# EV miRs in cognitive function decline associated with early life metal exposure

> **NIH NIH P42** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $225,566

## Abstract

PROJECT SUMMARY/ ABSTRACT
Early-life exposure to Superfund metal toxicants such as lead (Pb), arsenic (As), cadmium (Cd) and
Manganese (Mn) has been associated with worse cognitive function during aging and is suspected of
contributing to the development of neurodegenerative diseases, such as Alzheimer’s disease. However, the
biological mechanisms underlying the associations remain poorly understood. Mammalian cells, including
neurons and neural stem cells, secrete into the extracellular milieu a variety of tiny membrane-encapsulated
vesicles. These extracellular vesicles (EVs) contain functional signaling molecules that can be taken up by
recipient cells to mediate intercellular communication. One such group of signaling molecules is
microRNAs, which function as master tuners of gene expression by degrading target mRNA and/or
inhibiting translation of the message. Since EVs are encapsulated by a lipid bilayer membrane, molecules
such as microRNAs enclosed in the vesicles are protected from nuclease-mediated degradation and thus
are thus very stable. As a result, EV microRNAs can be easily detected and quantitated in biological fluids
such as plasma/serum and have been used as novel biomarkers for a variety of human diseases. Although
some limited studies have explored the role of EV microRNAs in neural cells, no studies have examined the
role of EV microRNAs on cognitive function in the context of environmental exposures such as metal
toxicants. We hypothesize that metal exposures in early life alter EV microRNAs in the brain and that these
changes in EV microRNAs affect the function of neurons and neural stem cells to accelerate cognitive
aging. We propose three interconnected Specific Aims to test this hypothesis. Aim 1 will determine the
effects of exposures to individual metal exposures (Pb, As, Mn, and Cd) as well as “real-world” metal
mixtures (pre- and post-remediation water samples collected at the San Luis Valley Superfund site) on
developing human fetal brain organoids. Aim 2 will determine the effects of early-life exposure to individual
metals (Pb and As) as well as to the real-world metal mixtures on EV miRs and the cognitive function of
mice later in life. Aim 3 will determine the functional role of selected EV microRNAs in modulating functions
of brain organoids and cognitive function in mice. Our highly multidisciplinary study integrating mouse
models, human epidemiology, and functional cellular studies seeks to establish EV microRNAs not only as
novel biomarkers for metal exposure-related cognitive function, but also as a mechanistic basis for metal-
induced neurotoxicity and cognitive impairment. This project links with the MEMCARE-SRC by
complementing human studies in Project 1 and seeking to identify biologic mechanisms for health effects of
water contamination at Superfund sites.

## Key facts

- **NIH application ID:** 9840756
- **Project number:** 1P42ES030990-01
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Quan Lu
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,566
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840756

## Citation

> US National Institutes of Health, RePORTER application 9840756, EV miRs in cognitive function decline associated with early life metal exposure (1P42ES030990-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840756. Licensed CC0.

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