Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Jonathan Boyd

Committee Co-Chair

Fred King

Committee Member

Justin Legleiter

Committee Member

James O'Callaghan

Committee Member

Brian Popp

Abstract

Humans are continuously exposed to a vast number of chemicals, whether it be from the air we breathe, the water we drink, or the medications we take daily. Early cellular changes after exposure to chemical insult, both individual chemicals and mixtures (two or more chemicals) thereof, can offer a wealth of information about cellular adaptation (e.g., cell death or survival decision processes). From this understanding, better prediction models for chemical risk assessment, such as toxicity or carcinogenicity, can be elucidated. Further, these prediction models can greatly improve the large backlog of chemicals waiting to be evaluated for potential adverse effects. One approach to understand cellular changes and responses after chemical or mixture exposure is with toxicodynamics. From a toxicodynamic approach, a host of information can be determined, such as spatiotemporal interactions of chemical insult with biological targets, the corresponding disruption of intracellular pathways and bioenergetics, and downstream effects after exposure. Appropriately measuring these dynamic cellular changes is imperative. The recent advances in molecular biology, high-throughput in vitro screening assays, and numerous computational techniques have allowed toxicologists to collect large data sets on signaling pathways that are perturbed in response to chemical insults. From these early cellular perturbations, whether they be signaling proteins, biomolecules (e.g., ATP, hormones, NADH), or ions (e.g., Ca2+ or K+), in response to a wide range of doses, especially low concentrations, improved risk assessment prediction models for individual chemical and mixture exposures can be utilized by many fields, such as risk assessment for environmental toxicology and target molecule/pathway analysis for drug development and pharmacology.

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