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Principal Investigator: Wise, John Pierce
Institute Receiving Award University Of Louisville
Location Louisville, KY
Grant Number R21ES033327
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 17 Sep 2021 to 31 Aug 2024
DESCRIPTION (provided by applicant): PROJECT SUMMARY Today our societies are challenged with the health burdens of environmental pollution and a rapidly aging population. Global lifespan is 30 years longer than it was 100 years ago, and 1 in 5 Americans will be geriatric by the year 2030. Given this prolonged aging combined with environmental exposures, we urgently need to understand how environmental pollution affects an aged body differently from a younger body and how environmental pollution contributes to aging phenotypes. Most of our understanding of toxic effects of chemicals come from human research focused on young to middle aged people or from animal studies using young to middle aged rodents. Very few studies have considered toxicity of environmental pollutants in an aged body or population and we simply do not understand the impacts on an aged population. Traditionally, the brain was considered composed of mostly post-mitotic neurons and hence genotoxic agents were considered less of a threat. Now, we know the opposite is true – most of the brain’s cells, the glia, are mitotic and play critical roles in protecting and supporting neuronal health. Recent studies show these glial cells can exhibit increased aneuploidy and chromosome instability with aging and early in neurodegenerative diseases. Hence, there is a critical need to understand how genotoxic chemicals affect brain health and contribute to premature aging. Hexavalent chromium [Cr(VI)] is a major environmental health concern that can induce aging phenotypes and has the best defined clastogenic mechanism of metals. Cr(VI) also causes brain damage that may be linked to a variety of neurological symptoms. We propose to investigate the role of Cr(VI) in this aging paradigm, using young vs middle-aged vs geriatric rats exposed to Cr(VI) for 90 days via drinking water. We hypothesize aged animals will be more susceptible to Cr(VI)-induced neurotoxicity and that Cr(VI)-induces brain aging by causing aneuploidy and chromosome instability resulting in glial senescence. We will test our hypothesis with two aims. Aim 1 will identify brain regions and cell populations vulnerable to Cr(VI) toxicity across ages. This aim will allow us to compare Cr(VI) neurotoxicity across ages and endpoints for premature or advanced aging. Aim 2 will determine the role of aneuploidy and chromosome instability in Cr(VI) neurotoxicity and brain aging. Our study will provide essential detailed insights into Cr(VI) neurotoxicity, considering age-, sex-, region-, and cell type-specific effects. Our study will further consider mechanistically how genotoxicity contributes to brain aging with in vivo and in vitro techniques. Outcomes will provide key and novel insights for understanding Cr(VI)’s role in the aging process, identifying cellular and regional targets in the brain, and how an aged brain is affected by toxicants differently. This study will also characterize a new model system for further study of neurotoxicity and aging for Cr(VI) or other metals, and will contribute to improvements in Cr(VI) risk assessment and management that are not currently possible because of limitations due to the absence of these data.
Science Code(s)/Area of Science(s) Primary: 61 - Neurodevelopmental
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Jonathan Hollander
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