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.

Occupational and environmental exposures to toxic metals are established risk factors for the development of hypertension and kidney disease in adults. There is some evidence of developmental metal nephrotoxicity in children and from animal studies; however, to our knowledge no previous studies have examined associations between co-exposure to nephrotoxic environmental metals and children's kidney health. The objective of this study was to assess the association between co-exposure to lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), measured in urine and blood, and kidney parameters in US adolescents. We performed a cross-sectional analysis of a subsample of 2709 children aged 12-19 participating in the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2014. We analyzed urine levels of 4 nephrotoxic metals selected a priori (As, Cd, Pb and Hg), Umix, and 3 nephrotoxic metals in blood (Cd, Pb, and Hg), Bmix, using a weighted quantile sum (WQS) approach. We applied WQS regression to analyze the association of Bmix and Umix with estimated glomerular filtration rate (eGFR), serum uric acid (SUA), urine albumin, blood urea nitrogen (BUN), and systolic blood pressure (SBP), adjusting for sex, race/ethnicity, age, head of household's education level, height, BMI, serum cotinine, and NHANES cohort year. Umix and urine albumin models were also adjusted for urine creatinine, and Bmix models were also adjusted for fish consumption. Subanalyses included stratification by sex and an arsenic-only model including six speciated forms of As measured in urine. In WQS regression models, each decile increase of Umix was associated with 1.6% (95% CI: 0.5, 2.8) higher BUN, 1.4% (95% CI: 0.7, 2.0) higher eGFR, and 7.6% (95% CI: 2.4, 13.1) higher urine albumin. The association between Umix and BUN was primarily driven by As (72%), while the association with eGFR was driven by Hg (61%), and Cd (17%), and the association with urine albumin was driven by Cd (37%), Hg (33%), and Pb (25%). There was no significant relationship between Umix and SUA or SBP. In WQS models using the combined blood metals, Bmix, each decile increase of Bmix was associated with 0.6% (95% CI: 0.0, 1.3) higher SUA; this association was driven by Pb (43%), Hg (33%), and Cd (24%) and was marginally significant (p = 0.05). No associations were observed between Bmix and urine albumin, eGFR, BUN, or SBP. The findings suggest metals including As, Pb, Hg, Cd and their combinations may affect renal parameters, although potential reverse causation cannot be ruled out due to the cross-sectional study design. Implications of early life low-level exposure to multiple metals on kidney function may have far-reaching consequences later in life in the development of hypertension, kidney disease, and renal dysfunction. Longitudinal studies should further evaluate these relationships.

Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in ne...

Hepato- and nephrotoxicity of fluoride have been demonstrated in animals, but few studies have examined potential effects in humans. This population-based study examines the relationship between chronic low-level fluoride exposure and kidney and liver function among United States (U.S.) adolescents. This study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver parameters among U.S. youth. This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2013-2016). We analyzed data from 1983 and 1742 adolescents who had plasma and water fluoride measures respectively and did not have kidney disease. Fluoride was measured in plasma and household tap water. Kidney parameters included estimated glomerular filtration rate (calculated by the original Schwartz formula), serum uric acid, and the urinary albumin to creatinine ratio. Liver parameters were assessed in serum and included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase, and albumin. Survey-weighted linear regression examined relationships between fluoride exposure and kidney and liver parameters after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons. The average age of adolescents was 15.4 years. Median water and plasma fluoride concentrations were 0.48 mg/L and 0.33 μmol/L respectively. A 1 μmol/L increase in plasma fluoride was associated with a 10.36 mL/min/1.73 m2 lower estimated glomerular filtration rate (95% CI: -17.50, -3.22; p = 0.05), a 0.29 mg/dL higher serum uric acid concentration (95% CI: 0.09, 0.50; p = 0.05), and a 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: -1.87, -0.70; p < 0.001). A 1 mg/L increase in water fluoride was associated with a 0.93 mg/dL lower blood urea nitrogen concentration (95% CI: -1.44, -0.42; p = 0.007). Fluoride exposure may contribute to complex changes in kidney and liver related parameters among U.S. adolescents. As the study is cross-sectional, reverse causality cannot be ruled out; therefore, altered kidney and/or liver function may impact bodily fluoride absorption and metabolic processes.

Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile). Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects.

Healthy feto-maternal communication is critical during pregnancy and is orchestrated by the placenta. Dysfunction of the placenta leads to fetal growth complications; however, the underlying biological mechanisms have yet to be fully elucidated. Circulating extracellular microRNAs (exmiRNAs) in the blood have been implicated in cell-to-cell communication. Therefore, exmiRNAs may provide useful biological information about communication between the mother, the fetus, and the placenta during pregnancy. We used logistic regression to determine the association of exmiRNAs with abnormal fetal growth by comparing mothers of infants classified as small-for-gestational age (SGA) (n = 36) and large-for-gestational age (LGA) (n = 13) to appropriate-for-gestational age (AGA), matched by gestational age at delivery and infant sex. In addition, we used linear regression to determine associations between exmiRNAs and birth weight-for-gestational age (BWGA) z-score (n = 100), adjusting for maternal age, body mass index, and parity. We found that higher levels of miR-20b-5p, miR-942-5p, miR-324-3p, miR-223-5p, and miR-127-3p in maternal serum were associated with lower odds for having a SGA vs. AGA infant, and higher levels of miR-661, miR-212-3p, and miR-197-3p were associated with higher odds for having a LGA vs. AGA infant. We also found associations between miR-483-5p, miR-10a-5p, miR-204-5p, miR-202-3p, miR-345-5p, miR-885-5p, miR-127-3p, miR-148b-3p, miR-324-3p, miR-1290, miR-597-5p, miR-139-5p, miR-215-5p, and miR-99b-5p and BWGA z-score. We also found sex-specific associations with exmiRNAs and fetal growth. Our findings suggest that exmiRNAs circulating in maternal blood at second trimester are associated with fetal growth. Validation of our findings may lead to the development of minimally-invasive biomarkers of fetal growth during pregnancy.