of life and prevent neurodegenerative diseases as long-term health implications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The benefits of nutritional factors on birth outcomes have been recognized, however, limited studies have examined the role of nutritional factors in mitigating the detrimental effects of metals exposure during gestation. We used data collected from 526 mother-infant dyads enrolled in the Programming of Intergenerational Stress Mechanisms longitudinal pregnancy cohort to examine the joint effects of prenatal exposure to metals and maternal nutrition on birth weight for gestational age (BWGA) z-scores. We measured concentrations of twelve metals and trace elements in urine samples collected during pregnancy. Maternal nutritional intake was measured using the Block98 Food Frequency Questionnaire and converted into energy-adjusted consumption of individual nutrients. Using multivariable linear regression and Bayesian Kernel Machine Regression, we found that three metals [cobalt (Co), nickel (Ni), and lead (Pb)] and five metals [barium (Ba), caesium (Cs), copper (Cu), Ni, and zinc (Zn)] were associated with BWGA z-score in male and female infants, respectively. When examining the sex-specific interactions between these metals and nutrient groups [macro nutrients, minerals, A vitamins, B vitamins, anti-oxidant, methyl-donor nutrients, and inflammatory (pro- and anti-)] using a Cross-validated Kernel Ensemble model, we identified significant interactions between the macro nutrients and Co (p = 0.05), minerals and Pb (p = 0.04), and A vitamins and Ni (p = 0.001) in males. No significant interactions were found in females. Furthermore, three minerals (phosphorus, iron, potassium) and vitamin A were found to be more crucial than other nutrients in modifying the association between each respective metal and BWGA z-score in males. A better understanding of the sex-specific interactions between nutrients and metals on birth weight can guide pregnant women to protect their neonates from the adverse health impacts of metal exposures by optimizing nutrient intakes accordingly., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Exposure to low-dose toxic metals in the environment is ubiquitous. Several murine studies have shown metals induce anxiety-like behaviors, and mechanistic research supports that metals disrupt neurotransmitter signaling systems implicated in the pathophysiology of anxiety. In this study, we extend prior research by examining joint exposure to six metals in relation to maternal anxiety symptoms during pregnancy., Methods: The sample includes 380 participants enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. Spot urine was collected during pregnancy (mean ± standard deviation: 31.1 ± 6.1 weeks), and concentrations of six metals (barium [Ba], cadmium [Cd], chromium [Cr], cesium [Cs], lead [Pb], antimony [Sb]) were measured by Inductively Coupled Plasma - Mass Spectrometry. Trait anxiety symptoms were measured during pregnancy using a short version of the Spielberger State Trait Anxiety Inventory (STAI-T) and information on covariates was collected by questionnaire. We used weighted quantile sum (WQS) regression as the primary modeling approach to examine metals, treated as a mixture, in relation to higher (≥20) vs. lower anxiety symptoms while adjusting for urinary creatinine and key sociodemographic variables., Results: The sample is socioeconomically and racially/ethnically diverse. Urinary metal concentrations were log-normally distributed and 25% of the sample had an STAI-T score ≥20. Joint exposure to metals was associated with elevated anxiety symptoms (OR WQS  = 1.56, 95% CI: 1.24, 1.96); Cd (61.8%), Cr (14.7%), and Cs (12.7%) contributed the greatest weight to the mixture effect., Conclusion: Exposure to metals in the environment may be associated with anxiety symptoms during pregnancy. This is a public health concern, as anxiety disorders are highly prevalent and associated with significant co-morbidities, especially during pregnancy when both the mother and developing fetus are susceptible to adverse health outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75 t h percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment., (© 2022 John Wiley & Sons Ltd.)

Background: Dietary sources of metals are not well established among pregnant women in the United States., Objective: We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy., Methods: In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999-2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food-metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals' concentrations., Results: Participants' mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (-0.55 ng/g; 95% CI: -0.82, -0.28 ng/g) and lower Hg (-2.67 ng/g; 95% CI: -3.55, -1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%-50%) and Hg (35%-70%)., Conclusions: Our DWAS provides a systematic evaluation of diet-metals relations. Prenatal diet may be an important source of exposures to metals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The predisposition, severity, and progression of many diseases differ between males and females. Sex-related differences in susceptibility to neurotoxicant exposures may provide insight into the cause of the observed discrepancy. Early adolescence, a period of substantial structural and functional brain changes, may present a critical window of vulnerability to environmental exposures. This study aimed to examine sex-specific associations between co-exposure to multiple metals and visuospatial memory in early adolescence. Manganese (Mn), lead (Pb), chromium (Cr), and copper (Cu) were measured in blood, urine, hair, nails, and saliva of 188 participants (88 girls; 10-14 years of age). Visuospatial memory skills were assessed using a computerized maze task, the virtual radial arm maze (VRAM). Using generalized weighted quantile sum regression, we investigated sex-specific associations between the combined effect of exposure to the metal mixture and visuospatial working memory and determined the contribution of each component to the outcome. The results suggest that sex moderates the association between the metal mixture and visuospatial learning for all outcomes measured. In girls, exposure was associated with slower visuospatial learning and driven by Mn and Cu. In boys, exposure was associated with faster visuospatial learning, and driven by Cr. These results suggest that (a) the effect of metal co-exposure on learning differs in magnitude, and in the direction between sexes, and (b) early adolescence may be a sensitive developmental period for metal exposure.

Background: Research on the health effects of chemical mixtures has focused mainly on early life rather than adolescence, a potentially important developmental life stage., Objectives: We examined associations of a metal mixture with general cognition in a cross-sectional study of adolescents residing near ferromanganese industry, a source of airborne metals emissions., Methods: We measured manganese (Mn), lead (Pb), copper (Cu), and chromium (Cr) in hair, blood, urine, nails, and saliva from 635 Italian adolescents 10-14 years of age. Full-scale, verbal, and performance intelligence quotient (FSIQ, VIQ, PIQ) scores were assessed using the Wechsler Intelligence Scale for Children-III. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of the metal mixture with IQ. In secondary analyses, we used BKMR's hierarchical variable selection option to inform biomarker selection for Mn, Cu, and Cr., Results: Median metal concentrations were as follows: hair Mn, 0.08 μ g / g ; hair Cu, 9.6 μ g / g ; hair Cr, 0.05 μ g / g ; and blood Pb, 1.3 μ g / dL . Adjusted models revealed an inverted U-shaped association between hair Cu and VIQ, consistent with Cu as an essential nutrient that is neurotoxic in excess. At low levels of hair Cu (10th percentile, 5.4 μ g / g ), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr ( 0.3 μ g / g , 2.6 μ g / dL , and 0.1 μ g / g , respectively) were associated with a 2.9 (95% CI: - 5.2 , - 0.5 )-point decrease in VIQ score, compared with median concentrations of the mixture. There was suggestive evidence of interaction between Mn and Cu. In secondary analyses, saliva Mn, hair Cu, and saliva Cr were selected as the biomarkers most strongly associated with VIQ score., Discussion: Higher adolescent levels of Mn, Pb, and Cr were associated with lower IQ scores, especially at low Cu levels. Findings also support further investigation into Cu as both beneficial and toxic for neurobehavioral outcomes. https://doi.org/10.1289/EHP6803.

Background: Stunting is an indicator of poor linear growth in children and is an important public health problem in many countries. Both nutritional deficits and toxic exposures can contribute to lower height-for-age Z-score (HAZ) and stunting (HAZ < -2)., Objectives: In a community-based cross-sectional sample of 97 healthy children ages 6-59 months in Kampala, Uganda, we examined whether exposure to Pb, As, Cd, Se, or Zn were associated with HAZ individually or as a mixture., Methods: Blood samples were analyzed for a mixture of metals, which represent both toxins and essential nutrients. The association between HAZ and metal exposure was tested using multivariable linear regression and Weighted Quantile Sum (WQS) regression, which uses mixtures of correlated exposures as a predictor., Results: There were 22 stunted children in the sample, mean HAZ was -0.74 (SD = 1.84). Linear regression showed that Pb (β = -0.80, p = 0.021) and Se (β = 1.92, p = 0.005) were significantly associated with HAZ. The WQS models separated toxic elements with a presumed negative effect on HAZ (Pb, As, Cd) from essential nutrients with presumed positive effect on HAZ (Se and Zn). The toxic mixture was significantly associated with lower HAZ (β = -0.47, p = 0.03), with 62% of the effect from Pb. The nutrient WQS index did not reach statistical significance (β = -0.47, p = 0.16)., Discussion: Higher blood lead and lower blood selenium level were both associated with lower HAZ. The significant associations by linear regression were reinforced by the WQS models, although not all associations reached statistical significance. These findings suggest that healthy children in this neighborhood of Kampala, Uganda, who have a high burden of toxic exposures, may experience detrimental health effects associated with these exposures in an environment where exposure sources are not well characterized., Competing Interests: The authors have declared that no competing interests exist.

Residential proximity to ferroalloy production has been associated with increased manganese exposure, which can adversely affect health, particularly among children. Little is known, however, about which environmental samples contribute most to internal levels of manganese and other ferroalloy metals. We aimed to characterize sources of exposure to metals and evaluate the ability of internal biomarkers to reflect exposures from environmental media. In 717 Italian adolescents residing near ferromanganese industry, we examined associations between manganese, lead, chromium, and copper in environmental samples (airborne particles, surface soil, indoor/outdoor house dust) and biological samples (blood, hair, nails, saliva, urine). In multivariable regression analyses adjusted for child age and sex, a 10% increase in soil Mn was associated with increases of 3.0% (95% CI: 1.1%, 4.9%) in nail Mn and 1.6% (95% CI: -0.2%, 3.4%) in saliva Mn. Weighted-quantile-sum (WQS) regression estimated that higher soil and outdoor dust Mn accounted for most of the effect on nail Mn (WQS weights: 0.61 and 0.22, respectively, out of a total of 1.0). Higher air and soil Mn accounted for most of the effect on saliva Mn (WQS weights: 0.65 and 0.29, respectively). These findings can help inform biomarker selection in future epidemiologic studies and guide intervention strategies in exposed populations.

Background: Trace metal concentrations may affect cardiometabolic risk, but the role of prenatal exposure is unclear. We examined (1) the relation between blood metal concentrations during pregnancy and child cardiometabolic risk factors; (2) overall effects of metals mixture (essential vs. nonessential); and (3) interactions between metals., Methods: We measured 11 metals in maternal second-trimester whole blood in a prospective birth cohort in Mexico City. In children 4-6 years old, we measured body mass index (BMI), percent body fat, and blood pressure (N = 609); and plasma hemoglobin A1C (HbA1c), non-high-density lipoprotein (HDL) cholesterol, triglycerides, leptin, and adiponectin (N = 411). We constructed cardiometabolic component scores using age- and sex-adjusted z scores and averaged five scores to create a global risk score. We estimated linear associations of each metal with individual z scores and used Bayesian Kernel Machine Regression to assess metal mixtures and interactions., Results: Higher total metals were associated with lower HbA1c, leptin, and systolic blood pressure, and with higher adiponectin and non-HDL cholesterol. We observed no interactions between metals. Higher selenium was associated with lower triglycerides in linear (β = -1.01 z score units per 1 unit ln(Se), 95% CI = -1.84, -0.18) and Bayesian Kernel Machine Regression models. Manganese was associated with decreased HbA1c in linear models (β = -0.32 and 95% CI = -0.61, -0.03). Antimony and arsenic were associated with lower leptin in Bayesian Kernel Machine Regression models. Essential metals were more strongly associated with cardiometabolic risk than were nonessential metals., Conclusions: Low essential metals during pregnancy were associated with increased cardiometabolic risk factors in childhood.

Exposure to environmental chemicals during periods of renal development from embryogenesis to birth and through childhood can inform critical windows of nephrotoxicity, including changes in childhood blood pressure. This review assessed recent studies that examined the relationship of air pollution, metals, and other organic pollutants with children's blood pressure outcomes. We restricted this review to peer-reviewed studies published in English between January 2007 and July 2017. We identified a total of 36 articles that estimated associations with childhood blood pressure, of which 14 studies examined the effects of air pollution, 10 examined metals, and 12 examined other organic pollutants including phthalates (n = 4), Bisphenol A (n = 3), polychlorinated biphenols (n = 2), organophosphate pesticides (n = 2), or perfluoroalkyl acids (n = 1). Similar to the established relationship between tobacco smoke exposure and childhood blood pressure, the majority of studies that examined air pollutants, particularly exposure to PM 10 and PM 2.5 , reported associations with increased childhood blood pressure. The literature reported conflicting evidence for metals, and putative evidence of the effects of exposure to phthalates, Bisphenol A, polychlorinated biphenols, and pesticides. Overall, our review underscores the need for additional studies that assess the impact of nephrotoxicant exposure during early life, particularly the perinatal period, and blood pressure in childhood.

The impact of neurotoxic chemical mixtures on children's health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.

Distributed Lag Models (DLMs) are used in environmental health studies to analyze the time-delayed effect of an exposure on an outcome of interest. Given the increasing need for analytical tools for evaluation of the effects of exposure to multi-pollutant mixtures, this study attempts to extend the classical DLM framework to accommodate and evaluate multiple longitudinally observed exposures. We introduce 2 techniques for quantifying the time-varying mixture effect of multiple exposures on an outcome of interest. Lagged WQS, the first technique, is based on Weighted Quantile Sum (WQS) regression, a penalized regression method that estimates mixture effects using a weighted index. We also introduce Tree-based DLMs, a nonparametric alternative for assessment of lagged mixture effects. This technique is based on the Random Forest (RF) algorithm, a nonparametric, tree-based estimation technique that has shown excellent performance in a wide variety of domains. In a simulation study, we tested the feasibility of these techniques and evaluated their performance in comparison to standard methodology. Both methods exhibited relatively robust performance, accurately capturing pre-defined non-linear functional relationships in different simulation settings. Further, we applied these techniques to data on perinatal exposure to environmental metal toxicants, with the goal of evaluating the effects of exposure on neurodevelopment. Our methods identified critical neurodevelopmental windows showing significant sensitivity to metal mixtures., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Exposure to chemical mixtures is recognized as the real-life scenario in all populations, needing new statistical methods that can assess their complex effects., Objectives: We aimed to assess the joint effect of in utero exposure to arsenic, manganese, and lead on children's neurodevelopment., Methods: We employed a novel statistical approach, Bayesian kernel machine regression (BKMR), to study the joint effect of coexposure to arsenic, manganese, and lead on neurodevelopment using an adapted Bayley Scale of Infant and Toddler Development™. Third Edition, in 825 mother-child pairs recruited into a prospective birth cohort from two clinics in the Pabna and Sirajdikhan districts of Bangladesh. Metals were measured in cord blood using inductively coupled plasma-mass spectrometry., Results: Analyses were stratified by clinic due to differences in exposure profiles. In the Pabna district, which displayed high manganese levels [interquartile range (IQR): 4.8, 18 μg/dl], we found a statistically significant negative effect of the mixture of arsenic, lead, and manganese on cognitive score when cord blood metals concentrations were all above the 60th percentile (As≥0.7 μg/dl, Mn≥6.6 μg/dl, Pb≥4.2 μg/dl) compared to the median (As=0.5 μg/dl, Mn=5.8 μg/dl, Pb=3.1 μg/dl). Evidence of a nonlinear effect of manganese was found. A change in log manganese from the 25th to the 75th percentile when arsenic and manganese were at the median was associated with a decrease in cognitive score of −0.3 (−0.5, −0.1) standard deviations. Our study suggests that arsenic might be a potentiator of manganese toxicity., Conclusions: Employing a novel statistical method for the study of the health effects of chemical mixtures, we found evidence of neurotoxicity of the mixture, as well as potential synergism between arsenic and manganese. https://doi.org/10.1289/EHP614.

Fetal exposure to essential and toxic metals can influence life-long health trajectories. The placenta regulates chemical transmission from maternal circulation to the fetus and itself exhibits a complex response to environmental stressors. The placenta can thus be a useful matrix to monitor metal exposures and stress responses in utero, but strategies to explore the biologic effects of metal mixtures in this organ are not well-developed. In this proof-of-concept study, we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to measure the distributions of multiple metals in placental tissue from a low-birth-weight pregnancy, and we developed an approach to identify the components of metal mixtures that colocalized with biological response markers. Our novel workflow, which includes custom-developed software tools and algorithms for spatial outlier identification and background subtraction in multidimensional elemental image stacks, enables rapid image processing and seamless integration of data from elemental imaging and immunohistochemistry. Using quantitative spatial statistics, we identified distinct patterns of metal accumulation at sites of inflammation. Broadly, our multiplexed approach can be used to explore the mechanisms mediating complex metal exposures and biologic responses within placentae and other tissue types. Our LA-ICP-MS image processing workflow can be accessed through our interactive R Shiny application 'shinyImaging', which is available at or through our laboratory's website, ., Competing Interests: Competing Financial Interests: The authors declare no competing financial interests.

Lead (Pb) and mercury (Hg) neurotoxicity is well established. In recent years, a growing body of evidence suggests that environmental exposure to other metals including arsenic (As), cadmium (Cd), and manganese (Mn) and their mixtures also poses public health threats. In this paper, we summarize the recent literature examining the relationship of prenatal and childhood environmental metal exposures with cognitive and behavioral outcomes in children. We conducted a literature search to identify epidemiologic studies that examined the relationship of Cd, Mn, and metal mixtures with children's neurodevelopmental/cognitive and behavioral outcomes. We restricted the search to peer-reviewed studies published in English between January 2009 and March 2015. We identified a total of 31 articles of which 16, 17, and 16 studies examined the effects of Cd, Mn, or metal mixtures, respectively. Based on our review, there is suggestive evidence that prenatal/childhood Cd exposure may be associated with poorer cognition, but additional research is clearly needed. We found little evidence of behavioral effects of early life Cd exposure, and no studies found a significant relationship with attention deficit hyperactivity disorder. Studies of early life Mn exposure consistently reported negative impacts on both cognition and behavior. There is also growing evidence that co-exposure to multiple metals can result in increased neurotoxicity compared to single-metal exposure, in particular during early life. Few studies have evaluated behavioral effects related to metal co-exposure.

Children living near hazardous waste sites may be exposed to environmental contaminants, yet few studies have conducted multi-media exposure assessments, including residential environments where children spend most of their time. We sampled yard soil, house dust, and particulate matter with aerodynamic diameter <2.5 in 59 homes of young children near an abandoned mining area and analyzed samples for lead (Pb), zinc (Zn), cadmium (Cd), arsenic (As), and manganese (Mn). In over half of the homes, dust concentrations of Pb, Zn, Cd, and As were higher than those in soil. Proximity to mine waste (chat) piles and the presence of chat in the driveway significantly predicted dust metals levels. Homes with both chat sources had Pb, Zn, Cd, and As dust levels two to three times higher than homes with no known chat sources after controlling for other sources. In contrast, Mn concentrations in dust were consistently lower than in soil and were not associated with chat sources. Mn dust concentrations were predicted by soil concentrations and occupant density. These findings suggest that nearby outdoor sources of metal contaminants from mine waste may migrate indoors. Populations farther away from the mining site may also be exposed if secondary uses of chat are in close proximity to the home.

The extent of children's exposure to multiple toxic metals is not well described in many developing countries. We examined metal exposures in young children (6-37 months) from Montevideo, Uruguay and their mothers (15-47 years) participating in a community-based study. Hair samples collected from 180 children and their mothers were analyzed for: lead (Pb), cadmium (Cd), manganese (Mn), and arsenic (As) concentration using inductively coupled plasma-mass spectrometry (ICP-MS). Median metal levels (microg/g) were: Pb 13.69, Mn 1.45, Cd 0.17, and As 0.09 for children and Pb 4.27, Mn 1.42, Cd 0.08, and As 0.02 for mothers. Of the child and maternal samples, 1.7% and 2.9% were below the limit of detection (LOD) for Cd, and 21.3% and 38.5% were below the LOD for As, respectively. Correlations between maternal and child levels ranged 0.38-0.55 (p<0.01). Maternal hair metal levels were the strongest predictors of metal concentrations in children's hair. Girls had significantly lower As levels than boys (p<0.01) but did not differ on other metals. In addition, in bivariate logistic regressions predicting the likelihood that the child would be exposed to multiple metals, hemoglobin <10.5 g/dL (OR=2.12, p<0.05), blood lead (OR=1.17, p<0.01), and the mother being exposed to two or more metals (OR=3.34, p<0.01) were identified as significant predictors of increased likelihood of multiple metal exposure. Older child age (OR=0.96, p<0.05), higher maternal education (OR=0.35, p<0.01), and higher number of household possessions (OR=0.83, p<0.01) were significantly associated with decreased likelihood of multiple metal exposure. Preschool children in Uruguay are exposed to multiple metals at levels that in other studies have been associated with cognitive and behavioral deficits. Sources of exposure, as well as cognitive and behavioral consequences of multiple metal exposure, should be investigated in this population., (Copyright 2010 Elsevier B.V. All rights reserved.)

Metals are ubiquitous and play a critical role in neurobiology. Transition metals are important because they alter the redox state of the physical environment. Biologically, transition metals catalyze redox reactions that are critical to cellular respiration, chemical detoxification, metabolism, and even neurotransmitter synthesis. Many metals are both nutrients and neurotoxicants, such as iron, zinc, copper, and manganese. Other metals, such as lead and cadmium, are metabolized similarly to these metals, particularly iron. Iron metabolism and genes that regulate iron metabolism may be the key to understanding metal toxicity. Finally, recent evidence demonstrates that early life exposures may program later life and adult disease phenotypes via processes of epigenetics. Parallel work in metals demonstrates that epigenetics may be a critical pathway by which metals produce health effects.

BackgroundPrenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR

BackgroundMetal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants.ObjectivesWe evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress.MethodsWe measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions.ResultsA 2-fold increase in maternal magnesium was associated with lower maternal [β=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (β=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (β=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium.DiscussionMaternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.

BackgroundLead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays.MethodsWe developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity.FindingsParticipants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.InterpretationDNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

We applied a novel hierarchical Bayesian weighted quantile sum (HBWQS) regression to combine data across 3 study sites to examine associations between prenatal exposure to metals and cognitive functioning in childhood. Data from 326 mother-child dyads enrolled in an ongoing cohort study, the Programming of Intergenerational Stress Mechanisms (PRISM) Study, based in New York, New York (recruitment in 2013–2020) and Boston, Massachusetts (recruitment 2011–2013), and the First Thousand Days of Life (FTDL) cohort study (recruitment 2012–2019), based in northern Virginia, were used. Arsenic, cadmium, manganese, lead, and antimony were measured in urine collected during pregnancy. Cognitive functioning was assessed in children aged 3–11 years using the National Institutes of Health Toolbox Cognition Battery. The HBWQS regression showed a negative association between the urinary metal mixture and the Cognition Early Childhood Composite Score in the PRISM New York City (β = −3.67, 95% credible interval (CrI): −7.61, −0.01) and FTDL (β = −3.76, 95% CrI: −7.66, −0.24) samples, with a similar trend in the PRISM Boston sample (β = −3.24, 95% CrI: −6.77, 0.144). We did not detect these associations in traditionally pooled models. HBWQS regression allowed us to account for site heterogeneity and detect associations between prenatal metal-mixture exposure and cognitive outcomes in childhood. Given the ubiquity of metals exposure, interventions aimed at reducing prenatal exposure may improve cognitive outcomes in children. This article is part of a Special Collection on Environmental Epidemiology. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. METHODS: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10–14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale–Long Form, Parent Rating Scales Revised–Short Form, and Teacher Rating Scales Revised–Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. RESULTS: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [&#946= 0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% (&#946= 0.04; 95% CrI: 0.00, 0.08), and 4.1% (β= 0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale. CONCLUSIONS: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. [ABSTRACT FROM AUTHOR]

In‐utero exposures interact in complex ways that influence neurodevelopment. Animal research demonstrates that fetal sex moderates the impact of joint exposure to metals and prenatal stress measures, including cortisol, on offspring socioemotional outcomes. Further research is needed in humans. We evaluated the joint association of prenatal exposures to a metal mixture and cortisol with infant negative affectivity, considering sex differences. Analyses included 226 (29% White, Non‐Hispanic) mother‐infant pairs with data on exposures and negative affectivity assessed using the Infant Behavior Questionnaire‐Revised in 6‐month‐olds. Results showed that girls whose mothers had higher cortisol had significantly higher scores of Fear and Sadness with greater exposure to the mixture. Examining higher‐order interactions may better elucidate the effects of prenatal exposure to metals and cortisol on socioemotional functioning. [ABSTRACT FROM AUTHOR]

BACKGROUND: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. OBJECTIVES: Our aim was to evaluate associations of first-trimester (~10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (~3 y) and mid-childhood (~8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. METHODS: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the “nutrient mixture,” as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the “neurotoxic mixture,” in first-trimester (~10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (~3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (~8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. RESULTS: Analyses included 900 mother–child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. DISCUSSION: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. [ABSTRACT FROM AUTHOR]

Background: Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity.Methods: We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715-859), waist circumference (cm) (N = 717-882), and body mass index (BMI) (z-score) (N = 716-875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511-599). We estimated associations using adjusted quantile g-computation and linear regression.Results: The nonessential metal mixture was associated with higher total (β = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (β = 0.12, CI = 0.02, 0.22), waist circumference (β = 0.01, CI = 0.00, 0.01), and BMI (β = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (β = 0.07, CI = 0.01, 0.14), and BMI (β = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(β = -0.11, CI = -0.17, -0.04) and trunk- fat mass index (β = -0.13, CI = -0.21, -0.05), subscapular+tricep skinfold thickness (β = -0.02, CI = -0.03, -0.00), waist circumference (β = -0.003, CI = -0.01, -0.00), and BMI (β = -0.16, CI = -0.28, -0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints.Conclusions: Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence. [ABSTRACT FROM AUTHOR]

Background: Trace metal concentrations may affect cardio-metabolic risk, but the role of prenatal exposure is unclear. We examined: 1) the relationship between blood metal concentrations during pregnancy and child cardio-metabolic risk factors; 2) overall effects of metals mixture (essential vs. nonessential); and 3) interactions between metals.Methods: We measured 11 metals in maternal 2 trimester whole blood in a prospective birth cohort in Mexico City. In children 4-6 years old, we measured body mass index (BMI), percent body fat, and blood pressure (N=609); and plasma hemoglobin A1C (HbA1c) , non-high density lipoprotein (HDL) cholesterol, triglycerides, leptin, and adiponectin (N=411). We constructed cardio-metabolic component scores using age- and sex-adjusted z-scores and averaged five scores to create a global risk score. We estimated linear associations of each metal with individual z-scores and used Bayesian Kernel Machine Regression to assess metal mixtures and interactions.Results: Higher total metals were associated with lower HbA1c, leptin, and systolic blood pressure, and with higher adiponectin and non-HDL cholesterol. We observed no interactions between metals. Higher selenium was associated with lower triglycerides in linear (β=-1.01 z-score units per 1 unit ln(Se), 95%CI = -1.84; -0.18) and Bayesian Kernel Machine Regression models. Manganese was associated with decreased HbA1c in linear models (β = -0.32 and 95% CI: -0.61, -0.03). Antimony and arsenic were associated with lower leptin in Bayesian Kernel Machine Regression models. Essential metals were more strongly associated with cardio-metabolic risk than were nonessential metals.Conclusions: Low essential metals during pregnancy were associated with increased cardio-metabolic risk factors in childhood. [ABSTRACT FROM AUTHOR]

Background: Low-level environmental cadmium exposure and neurotoxicity has not been well studied in adults. Our goal was to evaluate associations between neurocognitive exam scores and a biomarker of cumulative cadmium exposure among adults in the Third National Health and Nutrition Examination Survey (NHANES III). Methods: NHANES III is a nationally representative cross-sectional survey of the U.S. population conducted between 1988 and 1994. We analyzed data from a subset of participants, age 20-59, who participated in a computer-based neurocognitive evaluation. There were four outcome measures: the Simple Reaction Time Test (SRTT: visual motor speed), the Symbol Digit Substitution Test (SDST: attention/perception), the Serial Digit Learning Test (SDLT) trialsto- criterion, and the SDLT total-error-score (SDLT-tests: learning recall/short-term memory). We fit multivariable-adjusted models to estimate associations between urinary cadmium concentrations and test scores. Results: 5662 participants underwent neurocognitive screening, and 5572 (98%) of these had a urinary cadmium level available. Prior to multivariable-adjustment, higher urinary cadmium concentration was associated with worse performance in each of the 4 outcomes. After multivariable-adjustment most of these relationships were not significant, and age was the most influential variable in reducing the association magnitudes. However among never-smokers with no known occupational cadmium exposure the relationship between urinary cadmium and SDST score (attention/perception) was significant: a 1 µg/L increase in urinary cadmium corresponded to a 1.93% (95%CI: 0.05, 3.81) decrement in performance. Conclusions: These results suggest that higher cumulative cadmium exposure in adults may be related to subtly decreased performance in tasks requiring attention and perception, particularly among those adults whose cadmium exposure is primarily though diet (no smoking or work based cadmium exposure). This association was observed among exposure levels that have been considered to be without adverse effects and these levels are common in U.S. adults. Thus further research into the potential neurocognitive effects of cadmium exposure is warranted. Because cumulative cadmium exposure may mediate some of the effects of age and smoking on cognition, adjusting for these variables may result in the underestimation of associations with cumulative cadmium exposure. Prospective studies that include never-smokers and non-occupationally exposed individuals are needed to clarify these issues. [ABSTRACT FROM AUTHOR]

Background: Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD.Methods: Participants were older men from the Normative Aging Study without preexisting coro­nary heart disease, diabetes, or active infection at baseline (n = 426). Serum biomarkers included lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides] and inflammatory markers [C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor receptor-2 (TNF-R2)]. We measured lead in blood and in bone by K-shell X-ray fluorescence. In this sample, 194 men (44.3%) had two or more repeated measures, resulting in 636 observations for analysis. We conducted analyses using mixed effects models with random subject intercepts.Results: Lead levels were associated with several CVD biomarkers, including levels of TNF-R2 and lipid markers. Specifically, in multivariable models, a 50% increase in blood lead level was associ­ated with 26% increased odds of high TNF-R2 levels (> 5.52 ng/mL; odds ratio = 1.26; 95% confi­dence interval: 1.09, 1.45). There were positive associations of blood lead level with total cholesterol and HDL levels, and these associations were more evident when modeled as continuous outcomes than when categorized using clinically relevant cut points. In addition, longitudinal analyses indi­cated a significant increase in TNF-R2 levels over time to be associated with high blood lead level at the preceding visit.Conclusions: Blood lead level may be related with CVD in healthy older men through its asso­ciation with TNF-R2 levels. In addition, the magnitude of the association of blood lead level with TNF-R2 level increased with age in the study population. [ABSTRACT FROM AUTHOR]

Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts. Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP. Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders. Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals. Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure. [ABSTRACT FROM AUTHOR]

Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese-lead interactions in early childhood to examine whether manganese-lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development-II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 µg/L and 21.5 ± 7.4 µg/L for manganese and 5.1 ± 2.6 µg/dL and 5.0 ± 2.9 µg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile x continuous lead; mental development score, â = -1.27 [95% confidence interval (CI): -2.18, -0.37]; psychomotor development score, β = -0.92 (95% CI: -1.76, -0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood. [ABSTRACT FROM AUTHOR]

Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson's disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead. OBJECTIVES: We sought to assess the association between bone lead and PD. METHODS: Bone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression. RESULTS: The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17-8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11-5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01-3.60). We found no association with patella bone lead. CONCLUSIONS: These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead. Objective: In this study we compared associations between lead biomarkers and DNA methylation. Methods: We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data. Results: Overall mean global methylation (± SD) was 26.3 ± 1.0 as measured by Alu and 76.8 ± 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (β = -0.25; p < 0.01) but not Alu (β = -0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1. Conclusion: Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure. [ABSTRACT FROM AUTHOR]

Background: Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD. Methods: Participants were older men from the Normative Aging Study without preexisting coronary heart disease, diabetes, or active infection at baseline (n = 426). Serum biomarkers included lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides] and inflammatory markers [C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor receptor-2 (TNF-R2)]. We measured lead in blood and in bone by K-shell X-ray fluorescence. In this sample, 194 men (44.3%) had two or more repeated measures, resulting in 636 observations for analysis. We conducted analyses using mixed effects models with random subject intercepts. Results: Lead levels were associated with several CVD biomarkers, including levels of TNF-R2 and lipid markers. Specifically, in multivariable models, a 50% increase in blood lead level was associated with 26% increased odds of high TNF-R2 levels (> 5.52 ng/mL; odds ratio = 1.26; 95% confidence interval: 1.09, 1.45). There were positive associations of blood lead level with total cholesterol and HDL levels, and these associations were more evident when modeled as continuous outcomes than when categorized using clinically relevant cut points. In addition, longitudinal analyses indicated a significant increase in TNF-R2 levels over time to be associated with high blood lead level at the preceding visit. Conclusions: Blood lead level may be related with CVD in healthy older men through its association with TNF-R2 levels. In addition, the magnitude of the association of blood lead level with TNF-R2 level increased with age in the study population.

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.

Background: Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead. Objectives: We sought to assess the association between bone lead and PD. Methods: Bone lead concentrations were measured using 109Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression. Results: The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead. Conclusions: These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Background: DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead. Objective: In this study we compared associations between lead biomarkers and DNA methylation. Methods: We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data. Results: Overall mean global methylation (± SD) was 26.3 ± 1.0 as measured by Alu and 76.8 ± 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (β = −0.25; p less than 0.01) but not Alu (β = −0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1. Conclusion: Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.

Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.

Background: Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the "exposome." Mixtures likely have temporal "critical windows" of susceptibility like single agents and measuring them repeatedly might help to define such windows. Common approaches to evaluate the effects of chemical mixtures have focused on their effects at a single time point. Our goal is to expand upon these previous techniques and examine the time-varying critical windows for metal mixtures on subsequent neurobehavior in children.Methods: We propose two methods, joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS), to estimate the effects of chemical mixtures measured across multiple time points, while providing data on their critical windows of exposure. We compare the performance of both methods using simulations. We also applied both techniques to assess second and third trimester metal mixture effects in predicting performance in the Rapid Visual Processing (RVP) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessed at 6-9 years in children who are part of the PROGRESS (Programming Research in Obesity, GRowth, Environment and Social Stressors) longitudinal cohort study. The metals, arsenic, cadmium (Cd), cesium, chromium, lead (Pb) and antimony (Sb) were selected based on their toxicological profile.Results: In simulations, JWQS and MWQS had over 80% accuracy in classifying exposures as either strongly or weakly contributing to an association. In real data, both JWQS and MWQS consistently found that Pb and Cd exposure jointly predicted longer latency in the RVP and that second trimester exposure better predicted the results than the third trimester. Additionally, both JWQS and MWQS highlighted the strong association Cd and Sb had with lower accuracy in the RVP and that third trimester exposure was a better predictor than second trimester exposure.Conclusions: Our results indicate that metal mixtures effects vary across time, have distinct critical windows and that both JWQS and MWQS can determine longitudinal mixture effects including the cumulative contribution of each exposure and critical windows of effect. [ABSTRACT FROM AUTHOR]

Relatively little is known about the immediate and prospective neurodevelopmental impacts of joint exposure to multiple metals (i.e., metal mixtures) in early childhood. To estimate associations of early childhood (∼3 years of age) blood metal concentrations with cognitive test scores at early and mid-childhood (∼8 years of age). We studied children from the Project Viva cohort. We measured erythrocyte concentrations of seven essential (Co, Cu, Mg, Mn, Mo, Se, and Zn) and eight non-essential metals (As, Ba, Cd, Cs, Hg, Pb, Sn, and Sr) in early childhood blood samples. Trained research assistants administered cognitive tests assessing vocabulary, visual-motor ability, memory, and general intelligence (standard deviations: ∼10 points), in early and mid-childhood. We employed multivariable linear regression to examine associations of individual metals with test scores adjusting for confounders, other concurrently measured metals, and first-trimester maternal blood metals. We also estimated joint associations and explored interaction between metals in mixture analyses. We analyzed 349 children (median whole blood Pb ∼1 μg/dL). In cross-sectional analyses, each doubling of Pb was associated with lower visual-motor function (mean difference: −2.43 points, 95% confidence interval (CI): −4.01, −0.86) and receptive vocabulary, i.e., words understood (−1.45 points, 95% CI: −3.26, 0.36). Associations of Pb with mid-childhood cognition were weaker and less precise by comparison. Mg was positively associated with cognition in cross-sectional but not prospective analyses, and cross-sectional associations were attenuated in a sensitivity analysis removing adjustment for concurrent metals. We did not observe joint associations nor interactions. In this cohort with low blood Pb levels, increased blood Pb was robustly associated with lower cognitive ability in cross-sectional analyses, even after adjustment for prenatal Pb exposure, and regardless of adjustment for metal co-exposures. However, associations with mid-childhood cognition were attenuated and imprecise, suggesting some buffering of Pb neurotoxicity in early life. Relatively few studies have comprehensively separated the effects of neurotoxic metals such as lead (Pb) from pre- and postnatal co-occurring metals, nor examined persistence of associations across childhood. In a cohort of middle-class children, we found higher early childhood (∼3 y) blood Pb was associated with lower scores on cognitive tests, independent of other metals and prenatal blood Pb. However, early childhood Pb was only weakly associated with cognition in mid-childhood (∼8 y). Our results suggest the effects of low-level Pb exposure may attenuate over time in some populations, implying the presence of factors that may buffer Pb neurotoxicity in early life. • There is no known safe concentration of lead (Pb) in the blood. • Child blood Pb was associated with lower cognitive ability cross-sectionally. • These associations were weakened in later childhood. • Adverse cognitive effects of Pb may be modifiable. [ABSTRACT FROM AUTHOR]

Abstract Background Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men. Methods In a longitudinal cohort of men age 51–97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates. Results HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (p interaction = 0.021), as well as HFE H63D and vitamin C intake (p interaction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries. Conclusions These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide. Highlights • Interactions with HFE H63D suggest the existence of sensitive subpopulations. • Among HFE H63D homozygotes: those with lower hemoglobin had higher toenail Cd. • The link between low Vitamin C intake and high Cd is amplified with HFE H63D variants. • Those with HFE H63D variants and low hemoglobin or Vitamin C may absorb more Cd. [ABSTRACT FROM AUTHOR]

Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status. We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations. We used cross-sectional data from 383 Italian adolescents (10–14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined. Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = −0.27, 0.50), 0.16 SD (95% CI = −0.11, 0.44), and 0.11 SD (95% CI = −0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: β = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles. In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications. • Metals have been associated with neurodevelopment, and these associations may be modified by iron status. But less is known about metal mixtures. • A mixture of manganese, lead, copper (Cu), chromium, and ferritin was beneficially associated with learning and memory, which was driven by Cu. • A Cu-ferritin interaction was estimated, where Cu was more strongly associated with learning and memory at higher percentiles of ferritin. [ABSTRACT FROM AUTHOR]