Project 2 – Summary/Abstract Seafood is a major dietary source of diverse chemical pollutants, especially for populations who rely on seafood as their primary protein source. Despite industrial chemicals such as PBDE fire retardants, the insecticide DDT, and PCB lubricants being banned in the U.S. for decades due to their harm to humans and the environment, these legacy chemicals still pose health risks due to their persistence in the ocean environment. They all share similar chemical features of polyhalogenation that account for their toxic properties that underlie a variety of reproductive, teratogenic, neurological, cardiovascular, and immune disease outcomes. Polyhalogenation is also a distinctive hallmark of natural chemicals common to marine life. Natural polybrominated compounds produced by marine bacteria and algae, such as the ubiquitous hydroxylated and methoxylated polybrominated diphenyl ethers (OH/MeO-BDEs), polybrominated pyrroles (PBPs), and recently discovered polybrominated bis-indole toxins, have emerged as chemicals of human health concern. We and others have demonstrated that OH-BDEs such as 6-OH-BDE-47 (thyroid hormone receptor) and PBPs such as tetrabromopyrrole (ryanodine receptor) are developmental toxins and pose potential risks to humans. Many fundamental questions remain about the extent of sources for these natural organohalogen molecules, how these chemicals enter and move through the marine food web, and in what situations humans may be more impacted by natural organohalogens versus their anthropogenic counterparts. Recent discoveries by the Moore and Allen laboratories have rigorously established the genetic and biochemical basis for the microbial synthesis of natural OH/MeO-BDE, PBP, dioxins, and bromoindole molecules in diverse lineages of marine and aquatic bacteria. However, the global distribution and ubiquity of these molecules in marine biota is yet to be explained by the sources thus far discovered, suggesting additional bioge