Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Wise, Jr., John

Committee Member

Cai, Lu

Committee Member

Aschner, Michael

Committee Member

Cai, Jun

Committee Member

Sammi, Shreesh Raj

Committee Member

Wise, Sr., John

Author's Keywords

Hexavalent chromium; neurotoxicity; behavior; metallomics; caenorhabditis elegans

Abstract

Hexavalent chromium [Cr(VI)] is a ubiquitous environmental pollutant and potent toxicant. Exposure to Cr(VI) in drinking water is primarily associated with cancers, inflammation, and hepatotoxicity; however, recent studies have identified Cr(VI) as a neurotoxicant in rodent and cell culture models. The literature suggest chromium accumulates in the brain, induces widespread neurodegeneration, and alters rodent behaviors. Despite these data, we lack a detailed and consistent assessments of Cr(VI) neurotoxicity across models, and interactions between aging and Cr(VI) neurotoxicity are not reported in the literature. In this dissertation, we characterize Cr(VI) neurotoxicity across 3 laboratory models: Sprague-Dawley rats, Caenorhabditis elegans, and Hartley guinea pigs. Our rat model assessed Cr(VI) neurotoxicity, with respect to age and sex differences, after 90-days exposure to Cr(VI) in drinking water at U.S. Environmental Protection Agency and World Health Organization maximum contaminant levels. Data from this model demonstrated altered rat behavior, preferential chromium accumulation in the hippocampus, and hippocampal essential metals dyshomeostasis – with age- and sex-specific effects. We also report DNA damage in the hippocampus of Cr(VI)-exposed 7-month-old female rats. Our rat model provides a detailed characterization of Cr(VI) behavioral neurotoxicity and regional vulnerability to Cr(VI), but specific cellular targets for Cr(VI) in the nervous system remained unelucidated. To address this knowledge gap, we generated a novel C. elegans model for Cr(VI) neurotoxicity – which identified GABAergic neurons as the primary target and most affected neuronal phenotype by Cr(VI) in C. elegans. This model also demonstrated that Cr(VI) accelerated biological aging in a C. elegans model. Finally, we considered Cr(VI) neurotoxicity in Hartley guinea pigs exposed to environmentally relevant levels of Cr(VI) in drinking water, as guinea pigs exhibit more similar physiology to humans than other rodents. Our guinea pig model revealed that chromium preferentially accumulated in the dorsal hippocampus and pituitary gland and induced sex- and region-dependent essential metals dyshomeostasis in the brain. In all, the data contained in this dissertation provide a detailed characterization for Cr(VI) neurotoxicity by describing behavioral deficits, identifying vulnerable brain regions and cellular populations, demonstrating Cr(VI)-induced changes in the brain metallome, and elucidating preliminary milestones in Cr(VI) neurotoxicity.

Download

Included in

Toxicology Commons

Share

COinS