Deciduous teeth from the New Hampshire birth cohort study: Early life environmental and dietary predictors of dentin elements.

BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

Fish intake and mercury exposure in young children.

Fish consumption is one of the main sources of mercury (Hg) exposure, but few studies have examined Hg exposure from fish consumption among children. This study aimed to assess the frequency of fish intake and associations with Hg and other element concentrations among 700 three-year-old children from the New Hampshire Birth Cohort Study. Usual fish intake was derived from a validated food frequency questionnaire (Block Questionnaire for ages 2-7) and toenail element concentrations were determined using ICP-MS. Multiple linear regression analysis was used to assess the association between fish intake and toenail element concentrations. A mixture analysis, using Weighted quantile sum (WQS) regression, was used to estimate the relative contribution of fish consumption to element exposures. Twenty-three percent of children were reported to consume at least one fish meal/week on average during the previous 6 months. In adjusted linear regression models, children with any type of fish consumption versus no consumption had 108% (95% confidence interval (CI: 68%, 153%)) higher toenail Hg concentrations. To a lesser extent, children consuming "other fish (not fried) including tuna" and "fried fish or fish sticks" had 120% (95% CI: 82%, 164%), and 23% (95% CI: 2%, 51%) higher toenail concentrations, respectively, than those consuming no fish. Using WQS regression, Hg was the element most strongly related to fish consumption. Fish intake among young children was related to Hg exposure even at low levels of consumption. Future studies will need to determine the health consequences of this exposure.

Associations of Perinatal Metal and Metalloid Exposures with Early Child Behavioral Development Over Time in the New Hampshire Birth Cohort Study.

Research on the neurodevelopmental effects of metal(loid)s has focused mainly on outcomes assessed at one time point, even though brain development progresses over time. We investigated biomarkers of perinatal exposure to metals and changes in child behavior over time. We followed 268 participants from the prospective New Hampshire Birth Cohort Study between birth and age 5 years. We measured arsenic (As), copper (Cu), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) in toenails from 6-week-old infants. The Behavioral Symptoms Index (BSI), externalizing, and internalizing symptoms were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2) at ages 3 and 5 years. Multivariable linear regression was used to estimate associations of metals with behavior change, calculated as the difference in symptom raw scores between 3 and 5 years, in addition to the associations for symptom scores at 3 and 5 years separately. Sex-specific associations were also explored using stratified models and a sex-metal interaction term. Adjusted associations of metals and change in behavior varied by exposure and outcome. Each 1 µg/g increase in ln toenail Cu was associated with improved behavior between 3 and 5 years [BSI: ß = - 3.88 (95%CI: - 7.12, - 0.64); Externalizing problems: ß = - 2.20 (95%CI: - 4.07, - 0.33)]. Increasing Zn was associated with increased externalizing behavior over time (ß = 3.42 (95%CI: 0.60, 6.25). Sex-stratified analyses suggested more pronounced associations among boys compared to girls. Perinatal exposure to metals may alter behavioral development between ages 3 and 5 years. Findings support the need for more research on associations between metals and neurodevelopment over longer time periods.

Patterns of infant fecal metabolite concentrations and social behavioral development in toddlers.

BACKGROUND: Gut-derived metabolites, products of microbial and host co-metabolism, may inform mechanisms underlying children's neurodevelopment. We investigated whether infant fecal metabolites were related to toddler social behavior. METHODS: Stool samples collected from 6-week-olds (n = 86) and 1-year-olds (n = 209) in the New Hampshire Birth Cohort Study (NHBCS) were analyzed using nuclear magnetic resonance spectroscopy metabolomics. Autism-related behavior in 3-year-olds was assessed by caregivers using the Social Responsiveness Scale (SRS-2). To assess the association between metabolites and SRS-2 scores, we used a traditional single-metabolite approach, quantitative metabolite set enrichment (QEA), and self-organizing maps (SOMs). RESULTS: Using a single-metabolite approach and QEA, no individual fecal metabolite or metabolite set at either age was associated with SRS-2 scores. Using the SOM method, fecal metabolites of six-week-olds organized into four profiles, which were unrelated to SRS-2 scores. In 1-year-olds, one of twelve fecal metabolite profiles was associated with fewer autism-related behaviors, with SRS-2 scores 3.4 (95%CI: -7, 0.2) points lower than the referent group. This profile had higher concentrations of lactate and lower concentrations of short chain fatty acids than the reference. CONCLUSIONS: We uncovered metabolic profiles in infant stool associated with subsequent social behavior, highlighting one potential mechanism by which gut bacteria may influence neurobehavior. IMPACT: Differences in host and microbial metabolism may explain variability in neurobehavioral phenotypes, but prior studies do not have consistent results. We applied three statistical techniques to explore fecal metabolite differences related to social behavior, including self-organizing maps (SOMs), a novel machine learning algorithm. A 1-year-old fecal metabolite pattern characterized by high lactate and low short-chain fatty acid concentrations, identified using SOMs, was associated with social behavior less indicative of autism spectrum disorder. Our findings suggest that social behavior may be related to metabolite profiles and that future studies may uncover novel findings by applying the SOM algorithm.

Quantified retrospective biomonitoring of fetal and infant elemental exposure using LA-ICP-MS analysis of deciduous dentin in three contrasting human cohorts.

BACKGROUND: Spatial elemental analysis of deciduous tooth dentin combined with odontochronological estimates can provide an early life (in utero to ~2 years of age) history of inorganic element exposure and status. OBJECTIVE: To demonstrate the importance of data normalization to a certified reference material to enable between-study comparisons, using populations with assumed contrasting elemental exposures. METHODS: We used laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) of dentin to derive a history of elemental composition from three distinct cohort studies: a present day rural cohort, (the New Hampshire Birth Cohort Study (NHBCS; N = 154)), an historical cohort from an urban area (1958-1970), (the St. Louis Baby Tooth Study (SLBT; N = 78)), and a present-day Nigerian cohort established to study maternal HIV transmission (Dental caries and its association with Oral Microbiomes and HIV in young children-Nigeria (DOMHaIN; N = 31)). RESULTS: We report Li, Al, Mn, Cu, Zn, Sr, Ba and Pb concentrations (µg/g) and qualitatively examine As, Cd and Hg across all three cohorts. Rates of detection were highest, both overall and for each cohort individually, for Zn, Sr, Ba and Li. Zinc was detected in 100% of samples and was stably present in teeth at a concentration range of 64 - 86 µg/g. Mercury, As and Cd detection rates were the lowest, and had high variability within individual ablated spots. We found the highest concentrations of Pb in the pre- and postnatal dentin of the SLBT cohort, consistent with the prevalent use of Pb as an additive to gasoline prior to 1975. The characteristic decline in Mn after the second trimester was observed in all cohorts. IMPACT: Spatially resolved elemental analysis of deciduous teeth combined with methods for estimating crown formation times can be used to reconstruct an early-life history of elemental exposure inaccessible via other biomarkers. Quantification of data into absolute values using an external standard reference material has not been conducted since 2012, preventing comparison between studies, a common and highly informative component of epidemiology. We demonstrate, with three contrasting populations, that absolute quantification produces data with the lowest variability, compares well with available data and recommends that future tooth biomarker studies report data in this way.

Early-life manganese exposure during multiple developmental periods and adolescent verbal learning and memory.

BACKGROUND: Manganese (Mn) is both an essential and toxic metal, and associations with neurodevelopment depend on exposure timing. Prospective data examining early life Mn with adolescent cognition are sparse. METHODS: We enrolled 140 Italian adolescents (10-14 years old) from the Public Health Impact of Metals Exposure study. Mn in deciduous teeth was measured using laser ablation-mass spectrometry to represent prenatal, postnatal and early childhood exposure. The California Verbal Learning Test for Children (CVLT-C) was administered to assess adolescent verbal learning and memory. Multivariable regression models estimated changes in CVLT-C scores and the odds of making an error per doubling in dentine Mn in each exposure period. Multiple informant models tested for differences in associations across exposure periods. RESULTS: A doubling in prenatal dentine Mn levels was associated with lower odds of making an intrusion error (OR = 0.23 [95% CI: 0.09, 0.61]). This beneficial association was not observed in other exposure periods. A doubling in childhood Mn was beneficially associated with short delay free recall: (ß = 0.47 [95% CI: -0.02, 0.97]), which was stronger in males (ß = 0.94 [95% CI: 0.05, 1.82]). Associations were null in the postnatal period. CONCLUSION: Exposure timing is critical for understanding Mn-associated changes in cognitive function.

Associations of an industry-relevant metal mixture with verbal learning and memory in Italian adolescents: The modifying role of iron status.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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: ß = 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. CONCLUSIONS: 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.

Associations of a Metal Mixture Measured in Multiple Biomarkers with IQ: Evidence from Italian Adolescents Living near Ferroalloy Industry.

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, 0.08µg/g; hair Cu, 9.6µg/g; hair Cr, 0.05µg/g; and blood Pb, 1.3µg/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, 5.4µg/g), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (0.3µg/g, 2.6µg/dL, and 0.1µg/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.

Associations of metals and neurodevelopment: a review of recent evidence on susceptibility factors.

PURPOSE OF REVIEW: Epidemiologic evidence exists that many metals are associated with adverse neurobehavioral effects in young children, including lead (Pb), methylmercury (meHg), manganese (Mn) and arsenic (As)5-8. Importantly, chemical insult can vary depending on host factors and exposure circumstance. This systematic review summarizes the recent literature investigating modifying factors of the associations between metals and neurodevelopment, including immutable traits (sex or genetics) or exposure conditions (timing or co-exposures). RECENT FINDINGS: Of the 53 studies included in this review, the number investigating modification of exposure effects were: 30 for sex, 21 for co-exposures, 12 for timing of exposure, and six for genetic modifiers. Sex-specific effects of metal-neurobehavioral associations were inconclusive for all metals, likely due to the heterogeneity of outcome domains assessed and the exposure time points measured. Seven studies evaluated both sex and exposure timing as modifying factors using deciduous teeth or other biomarkers with repeated measures to characterize metals exposure over time. Only five studies used statistical methods for mixtures to evaluate associations of more than two metals with neurobehavioral domains. SUMMARY: Despite the expansion of research on susceptibility to the neurodevelopmental effects of metals exposure, considerable gaps remain. This work remains critical, as characterizing susceptible subpopulations can aid in identifying biological mechanisms and is fundamental for the protection of public health.