Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum Ca2+ Dynamics

Contemporary sources of organohalogens produced as disinfection byproducts (DBPs) are receiving considerable attention as emerging pollutants because of their abundance, persistence, and potential to structurally mimic natural organohalogens produced by bacteria that serve signaling or toxicological functions in marine environments. Here, we tested 34 organohalogens from anthropogenic and marine sources to identify compounds active toward ryanodine receptor (RyR1), known toxicological targets of non-dioxin-like polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). [3H]Ryanodine ([3H]Ry) binding screening (≤2 μM) identified 10 highly active organohalogens. Further analysis indicated that 2,3-dibromoindole (14), tetrabromopyrrole (31), and 2,3,5-tribromopyrrole (34) at 10 μM were the most efficacious at enhancing [3H]Ry binding. Interestingly, these congeners also inhibited microsomal sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase (SERCA1a). Dual SERCA1a inhibition and RyR1 ac...