Low Concentrations of Hexavalent Chromium in Drinking Water Induce Alzheimer’s Disease Neuropathology: Using a Toxic Aging Coin Approach to Assess Hexavalent Chromium Neurotoxicity

Authors

Liam Buchanan, University of LouisvilleFollow
Samuel Vielee, University of LouisvilleFollow
Spencer Roof, University of LouisvilleFollow
Haiyan Lu, University of LouisvilleFollow
Jamie L Young, University of LouisvilleFollow
Idoia Meaza Isusi, University of LouisvilleFollow
Aggie Williams, University of LouisvilleFollow
Joseph Kouokam, University of LouisvilleFollow
Sandra Wise, University of LouisvilleFollow
Luping Guo, University of LouisvilleFollow
Jun Cai, University of LouisvilleFollow
John Wise, University of LouisvilleFollow
John P. Wise Jr., University of LouisvilleFollow

Program/Event

Arts and Research Showcase 2024

Abstract

Introduction: We are currently facing an aging crisis, as 20% of the U.S. population will be geriatric (65+) by 2030. This growing geriatric population will result in increasing prevalence of age-related diseases, coinciding with increasingly prevalent environmental pollution. Environmental pollution is a ubiquitous health threat that affects people at all ages and contributes to aging pathology. However, geriatric individuals are likely more susceptible to the negative health effects from environmental pollution. The distinct effects of environmental pollutants across age groups are currently understudied. We use a Toxic Aging Coin approach to investigate: 1) how age impacts toxicity (heads), and 2) how chemicals accelerate aging (tails). Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disease, projected to affect 153 million people by 2050. AD pathology is characterized by amyloid-β plaques and abnormally phosphorylated tau protein which leads to neurofibrillary tangles. Both amyloid-β plaques and tau protein tangles can induce oxidative stress and neurodegeneration in multiple brain regions. This AD pathology spreads through distinct brain regions in a pattern ­­­known as Braak staging, beginning with the entorhinal and transentorhinal regions before spreading to the hippocampus and eventually to neocortical areas. Behaviorally, AD often presents as memory loss, confusion, disorientation, and loss of muscle coordination. Many environmental pollutants, such as metals (e.g., lead, cadmium, and arsenic) are linked to AD etiology, but hexavalent chromium [Cr(VI)] has received limited attention in the context of AD. Cr(VI) has been linked to other neurological disorders in humans, such as polyneuropathy, motor neuron disease, and Autism Spectrum Disorder. In rodents, Cr(VI) impairs social memory and muscle coordination, which is symptomatic of AD. Blood levels of Cr were found significantly elevated in blood of AD patients and is linked to acute schizophrenia. Here, we use the heads side of our Toxic Aging Coin to assess Cr(VI) neurotoxicity across different age groups.

Methods: We exposed Sprague-Dawley rats (both sexes) at three ages (3-, 7-, and 18-months-old) to low concentrations of Cr(VI) in drinking water (0.05 and 0.1 mg/L) for 90 days. Importantly, 0.05 mg/L and 0.1 mg/L Cr(VI) correspond to the WHO and U.S. EPA permissible drinking water limits for Cr(VI), respectively. We assessed spatial memory by measuring spontaneous non-alternations in the Y-Maze assay after 4- and 10-weeks exposure. After 90 days, we harvested the brains and used silver stain to examine neurodegeneration in AD-associated brain regions (e.g., dorsal hippocampus, entorhinal cortex). Silver staining marks degenerating neurons jet black and provides a qualitative assessment of the degree of neurodegeneration.

Results: We observed middle-aged (7-month old) males exhibited a concentration-associated increase in non-alternations, suggesting impaired spatial memory. Whereas middle-aged females exposed to Cr(VI) exhibited a concentration-associated decrease in non-alternations, suggesting an improvement in spatial memory; however, extensive hippocampal damage may lead to a side preference that resembles improved memory. Upon examining rat brains for neurodegeneration using silver stain, the hippocampus was more affected than the entorhinal cortex, and 3-m.o. rats were the least affected. 7-month-old rats exhibited increased neurodegeneration in the CA1, CA3 and dentate gyrus of the dorsal hippocampus, with females exhibiting more severe neurodegeneration. 7-month-old females showed the most severe neurodegeneration compared to age- and sex-matched controls, suggesting this pathology may have induced a side-preference behavior in the Y-Maze assay. 18-month-old rats exhibited increased neurodegeneration in hippocampus compared to age-matched controls.

Conclusions: The extensive level of damage to the hippocampus, especially in 7-month-old females and geriatric rats, suggests that Cr(VI) exposure induced damage in a similar manner to Braak stages III and IV of AD pathology. Pathology and the noted sex differences suggest Cr(VI) exposure may increase the risk of AD. The observed sex differences also indicate that females are more susceptible to Cr(VI)-induced neurodegeneration. Future directions will examine other pathologies associated with AD (e.g., protein aggregation, white matter damage) and cell specific targets of Cr(VI) neurotoxicity (e.g. astrocytes, microglia).

Recommended Citation

Buchanan, Liam; Vielee, Samuel; Roof, Spencer; Lu, Haiyan; Young, Jamie L; Meaza Isusi, Idoia; Williams, Aggie; Kouokam, Joseph; Wise, Sandra; Guo, Luping; Cai, Jun; Wise, John; and Wise, John P. Jr. (2024) "Low Concentrations of Hexavalent Chromium in Drinking Water Induce Alzheimer’s Disease Neuropathology: Using a Toxic Aging Coin Approach to Assess Hexavalent Chromium Neurotoxicity," The Cardinal Edge: Vol. 2: Iss. 2, Article 16.
Available at: https://ir.library.louisville.edu/tce/vol2/iss2/16