Collaborative Research: Mechanisms of marine organohalogen bioaccumulation and neurotoxicity

There is an urgent public health need to better understand the relative risks and benefits associated with consumption of seafood. This project will investigate how natural and man-made organohalogen compounds, some of which are known to be toxic, accumulate in marine food webs on the way to human consumption. Researchers at UC San Diego Scripps Institution of Oceanography and UC Davis will investigate the biological mechanisms behind the uptake and concentration of these compounds, and also the mechanisms that make them toxic. The project will support two postdoctoral researchers, thus directly contributing to the development of early career scienctists. The research is jointly supported by NSF and by the National Institute for Environmental Health Sciences (NIEHS).<br/><br/>The project has two aims. Aim 1 seeks to understand cellular mechanisms that control how toxic marine compounds, specifically organohalogens, bioaccumulate, focusing on xenobiotic transporters as the key pathway. The investigators will determine the interactions of the four major human xenobiotic transporters (XTs) with environmentally relevant natural and man-made marine organohalogens. In parallel, they will take advantage of recent progress with heterologous transporter-expression and CRISPR/CAS9 gene editing in sea urchins, to dissect the functional role of XTs in governing bioaccumulation in marine cells. Aim 2 of the project will determine the structure-activity relationships governing neurotoxicity of marine pollutants. The team will use primary cultures of hippocampal neurons cultured from male and female wild type mice to determine how activity at these molecular targets alter neuronal calcium dynamics and morphology using real-time fluorescence cell imaging and morphometric approaches. In addition, they will determine how hippocampal neurons that express a particular mutation alter sensitivity to organohalogens, and ask whether these effects are gender-specific. These studies will address the critical need to better understand the molecular mechanisms by which naturally occurring and man-made seafood pollutants accumulate in target cells and perturb the calcium dynamics essential for normal neuronal network development.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.