Neurotoxicity due to Environmental complex Metal Mixtures Exposure

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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 mechanisms of metal mixture- induced neurotoxicity and help tailor risk management decisions to protect populations from metal-induced AD.