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

Abstract

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-dioxinlike 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 activation triggered Ca2+ efflux from microsomal vesicles with initial rates rank ordered 31 > 34 > 14. Hexabromobipyrroles (25) enhanced [3H]Ry binding moderately with strong SERCA1a inhibition, whereas pyrrole (24), 2,3,4-tribromopyrrole (26), and ethyl-4-bromopyrrole-2-carboxylate (27) were inactive. Of three PBDE derivatives of marine origin active in the [3H]Ry assay, 4′-hydroxy-2,3′,4,5′,6-pentabromodiphenyl ether (18) was also a highly potent SERCA1a inhibitor. Molecular targets of marine organohalogens that are also DBPs of emerging environmental concern are likely to contribute to their toxicity.

Genetic examination of the marine bacterium Pseudoalteromonas luteoviolacea and effects of its metamorphosis‐inducing factors

“…TBP has been implicated as an inducer of coral metamorphosis by testing the effect of fractionated and purified TBP on coral larvae (Tebben et al ., 2011, 2015; Sneed et al ., 2014). To determine whether larvae of Hydractinia respond to purified TBP in a similar manner, we investigated whether synthesized, exogenously added TBP (Zheng et al ., 2018) at similar concentrations to those tested for corals (Sneed et al ., 2014; Tebben et al ., 2015) stimulates Hydractinia metamorphosis. The development of Hydractinia larvae after exposure to TBP or bacteria was quantified after 72 h and scored positively for metamorphosis if they developed stolons and tentacles (Fig.…”

“…Studies of TBP exposure to phytoplankton reveals that TBP induces the release of intracellular calcium stores (Whalen et al ., 2018). TBP exposure to mammal microsomes triggers Ca 2+ efflux by activating the Ryanodine receptor, RyR1, and inhibiting microsomal sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase, SERCA1a (Zheng et al ., 2018). Calcium signalling and membrane potential depolarization have been linked to the induction of Hydroides metamorphosis (Carpizo‐Ituarte and Hadfield, 1998; Holm et al ., 1998; Chen et al ., 2012).…”

“…The pure 2,3,4,5‐TBP standard was synthesized as previously described (Zheng et al ., 2018). Eleven milligrams of TBP was re‐suspended in acetonitrile (0.0059 M) and was diluted into ASW (35 PSU for Hydroides and 29 PSU for Hydractinia ), which contained a final acetonitrile concentration of 2% (v/v).…”

The chemical cue tetrabromopyrrole induces rapid cellular stress and mortality in phytoplankton

“…huxleyi genome has an inositol 1,4,5-triphosphate receptor (ITPR) containing a protein architecture characteristic of canonical metazoan members of this superfamily 47 . Moreover, a recent study found that halogenated pyrroles, including TBP of marine origin, were modulators of mammalian ryanodine receptors 48 . These authors also noted that the pyrrole moiety at 2-position on the diterpenoid ryanodine was essential for both high-affinity binding to RyR1 and conferring toxicity in mice.…”

Neurotoxicity of polychlorinated biphenyls and related organohalogens

“…While PCBs are among the most extensively studied POP chemotype, other major POPs have been shown to have neuropathogenic potential, including organochlorine insecticides (e.g., DDT, cyclodienes, hexachlorocyclohexanes) and, more recently, polybrominated diphenyl ether flame retardants (PBDEs) and newly discovered organohalogens produced as disinfectant byproducts [96,146,223]. Figure 1 compares PCBs with chemotypes that have emerged more recently as POPs of human health concern because of their potential as neuromodulators and neurotoxicants.…”