# Prenatal metal mixtures and neurodevelopment:  Role of placental extracellular microRNAs

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $653,362

## Abstract

PROJECT SUMMARY
Neurodevelopment and cognitive function are among the most important public health outcomes. Loss of
functioning early in life due to toxins, such as metals, can have lifelong impacts. The prevention of
neurodevelopmental disorders of fetal origin is impeded by the lack of objective tools for early detection of
susceptible individuals. We will address the role of prenatal metal exposure on neurodevelopment, integrating
this work with the overall goal of understanding how metal exposures impact placental cues, specifically
release of extracellular vesicles (EVs), which facilitate and direct neurodevelopment. It has been shown that
placental trophoblasts actively release EVs, i.e., nano-sized membrane-bound vesicles, in both the maternal
and fetal circulation. EVs shuttle cargoes of bioactive molecules from trophoblasts to recipient cells, such as
microRNAs (miRNAs) that prime maternal tissues to support fetal development. In the fetal circulation, EVs
can cross the blood-brain barrier, particularly in prenatal life when the barrier around the fetal brain is still
porous and permeable. Not only is the placenta a primary target of metal toxicities, data show that EV signaling
is sensitive to environmental influences, including metals. No study to date has investigated whether
exposures to metals during the prenatal period determine alterations of circulating EV signals that, in turn, may
help to diagnose and predict alterations in neurodevelopment. Notably, many placental miRNAs are known to
regulate neurodevelopment and have significant overrepresentation of Gene Ontology terms associated with
neurogenesis. We propose that in utero metal exposure disrupt normal miRNA expression in placental tissue
and their release in circulating EVs, thus altering neural stem cell proliferation, self-renewal and differentiation
during fetal development. In turn, we propose that EV-packaged miRNAs in the maternal circulation in
pregnancy reflect early biological settings of this fetal programming. We will conduct a coordinated series of
human studies and in-vitro experiments to: 1) characterize the risk for maladaptive neurodevelopment from
prenatal exposure to toxic metals and their mixtures; 2) identify EV-encapsulated miRNAs released by the
placenta in response to metals by accessing this novel form of prenatal signaling through a maternal blood
draw during pregnancy, cord blood, and placental biopsy at birth; and 3) conduct in-vitro experiments to assess
whether EV-encapsulated miRNAs are released by trophoblasts after treatment with individual metals or their
mixtures; and whether miRNAs in EVs released from metal-treated trophoblasts alter critical functions of neural
stem cells. We leverage the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort with
prospective assessment of behavioral disinhibition in N=470 children followed to age 48 months. While we
propose underlying theoretical pathways, the primary goal is to search for b...

## Key facts

- **NIH application ID:** 9928464
- **Project number:** 5R01ES030302-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Quan Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,362
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928464

## Citation

> US National Institutes of Health, RePORTER application 9928464, Prenatal metal mixtures and neurodevelopment:  Role of placental extracellular microRNAs (5R01ES030302-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928464. Licensed CC0.

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