Eudesmacarbonate, a Eudesmane-Type Sesquiterpene from a Marine Filamentous Cyanobacterial Mat (Oscillatoriales) in the Florida Keys

Abstract

A new, cyclic carbonate eudesmane-type sesquiterpene, eudesmacarbonate (1), was isolated from marine filamentous cyanobacterial mats associated with apparent ingestionrelated intoxications of captive bottlenose dolphins in the Florida Keys. Sequencing of 16S rDNA revealed that mats were composed of closely related Oscillatoriacean species including a previously undocumented species of Neolyngbya. The structure of 1 was elucidated by (+)-HRESIMS, 1D and 2D NMR, single-crystal X-ray diffraction, and vibrational circular dichroism data. Toxicity of 1 was assessed in the zebrafish embryo/larval model, and 1 was found to exhibit effects qualitatively similar to those observed for the known neurotoxin brevetoxin-2 and consistent with neurobehavioral impairment.

An integrated systems-level model of the toxicity of brevetoxin based on high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) metabolic profiling of zebrafish embryos

“…To evaluate acute toxicity, in general, and additionally establish exposure concentrations for HRMAS-NMR experiments, embryotoxicity (i.e., lethality) was assessed for zebrafish embryos (PSA line) exposed over a concentration range of PbTx-2 (Cayman Chemical, Ann Arbor, MI U.S.A.) at 72 hpf as per previously established and validated protocols (Berry et al, 2007;Weiss-Errico et al, 2017;Gebreab et al, 2020;Lydon et al, 2020). Prior to assays, an exposure concentration range (2, 5, 7.5, 10, 15, 20 and 25 nM PbTx-2) was established in preliminary studies.…”

“…Acute toxicity of PbTx-2 was evaluated in embryonic stages of laboratory raised and bred zebrafish, and wild-caught, and hatcheryspawned, mahi-mahi. Zebrafish including, in particular, early life stages (i.e., embryos, larvae) are a well-established vertebrate toxicological model, and accordingly, assays for toxicity based on this species (such as those employed herein) have been widely developed, and applied to assess a range of environmental toxicants (Berry et al, 2007;Bambino and Chu, 2017;Weiss-Errico et al, 2017;Gebreab et al, 2020;Lydon et al, 2020). That said, while the zebrafish represents a useful laboratory model, neither the species itself, nor the established laboratory lines of the species, are especially representative of environmentally relevant (i.e., marine) fish as ecological receptors for brevetoxins.…”

“…In the latter case, foodborne exposure is associated with Neurotoxic Shellfish Poisoning (NSP) which is characterized by a range of both gastrointestinal and neurological symptoms (Watkins et al, 2008), whereas aerosolized PbTx has been largely linked to respiratory distress and related symptomology (e.g., burning of eyes and throat; Kirkpatrick et al, 2006). Blooms of PbTx-producing K. brevis are, however, most frequently associated with adverse effects on marine animal populations including mass mortality of fish (i.e., "fish kills"), and marine mammals including dolphins and manatees (Landsberg, 2002;Fire et al, 2015;Driggers et al, 2016), and numerous studies have, indeed, documented toxicity to fish (Rein et al, 1994;Kimm-Brinson and Ramsdell, 2001;Lu and Tomchik, 2002;Colman and Ramsdell, 2003;Choich et al, 2004;Bourdelais et al, 2005;Salierno et al, 2006;Bakke and Horsberg, 2007;Nam et al, 2010;Tian et al, 2011;Dorantes-Aranda et al, 2015;Lydon et al, 2020). Accordingly, fish (and other marine animals) represent potential "sentinel species" for understanding the role of PbTx toxicity in these ecosystems (i.e., risk assessment), as well as environmental monitoring strategies.…”

“…In the context of metabolomics, this approach allows diverse metabolic profiles to be resolved, quantified and identified within complex biological matrices including intact organisms: most recently, this approach has been specifically employed to investigate modulation of metabolic profiles by various toxicants in early life stages, i.e., embryos and larvae, of the zebrafish (Danio rerio). Zebrafish embryo and larval stages have, in general, been well established as a toxicological model, and toxicity assays based on this model system have been developed and applied to the assessment of a wide range of environmental toxicants including biotoxins and environmental pollutants (Berry et al, 2016;Bambino and Chu, 2017;Lydon et al, 2020), and when coupled to HRMAS NMR metabolic profiling have been effectively used to elucidate integrated pathways of toxicity for these (Roy et al, 2017;Zuberi et al, 2019;Gebreab et al, 2020). In addition to characterizing pathways of toxicity, the suite of metabolites altered by these toxins, furthermore, enables potential identification of biomarkers of exposure and effect, and therefore, has direct value to environmental monitoring and risk assessment efforts.…”

Metabolomic Characterization of a cf. Neolyngbya Cyanobacterium from the South China Sea Reveals Wenchangamide A, a Lipopeptide with In Vitro Apoptotic Potential in Colon Cancer Cells

“…More recently, the new genus Neolyngbya has also been created for several newly described Lyngbya -like organisms [ 21 ]. Despite having a reported biotechnological potential for drug discovery and development, only one new natural product has yet been reported from assemblages with Neolyngbya , namely the neurotoxic sesquiterpenoid eudesmacarbonate [ 22 , 23 ]. Neolyngbya organisms have not been previously reported in the South China Sea.…”