# Metal mixtures, exposure windows, and neurodevelopmental trajectories from adolescence to adulthood

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $711,418

## Abstract

Project Summary
The Developmental Origins of Health and Disease (DOHaD) theory posits that early life environment predicts
adverse health effects that may not manifest for decades. Adolescence is an understudied life stage
characterized by profound brain remodeling and behavioral development, which may be influenced by the early
life environment. We hypothesize that exposure to neuroactive (i.e., neurotoxic and neuroprotective) metals
during the early postnatal period (0-2 years) impacts the trajectory of brain and executive function
development, particularly in attention and working memory. The study of trajectories necessitates assessment
of phenotypic development over time, rather than at a single time point as is most common in environmental
health research. We propose studying longitudinal brain structure/function and executive function (EF)
trajectories using multi-modal magnetic resonance imaging (MRI) and computerized EF tasks in an
accelerated longitudinal design (ALD). An ALD is a commonly used epidemiologic tool that shortens the time
needed to assess neurodevelopmental trajectories compared to a traditional longitudinal cohort design. We do
so by leveraging the PHIME (Public Health Impact of Metals Exposure) study, a cohort of adolescents in
Northern Italy. One third of the PHIME community lives proximal to a steel producing plant that emits
neuroactive metals, supporting our ability to study the role of mixed metal exposures on health. Previously
we have shown cross-sectional associations between manganese (Mn), one of the more common plant
emissions, and adverse neurodevelopmental outcomes. More recently, we employed a novel, validated tooth
biomarker to reconstruct prenatal and early childhood Mn exposures in naturally shed baby teeth, allowing us
to show the prospective effects of early life Mn exposure on adolescent neurodevelopment measured at one
time point. In this renewal, we extend our tooth biomarker to reconstruct past exposure to a mixture of
common metals (Mn, Pb, Zn, Cu and Cr) and link specific exposure life stages [i.e., fetal life [(14 weeks
gestation through birth), early postnatal life (0-2 years) and childhood (2-6 years)] to trajectories of
structural/functional brain development and neurobehavior throughout adolescence. To complement the tooth
biomarker, we will enroll new cohort members to assess phenotype trajectories from age 7-25 years (i.e. the
onset through conclusion of adolescence). This renewal builds prior cross-sectional and prospective findings
by creating a life course study of adolescent developmental trajectories of brain structure/function and EF. All
told, our life course study covers 25 years in a single grant cycle and will be a model for future studies of early
life environment and adolescent health, an understudied life stage representing the transition into adulthood. In
sum, this renewal within PHIME will determine the critical exposure windows for early life metal exposure on
adolescent d...

## Key facts

- **NIH application ID:** 10842354
- **Project number:** 5R01ES019222-13
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Megan K Horton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $711,418
- **Award type:** 5
- **Project period:** 2010-09-10 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842354

## Citation

> US National Institutes of Health, RePORTER application 10842354, Metal mixtures, exposure windows, and neurodevelopmental trajectories from adolescence to adulthood (5R01ES019222-13). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10842354. Licensed CC0.

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