UC Davis

This dissertation employs zebrafish models as a robust tool for systematically assessing developmental toxicity across a spectrum of chemical classes. Zebrafish, owing to their genetic similarities to humans and transparent embryos that allow real-time observation, serve as an invaluable organism for unraveling the complexities of developmental toxicity. The initial investigation involved the screening of a diverse 91-compound library. The findings from this study highlighted the pivotal role of behavior as a sensitive and integrative endpoint for developmental toxicity assessment. It also established the importance of assessing it at more than one day during development. Intriguingly, compounds from various functional groups elicited distinctive behavioral abnormalities, underscoring the nuanced nature of toxic responses. Building upon the structure-activity relationship insights garnered from the first study, the subsequent investigation focused on non-dioxin-like PCB congeners. This study not only examined their developmental neurotoxicity but also elucidated a direct link between alterations in photomotor behavior and the sensitization of ryanodine receptors. This connection provides valuable mechanistic insights into the neurological impact of these compounds during development. The third study explored a novel class of compounds, halogenated pyrroles, with previously shown ryanodine receptor sensitization. The study further emphasized the importance of prolonged assessments in uncovering behavioral abnormalities and incorporated powerful imaging tools to understand the mechanism of action for observed behavioral changes. This nuanced approach contributes to a more comprehensive understanding of the developmental toxicity landscape associated with these compounds. Finally, the dissertation broadens its scope to encompass the assessment of 13 psychoactive compounds, including psychedelics, in larval zebrafish. This screening not only identified distinct neurotoxicity profiles but also serves as a valuable reference for the therapeutic development of these compounds. The inclusion of psychedelics in the study responds to the contemporary interest in their therapeutic potential and addresses a critical gap in the existing safety data. In essence, these interconnected studies collectively showcase the adaptability and versatility of zebrafish models in unraveling the intricate and multifaceted terrain of developmental toxicity and neurotoxicity induced by a diverse array of chemical exposures. The dissertation, through its systematic approach and mechanistic insights, significantly contributes to advancing our understanding of the potential risks associated with various chemical classes during critical stages of development.