The impact of prenatal iron deficiency (ID) on offspring's blood lead level (BLL) and blood manganese level (BML) in infancy remains poorly understood. This study aimed to assess associations between prenatal ID and BLL/BML in offspring in Benin. We also investigated associations between infant ID and corresponding BLL and BML in infants.

Data on hematological parameters, metal blood concentrations, and socioeconomic status were obtained from a prospective mother-child cohort study in Allada, Benin. Blood samples were collected during pregnancy (n = 501), at delivery (n = 501), and from 12-month-old infants (n = 501) to assess iron deficiency and haemoglobin concentration. Additionally, BML was analyzed for a subset of 12-month-old infants (n = 271), and BLL was determined for the full cohort of 12-month-old infants (n = 501). Associations between ID and metal concentrations were examined using logistic regressions.

Prenatal ID and IDA at the first and third antenatal care visit (ANC) were positively associated with infant BLL above 50 μg/L. Infants of mothers with prenatal ID and IDA had higher BLL. Moreover, prenatal ID and IDA at first and second ANC visits were positively associated with higher infant BML. In infancy, infants with ID and IDA had significantly higher BLL as compared to those without ID and IDA. Infant ID and IDA were positively associated with elevated BLL.

Elevated BLL and BML in infants were positively associated with ID and/or IDA prenatally during at least one ANC visit, while in infancy, infant ID and IDA were positively associated with elevated BLL only. Infants with ID and IDA showed higher BLL but not BML. This suggests that ID prenatally and during infancy may contribute to high blood lead concentrations in infants, which can lead to neurotoxicity. Treating ID and IDA is critical to prevent toxicity caused by high BLL in infants.

Anemia significantly impacts children's health and quality of life, and may be influenced by the levels of various trace metals in the body. Current research on trace metals and anemia is mostly limited to single metals, and the association of multiple trace metals and their mixtures with anemia among children remains unclear.

This study utilized cross-sectional data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES), including 2208 children aged 6-17 years in the United States, who were tested for five trace metals: lead(Pb), mercury(Hg), cadmium(Cd), selenium(Se), and manganese(Mn). The study used logistic regression, quantile g-computation, and Bayesian kernel machine regression models to examine how these metals individually and collectively affect anemia and to identify significant influencing factors. Age-stratified analysis was also conducted to analyze the association of trace metals with anemia in different age groups.

Children with anemia had significantly higher blood Cd levels and significantly lower Se and Mn levels. In the univariate metal model, increasing Se levels was associated with decreased anemia risk. Mn was the main protective factor for anemia in school-age children, while Se was the main protective factor in adolescents. Both qgComp and BKMR models showed a negative association between mixed trace metal exposure and anemia. The age-specific analysis showed that the protective effect of trace metals was not as apparent in adolescents.

This research discovered that mixed trace metal exposure was associated with a reduced risk of anemia in children, with Se acting as a protective factor across all populations. Mn played a protective role in school-age children but may become a risk factor in adolescents.

Heavy metal exposure has been associated with poor sleep, but little is known about the cumulative associations of multiple metals with sleep duration, particularly among adolescents. This study examined the association of blood lead (Pb), cadmium (Cd), and mercury (Hg) concentrations with sleep duration and possible effect modification by vitamin D.

The study sample consisted of 16-25-year-olds (n = 2637) from the 2011-2018 National Health and Nutrition Examination Survey. The association of each blood metal and serum vitamin D level with self-reported sleep duration was examined through linear regression models. Interaction terms and stratified models tested the effect modification of metal association with sleep by vitamin D level or status. Cumulative and interactive associations among the metals and serum vitamin D were also estimated using Bayesian Kernel Machine Regression (BKMR).

In linear regressions, there was little evidence of an association between individual metals, vitamin D level, and sleep duration. Both linear regressions and BMKR models showed little indication of interactions among metals and vitamin D levels. BKMR results suggested an overall joint association, with longer sleep duration at higher percentile of the metal-vitamin D mixture (75th percentile vs 50th: β=0.07 hours; 95 % CrI: 0.01, 0.13).

In the context of low-level metal exposure, individual metals were unrelated to sleep duration. We found some evidence that higher levels of the mixture of blood Pb, Cd, Hg, and serum vitamin D level may be associated with slightly longer sleep duration, underscoring the importance of considering multiple environmental exposures. Additional analyses, especially in higher risk groups (e.g., higher exposures; higher prevalence or severity of vitamin D deficiency) are warranted.

Chronic kidney disease (CKD) is now the world's top seventh cause of death from a non-communicable disease, and its incidence is projected to increase further as its major risk factors, including obesity, diabetes, hypertension, and non-alcoholic fatty liver disease (NAFLD), continue to rise. Current evidence has linked the increased prevalence of CKD, diabetes, hypertension, and NAFLD to chronic exposure to the metal pollutant cadmium (Cd). Exposure to Cd is widespread because diet is the main exposure route for most people. Notably, however, the health risk of dietary Cd exposure is underappreciated, and the existing tolerable exposure guidelines for Cd do not afford health protection. New health-protective exposure guidelines are needed. From one's diet, Cd is absorbed by the intestinal epithelium from where it passes through the liver and accumulates within the kidney tubular epithelial cells. Here, it is bound to metallothionine (MT), and as it is gradually released, it induces tubular damage, tubulointerstitial inflammation and fibrosis, and nephron destruction. The present review provides an update on our knowledge of the exposure levels of Cd that are found to be associated with CKD, NAFLD, and mortality from cardiovascular disease. It discusses the co-existence of hypertension and CKD in people environmentally exposed to Cd. It highlights nuclear and mitochondrial targeting and zinc deficiency as the universal cytotoxic mechanisms of Cd. Special emphasis is placed on the novel antioxidative function of zinc involving de novo heme biosynthesis and the induced expression of heme oxygenase-1 (HO-1). Other exogenous biomolecules with promising anti-Cd toxicity are highlighted.

Anemia significantly contributes to the global disease burden, with its incidence potentially influenced by the trace metal content within the body.

This study aims to examine the associations between trace metals and anemia risk, with a particular focus on investigating the potential mediating roles of iron status and inflammation in these associations.

Five trace metals (Ni, Co, Mn, Se, and Mo) were examined in 1274 US adults, utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020. The individual and combined effects of these metals on anemia were assessed using logistic regression, quantile g-computation (QGC), and Bayesian kernel machine regression (BKMR). A sex-stratified analysis was conducted to discern any gender-specific susceptibilities. Additionally, mediation analysis was employed to explore the potential mediating roles of iron status and inflammation in the associations between these metals and anemia.

Increased risks of anemia were positively associated with Co and Ni levels but negatively correlated with Se and Mn levels (all with p < 0.05). The trace metal mixture was negatively associated with anemia, with the highest weights of Co and Se in different directions in both the QGC and BKMR models. In the sex-specific analysis, we observed less pronounced protective effects from trace metals in females. Moreover, the mediating proportion of the iron status and inflammation in these relationships ranged from 10.29% to 58.18%.

Our findings suggest that the trace element mixture was associated with decreased anemia risk, among which Se was a protective factor while Co was a risk factor, and females were more susceptible. The effects of these trace metals on anemia may be mediated by the iron status and inflammation.

The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure.

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.

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.

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.

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% [β = 0.03 ; 95% credible interval (CrI): - 0.01 , 0.06], 4.1% (β = 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.

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. https://doi.org/10.1289/EHP12988.

Metals, including lead (Pb), manganese (Mn), chromium (Cr) and copper (Cu), have been associated with neurodevelopment; iron (Fe) plays a role in the metabolism and neurotoxicity of metals, suggesting Fe may mediate metal-neurodevelopment associations. However, no study to date has examined Fe as a mediator of the association between metal mixtures and neurodevelopment.

We assessed Fe status as a mediator of a mixture of Pb, Mn, Cr and Cu in relation to verbal learning and memory in a cohort of Italian adolescents.

We used cross-sectional data from 383 adolescents (10-14 years) in the Public Health Impact of Metals Exposure Study. Metals were quantified in blood (Pb) or hair (Mn, Cr, Cu) using ICP-MS, and three markers of Fe status (blood hemoglobin, serum ferritin and transferrin) were quantified using luminescence assays or immunoassays. Verbal learning and memory were assessed using the California Verbal Learning Test for Children (CVLT-C). We used Bayesian Kernel Machine Regression Causal Mediation Analysis to estimate four mediation effects: the natural direct effect (NDE), natural indirect effect (NIE), controlled direct effect (CDE) and total effect (TE). Beta (β) coefficients and 95 % credible intervals (CIs) were estimated for all effects.

The metal mixture was jointly associated with a greater number of words recalled on the CVLT-C, but these associations were not mediated by Fe status. For example, when ferritin was considered as the mediator, the NIE for long delay free recall was null (β = 0.00; 95 % CI = -0.22, 0.23). Conversely, the NDE (β = 0.23; 95 % CI = 0.01, 0.44) indicated a beneficial association of the mixture with recall that operated independently of Fe status.

An industry-relevant metal mixture was associated with learning and memory, but there was no evidence of mediation by Fe status. Further studies in populations with Fe deficiency and greater variation in metal exposure are warranted.

Iron deficiency (ID) and environmental exposure to metals frequently co-occur among Ugandan children, but little is known about their associations, although iron and other divalent metals share the same intestinal absorption transporter, divalent metal transporter 1 (DMT1).

We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture.

We used data on sociodemographic status, iron biomarkers, and blood concentrations of heavy metals collected from a cross-sectional survey of 100 children aged 6-59 mo in Kampala, Uganda. We compared blood concentrations of metals in ID with iron-sufficient children. We examined associations between a metal mixture and iron biomarkers using multiple linear regression and weighted quintile sum regression.

The median (interquartile range) blood Mn (μg/L) was higher in ID children defined by soluble transferrin receptor (sTfR) and ferritin (ID compared with iron-sufficient children): (sTfR [21.3 {15.1, 28.8}, 11.2 {8.6, 18.5}], ferritin [19.5 {15.0, 27.2}, 11.2 {8.8, 19.6}]; P < 0.001 for both). Similarly, the median (interquartile range) blood Co (μg/L) was higher in ID children by ferritin ([0.5 {0.4, 0.9}, 0.4 {0.3, 0.5}], P = 0.05). Based on the multiple linear regression results, higher blood Co and Mn were associated with poorer iron status (defined by all 4 iron indicators for Co and by sTfR for Mn). The weighted quintile sum regression result showed that higher blood concentrations of a metal mixture were associated with poorer iron status represented by sTfR, ferritin, and hepcidin, mainly driven by Co and Mn.

Our study findings suggest that poorer iron status is associated with overall heavy metal burden, predominantly Co and Mn, among Ugandan children. Further prospective studies should confirm our primary findings and investigate the combined effects of coexposures to neurotoxicants on the neurodevelopment of young children.

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.

Dioxins and dioxin-like polychlorinated biphenyls (DL-PCBs) are mainly released as by-products of human activities, often in the form of mixtures, and the potential harm on human health deserves attention. Therefore, our study aimed to analyze the combined effect of dioxins and DL-PCB exposures on hypertension (HTN) among US adults. Data of eligible participants were acquired from the National Health and Nutrition Examination Survey (NHANES). Multiple logistic regression models with adjustment for covariates were applied to explore the associations between 13 persistent organic pollutants (POPs) and HTN. Stratified analyses and interaction analyses were then conducted by age and gender. Finally, the combined effects of dioxins and DL-PCBs on HTN were assessed by the weighted quantile sum (WQS) model and the Bayesian kernel machine regression (BKMR) model. A total of 976 adults were included in our study, of whom 397 had HTN. Spearman correlations indicated positive correlations among 13 POPs. And most of them (except PCB28, PCB66, and 1,2,3,4,7,8,9-hpcdf) had significant effects on HTN. The result of WQS revealed that mixed exposure to dioxins and DL-PCBs was significantly associated with increased risk of HTN (OR: 2.205; 95% CIs: 1.555, 3.127). The BKMR model also presented a positive trend of HTN risk with exposure to multiple dioxins and DL-PCBs. And 1,2,3,4,6,7,8,9-ocdd may be the main factor for this positive association. Considering the limitations of our cross-sectional study with the small sample, further prospective studies are necessary to validate our findings.

In much of the world, currently employed upper limits of tolerable intake and acceptable excretion of cadmium (Cd) (ECd/Ecr) are 0.83 µg/kg body weight/day and 5.24 µg/g creatinine, respectively. These figures were derived from a risk assessment model that interpreted β2-microglobulin (β2MG) excretion > 300 μg/g creatinine as a "critical" endpoint. However, current evidence suggests that Cd accumulation reduces glomerular filtration rate at values of ECd/Ecr much lower than 5.24 µg/g creatinine. Low ECd/Ecr has also been associated with increased risks of kidney disease, type 2 diabetes, osteoporosis, cancer, and other disorders. These associations have cast considerable doubt on conventional guidelines. The goals of this paper are to evaluate whether these guidelines are low enough to minimize associated health risks reliably, and indeed whether permissible intake of a cumulative toxin like Cd is a valid concept. We highlight sources and levels of Cd in the human diet and review absorption, distribution, kidney accumulation, and excretion of the metal. We present evidence for the following propositions: excreted Cd emanates from injured tubular epithelial cells of the kidney; Cd excretion is a manifestation of current tissue injury; reduction of present and future exposure to environmental Cd cannot mitigate injury in progress; and Cd excretion is optimally expressed as a function of creatinine clearance rather than creatinine excretion. We comprehensively review the adverse health effects of Cd and urine and blood Cd levels at which adverse effects have been observed. The cumulative nature of Cd toxicity and the susceptibility of multiple organs to toxicity at low body burdens raise serious doubt that guidelines concerning permissible intake of Cd can be meaningful.

Exposure to environmental metals, like lead (Pb), manganese (Mn), and methylmercury (Me-Hg), has consistently been implicated in neurodevelopmental dysfunction. Recent research has focused on identifying modifying factors of metal neurotoxicity in childhood, such as age, sex, and co-exposures. Iron (Fe) status is critical for normal cognitive development during childhood, and current mechanistic, animal, and human evidence suggests that Fe status may be a modifier or mediator of associations between environmental metals and neurodevelopment. The goals of this review are to describe the current state of the epidemiologic literature on the role of Fe status (i.e., hemoglobin, ferritin, blood Fe concentrations) and Fe supplementation in the relationship between metals and children's neurodevelopment, and to identify research gaps.

We identified 30 studies in PubMed and EMBASE that assessed Fe status as a modifier, mediator, or co-exposure of associations of Pb, Me-Hg, Mn, copper (Cu), zinc (Zn), arsenic (As), or metal mixtures measured in early life (prenatal period through 8 years of age) with cognition in children. In experimental studies, co-supplementation of Fe and Zn was associated with better memory and cognition than supplementation with either metal alone. Several observational studies reported interactions between Fe status and Pb, Mn, Zn, or As in relation to developmental indices, memory, attention, and behavior, whereby adverse associations of metals with cognition were worse among Fe-deficient children compared to Fe-sufficient children. Only two studies quantified joint associations of complex metal mixtures that included Fe with neurodevelopment, though findings from these studies were not consistent. Findings support memory and attention as two possible cognitive domains that may be both vulnerable to Fe deficiency and a target of metals toxicity. Major gaps in the literature remain, including evaluating Fe status as a modifier or mediator of metal mixtures and cognition. Given that Fe deficiency is the most common nutritional deficiency worldwide, characterizing Fe status in studies of metals toxicity is important for informing public health interventions.