# Neurotoxicity due to Environmental complex Metal Mixtures Exposure

> **NIH NIH RF1** · JOHNS HOPKINS UNIVERSITY · 2022 · $2,421,557

## Abstract

Abstract: Increasing evidence supports the role of metal exposures as a ubiquitous source of neurological
diseases, including Alzheimer’s Disease (AD) and related dementia, in multiple populations worldwide. In real
life, one is more likely to be exposed to metal/metalloid mixtures than individual metals. The US EPA has
designated the ubiquitous combination of Pb, As, Cd, and Cr(VI) (PACC) as the top interaction profile of concern
for exposure. However, there is still a critical knowledge gap on the adverse outcome pathways (AOPs) due to
chronic exposure to mixtures of metals/metalloids, which hampers risk assessment of neurodegenerative
diseases. The goal is to elucidate the mechanisms by which metal mixtures act in concert to elicit
neurodegenerative AD effects to support the cumulative neurodegenerative disease risk assessment. Our
preliminary data from in-vivo mouse experiments indicate that, unlike single metal exposures, chronic PACC
mixture exposure during adulthood has sex-specific negative effects on cognition, memory, and anxiety. This
correlated with increased serum neuronal decay biomarker (NFL-a), neuroinflammation, and imbalanced redox
homeostasis due to altered Nrf2 signaling. In human brain organoids, the PACC mixture increased oxidative
stress, while it reduced the expression of the pre-synaptic marker, Syn1, and the neuroprogenitor marker, Nestin,
at different stages of organoid development. We hypothesize that interaction profile PACC metal mixtures
relative to single metals at or below regulatory limit impairs brain development as well as accelerates cognitive
decline, neurodegeneration, and eventually AD, due to epigenetic changes in interconnected inflammatory and
oxidative stress pathways. We will test this using the following aims: SA 1: To determine the biological
mechanisms by which exposure to PACC metal mixtures during adulthood cause AD-related
neurocognitive decline. The cumulative risk of sex- and dose-specific neurotoxicity and neurodegeneration
caused by adulthood exposures to individual metals vs. PACC mixtures will be determined using mouse models.
The causality of oxidative stress and the Nrf2/KEAP1 pathway will be tested using Nrf2fl/fl or Keap1fl/fl knock-out
mice. SA 2: To investigate the adverse neurological effects of perinatal exposure to PACC metal mixture
at environmentally relevant doses. We will determine the neurological effects of PACC metal mixture in
perinatally exposed adult mice and perform a cumulative risk assessment. SA 3: Determine potential gene x
environment (G×E) interactions involved in PACC metal mixture-induced AD-related neurodegeneration.
Using our CRISPR/Cas9 modified human organoids in which the AD risk gene APOEe4 is knocked out, we will
study metal combinations at different stages of brain maturity, and investigate oxidative stress, transcriptomic
and metabolic changes, and associated neurodegeneration.
Impact: This study will provide insights into the long-term impact and causal...

## Key facts

- **NIH application ID:** 10591120
- **Project number:** 1RF1NS130672-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Shyam Biswal
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,421,557
- **Award type:** 1
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591120

## Citation

> US National Institutes of Health, RePORTER application 10591120, Neurotoxicity due to Environmental complex Metal Mixtures Exposure (1RF1NS130672-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10591120. Licensed CC0.

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