Baines, Robert P.; (2020) Dictyostelium discoideum as a model for the evaluation of teratogenic compounds. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Before new chemicals can be put on the market, they must be evaluated for toxicological safety. Evaluating the safety of new chemicals, for either medical, cosmetic or environmental application, is tightly regulated by worldwide legislation. A critical aspect of toxicity evaluation is developmental and reproductive toxicity (DART) testing. Traditionally, DART testing has been conducted in vivo in mammalian model systems. In fact, current EU DART testing guidelines accounts for the majority of animals used and the financial costs of new compound compliance testing. Therefore, because of the need to reduce the financial and animal costs associated with DART testing, there is a growing demand for new alternative model systems for toxicity evaluation. Dictyostelium discoideum is a eukaryotic amoeba which due to its unique developmental cycle has the potential to serve as a non-animal alternative model in DART testing. However, for a new alternative model to be proven effective it must allow for high-throughput screening, whilst maintaining biological complexity; allowing developmental toxicity results to be predictive of mammalian systems. To address these concerns, we developed new high-throughput D. discoideum growth and developmental toxicity assays. We use the assays to characterise toxicity across a broad range of test compounds, thereby revealing a significant relationship between D. discoideum and mammalian toxicity values. Our data demonstrates that D. discoideum has the biological complexity necessary to be predictive of mammalian toxicity. We further assess whether D. discoideum could be used to genetically characterise developmentally toxic compounds. Using next generation functional genomic screens, we show how the developmentally toxicity compounds, lithium and VPA can be globally genetically phenotyped. Using this genetic phenotyping approach, we were also able to identify the biological targets and processes that mediate lithium and VPA toxicity. Together, these studies illustrate the potential of D. discoideum to be developed as a new alternative model in DART testing.

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