Leveraging Zebrafish to Identify Chemicals Disrupting Early Embryonic Development

For many compounds currently used in commerce, there are minimal developmental toxicity data available. Additionally, current developmental toxicity testing guidelines require the use of rodents, making them expensive, time consuming, and inefficient to address existing data gaps. Therefore, alternatives to conventional animal testing – such as cell-free assays, cell-based assays, and non-protected stages of non-mammalian models – are needed to support the screening and prioritization of chemicals for developmental toxicity testing. Zebrafish offer one of the most promising alternative and cost-effective vertebrate models to support drug discovery and toxicity testing. Their small size, rapid development, and conservation of early developmental processes with mammals (including humans), make the zebrafish embryo an ideal model for the identification of compounds that disrupt the normal trajectory of early embryonic development. Therefore, the overall goal of this research is to leverage early, non-protected life stages of zebrafish embryos to identify compounds that may be adversely impacting early development. For Aim 1, using high-content screening techniques, embryonic behavior was examined as a potential readout for detection of compounds adversely impacting the development and function of the nervous system. For Aim 2, the effects of niclosamide – a widely used anthelmintic that was identified from our high-content screen – on early embryonic development was assessed using a multipronged approach at multiple levels of biological organization. For Aim 3, based on our findings within Specific Aim 2, the mechanism of niclosamide-induced developmental toxicity was further examined using a combination of whole-embryo assessments and human embryonic stem cell-based assays. Overall, our findings highlight the utility of embryonic zebrafish as a physiologically-intact, non-mammalian model for 1) rapid chemical screening and prioritization for developmental toxicity testing; 2) discovering biologically active yet understudied chemicals; and 3) investigating mechanisms of developmental toxicity