Bioaccumulation and developmental toxicity of seafood pollutants

SUMMARY Consumption of seafood is a significant route of human exposure to persistent, teratogenic pollutants. Of concern are exposures that occur early in life, with adverse reproductive, teratogenic, neurological, cardiovascular, and immune outcomes. Effective prediction of the risks associated with these exposures requires an understanding of mechanisms of bioaccumulation and developmental toxicity. The goals of Project 3 are to determine structural and functional mechanisms of organohalogen interaction with Xenobiotic Transporters (XTs) and to determine their developmental toxicity on the nascent germ line, a sensitive and relevant target of exposure. Such mechanistic studies inform our understanding of how emerging pollutants, such as microbial transformation products, are transferred from the environment, to seafood, and ultimately to humans. The Aims of this proposal utilize knockout and transgenic sea urchins to determine the role of marine transporters in pollutant accumulation, as well as biophysical and structural characterization of human, fish and sea urchin transporters to precisely define their mechanisms of pollutant interaction. In parallel, we will use high throughput approaches with sea urchin embryos and human cells to define developmental targets of these compounds. This study is based on innovative approaches including development of novel marine models, high-throughput/high-content imaging, the use of cryo-electron microscopy of XTs across different species of fish, and the generation of synthetically evolved nanobodies. The results and resources have impact for a wide range of problems developmental biology, pharmacology and toxicology, providing a foundation of knowledge necessary for determining safe limits for seafood consumption.