UC San Diego

The field of toxicology is under growing pressure to meet the demand of hazard assessment for the increasingly vast number of environmental toxicants. Due to low throughput and high cost, the traditional toxicity testing strategy, using rodent and higher mammalian animal-based models, is unable to adequately meet these competing demands. Hence, there is increasing recognition of the value of transforming toxicity testing to reduce the usage of mammal models and to more efficiently and reliably predict human relevant toxicity. To this end, a battery approach, integrating diverse in vitro and alternative animal models, was initiated to complement and accelerate hazard assessment. These alternative models are amenable to inexpensive, rapid and robust screening. In this dissertation, I introduce the asexual freshwater planarian Dugesia japonica as a novel alternative animal model to study developmental neurotoxicity. I developed and expanded a fully automated planarian high-throughput (HTS) screening platform to accomplish rapid screening of multiple morphological and behavioral endpoints. This HTS platform was evaluated for robustness, strengths and weaknesses, using an 87-compound library with known and suspected compounds and a 15-compound flame retardant library. As a unique advantage, the similar size of adult and regenerating planarians allows for direct comparison of two worm types to discern development-specific toxicity from overt systemic toxicity. We show that planarian is a useful model to potentially link toxicity pathways to whole-animal adverse functional outcomes by providing a large repertoire of behavioral endpoints. Comparative analysis of the planarian model with other alternative models, including zebrafish, nematode and in vitro cell-based models, provides insight into how different models complement each other in the battery approach. Finally, I discuss our comparative screen of organophosphrous pesticides (OPs) using the expanded platform, to investigate the possible mechanisms of developmental toxicity in OPs. Altogether, by establishing a new alternative animal model this work adds value to the battery approach to accelerate toxicity screening and prioritize toxicants, and provide further insight into the potential mechanisms of OP neurotoxicity.