Identification of Neurotoxic Targets of Diverse Chemical Classes of Dietary Neurotoxins/Neurotoxicants

Rachel M Foguth, Purdue University

Abstract

Neurological disorders are a major public health concern due to prevalence, severity of symptoms, and impact on caregivers and economic losses. While genetic susceptibility likely has a role in most cases, exposure to toxicants can lead to neurotoxicity, including potentially developmental origins of adult disease or increased risk of disease onset. These exposures are not necessarily large, acute exposures, but could accumulate, with a chronic low-dose exposure, causing toxicity. This research focuses on the potential neurotoxicity of two classes of dietary toxins/toxicants, heterocyclic aromatic amines (HAAs) and per- and polyfluoroalkyl substances (PFAS). HAAs, such as PhIP, harmane, and harmine, are formed in charred or overcooked meat, coffee, tobacco, and other foods. PFAS are largely used in making household materials, but are found in small amounts in eggs and dairy products and largely in contaminated water. While these two classes are diverse in terms of structure, common neurotoxic targets and mechanisms often exist. Therefore, we tested the effects of these chemicals on cell viability and neurotoxicity. In the first aim, we aimed to elucidate the mechanism of toxicity of harmane and harmine, focusing on their ability to cause mitochondrial dysfunction. The second aim was to determine the effects of either harmane or PhIP on the nigrostriatal motor systems and motor function of rats and mice, respectively. The third aim determined the effects of PFAS on neurodevelopment of Northern leopard frogs, focusing on changes in neurotransmitter levels and accumulation in the brain. Harmane did not cause motor dysfunction, but potentially affected the nigro-striatal motor system in an age- or sex-dependent manner. PhIP had differential effects on dopamine levels over time and caused motor dysfunction after subchronic exposure in mice. Perfluorooctane sulfonate (PFOS) accumulated in the brains of frogs and PFAS caused changes in neurotransmitter levels that were dose- and time-dependent. Overall, this research shows that toxins/toxicants humans are exposed to over their whole lives through their diet and contaminated water can cause neurotoxicity, potentially leading to or increasing risk of disease states. *This dissertation contains published articles as part of its final work. Below is a list of the articles and book chapters that have been used. Each chapter that contains portions of articles or is published as an article has a note at the beginning of the chapter that specifies the citation. Foguth, RM, Hoskins, TD, Clark, GC, Nelson, M, Flynn, RW, de Perre, C, Hoverman, JT, Lee, LS, Sepúlveda, Cannon, JR; “Single and mixture per- and polyfluoroalkyl substances accumulate in developing Northern leopard frog brains and produce complex neurotransmission alterations.” Neurotoxicology and Teratology. 2020; 81:106907. doi: 10.1016/j.ntt.2020.106907. PMID: 32561179 Foguth, RM, Sepúlveda, MS, Cannon, JR; “Per- and polyfluoroalkyl substances (PFAS) neurotoxicity in sentinel and nontraditional laboratory model systems: potential utility in predicting adverse outcomes in human health.” Toxics. 2020; 8(2);E42. doi: 10.1016/j.taap.2019.114623. PMID: 31195004 Foguth, RM, Cannon, JR; “Emerging contaminants as contributors to parkinsonism: heterocyclic amines.” Parkinsonism and the Environment. Springer. In press.

Degree

Ph.D.

Advisors

Cannon, Purdue University.

Subject Area

Neurosciences|Organic chemistry

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