Organic-metal mixtures and neurodevelopment

Project Summary
The study of chemical mixtures is a high priority as mixtures represent the real-life exposure scenarios that
impact health. Mixtures are methodologically similar to studying the exposome (i.e. the study of all health
relevant exposures) and research on new methods to measure and analyze higher order mixtures will inform
future exposomic research. We have developed a tooth-based exposure biomarker that measures prenatal
and childhood exposure to elements and organic environmental chemicals that reduces exposure
misclassification and can accurately estimate both dose and timing of exposure. In our first grant cycle we
established the biomarker for a mixture of Pb, Mn, Zn, As and Cd in predicting neurodevelopment. In this
renewal we will longitudinally assess additional metals and more than 100 organic environmental chemicals
over the prenatal and early childhood periods. These early life stages are comprised of critical windows of
susceptibility when individuals are particularly vulnerable to chemical exposures. Current knowledge on the
effects of fetal exposure to chemical mixtures is limited. In reality, humans are exposed to a large number of
organic and inorganic toxicants simultaneously, but most studies only focused on one chemical at a time, and
while we know that elements and organic pollutants can interact biochemically, there are a lack of
comprehensive data on organic-element interactions. In addition, our biomarker can uniquely identify critical
windows that define heightened susceptibility with greater precision than blood or urine-based biomarkers.
Prospective birth cohorts that collect biomarkers during pregnancy and follow offspring into childhood can
provide evidence to assess the impact of exposures during key developmental windows, but this approach can
miss critical windows if biological sampling is mistimed. We propose to overcome these limitations by applying
precise tooth matrix-based biomarkers of organic chemical and elemental exposures at specific life stages that
comprehensively assess the prenatal and early childhood periods. Our overarching aim is to study the risk of
neurodevelopmental deficits due to high dimensional mixtures of elements and organic chemicals using a
single toxicant exposure biomarker. We will leverage 3 established and richly characterized birth cohorts in a
discovery–replication design. Our discovery cohort (called PROGRESS) and our 2 replication cohorts (called
ELEMENT and PRISM) were all recruited during early pregnancy and followed through late childhood. Two are
based in Mexico City, have similar designs and have multiple overlapping neurodevelopmental test data. The
3rd is based in New York City and allows us to better generalize results to the U.S.; thus, we replicate at
multiple levels. Finally, in preparation for this highly innovative proposal, we have collected deciduous teeth for
biomarker analysis in all 3 cohorts (80% of teeth are already collected) and have extensive rigorously collected
longitudinal neurodevelopment data, making our proposal time efficient (i.e. covers over a decade of life in one
grant cycle) and cost-effective.

Grant Number: 5R01ES026033-09
NIH Institute/Center: NIH
Principal Investigator: Manish Arora