Children are commonly exposed to metals in the environment, particularly those living in proximity to steel-producing ferroalloy industry. Exposure to metals, including lead (Pb), manganese (Mn), chromium (Cr) and copper (Cu), impacts neurodevelopment, but less attention has been given to examining associations of metal mixtures with cognitive function in children. Further, recent epidemiological studies have identified iron (Fe) status as a modifier of metals-induced neurotoxicity, such that adverse associations of metals (e.g., Mn or Pb) tend to be stronger among children with Fe deficiency. However, no study to date has quantified the modifying or mediating role of Fe status on a complex metal mixture in relation to any neurodevelopmental outcome. We used data from the Public Health Impact of Metals Exposure Study (PHIME), a cohort of 720 Italian adolescents (10–14 years) to quantify the association of an industry-relevant metal mixture (Pb, Mn, Cr, Cu) with neurodevelopment, and examine the role of Fe status as a modifier or mediator of these associations. Metals were measured in blood (Pb) or hair (Mn, Cr, Cu) using inductively-coupled plasma mass spectrometry, and Fe status was assessed using three clinically relevant biomarkers (ferritin, hemoglobin, transferrin) measured in whole blood or serum using luminescent or immunoassays. Of note, there was no indication of Fe deficiency in the study population. In Chapter 2, we identified associations of the metal mixture with verbal learning and memory, measured using the California Verbal Learning Test for Children (CVLT-C), using Bayesian Kernel Machine Regression (BKMR). In adjusted models, we found that the mixture was jointly associated with higher scores for the recall trials: compared to the 50th percentile, the 90th percentile of the mixture was associated with a 0.12 standard deviation increase (95% credible interval [CI]= -0.27, 0.50) in the number of words recalled on trial 5 recall, indicating better cognitive performance. This association was driven primarily by Cu, which was further modified by Fe status: the beneficial association of Cu with recall was stronger at increasing percentiles of ferritin. In Chapter 3, we found that the metal mixture was jointly associated with self-reported attention-related behaviors measured on the Conners Rating Scales. For example, the 90th percentile of the mixture, compared to the 50th percentile, was associated with a 4.1% increase (β= 0.04; 95% CI= 0.00, 0.08) in self-reported inattention T-scores in BKMR models, reflecting worse cognitive performance. These associations were driven primarily by Mn, though there was no indication of modification by Fe status. Lastly, in Chapter 4, we quantified the mediating role of Fe status on the association between the metal mixture and CVLT-C scores using the newly developed BKMR Causal Mediation Analysis (BKMR-CMA). Though the metal mixture was associated with aspects of Fe status (e.g., ferritin), there was no evidence that Fe status mediated the association between the metal mixture and CVLT-C scores. Overall, the findings from this dissertation suggest that an industry-relevant metal mixture can impact aspects of neurodevelopment, including learning, memory and attention-related behaviors, and that Fe status may be a modifier of these associations. These findings have significant implications for potential public health interventions aimed at improving cognitive development in adolescents. However, the generalizability of our findings in a Fe-replete population of healthy adolescents may be limited, and further research in Fe-deficient populations is warranted. / 2025-04-26T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/46103 |
| Date | 26 April 2023 |
| Creators | Schildroth, Samantha |
| Contributors | Claus Henn, Birgit G. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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