# Early Life Air Pollution Exposures as a Risk Factor for Neurodevelopmental Disorders

> **NIH NIH R35** · UNIVERSITY OF ROCHESTER · 2022 · $865,956

## Abstract

ABSTRACT
Numerous studies now report associations between air pollution (AP) exposure and neurodevelopmental
disorders (NDDs), including autism spectrum disorder, schizophrenia, and attention deficit disorder, all of which
share numerous features. My studies of early postnatal (human 3rd trimester brain equivalent) inhalation
exposures to concentrated ambient ultrafine (UFP, considered the most reactive component of AP) particles
(CAPS) in mice produced numerous neuropathological and behavioral features of these NDDs and of their
shared hypothesized mechanisms, including male bias, providing biological plausibility for the epidemiological
studies. Additionally, CAPS exposures markedly elevated brain levels of metals and trace elements, including
redox metals (Fe, Cu) as well as S, Ca, and Al, findings indicative of brain metal dyshomeostasis. This proposal
seeks to test the overarching hypothesis that AP-induced brain metal dyshomeostasis contributes to male-
biased NDD phenotypes via production of neuroinflammation and oxidative stress tested in a series of
questions designed to accelerate the understanding of mechanisms, and translational relevance of such effects
in 5 key integrated questions emanating from these novel, dramatic and unexpected findings: 1) Are toxic trace
element contaminants of UFPs a source of CAPS-induced NDD phenotypic features, specifically elevated brain
Fe and S (inhaled Fe nanoparticles and/or SO2) both of which are known neurotoxicants via ferroptotic and
oxidative stress mechanisms? 2) What accounts for male bias in UFP-induced neurotoxicity? Does it reflect an
earlier colonization of male brain by activated microglia and their interactions with Fe uptake? 3) What are the
portals of entry of UFPs into brain? We utilize the precocial African spiny mouse with its extended gestational
period relative to the altricial C57 mouse in which 3rd trimester occurs postnatally and can include nasal and
olfactory uptake to determine whether the African spiny mouse might serve as a more relevant human model. 4)
How does nanoparticle processing in brain subsequently influence/modulate toxicity and does it generate toxic
or protective mechanisms e.g., alterations in the ferritin cage? 5) Does post-mortem brain tissue from humans
that had been diagnosed with NDDs (Neurobiobank) contain exogenous metal nanoparticles as we see, e.g.,
with Fe located within damaged myelin in corpus callosum after CAPS? These integrated efforts will begin to
elaborate mechanisms of AP-induced NDDs and associated sex differences, to define the most relevant mouse
model, and to determine the need to regulate air metal levels for public health protection.

## Key facts

- **NIH application ID:** 10459253
- **Project number:** 5R35ES031689-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Deborah A Cory-Slechta
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $865,956
- **Award type:** 5
- **Project period:** 2021-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459253

## Citation

> US National Institutes of Health, RePORTER application 10459253, Early Life Air Pollution Exposures as a Risk Factor for Neurodevelopmental Disorders (5R35ES031689-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459253. Licensed CC0.

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