Academic journal article Environmental Health Perspectives

Brevetoxin Forms Covalent DNA Adducts in Rat Lung Following Intratracheal Exposure

Academic journal article Environmental Health Perspectives

Brevetoxin Forms Covalent DNA Adducts in Rat Lung Following Intratracheal Exposure

Article excerpt

BACKGROUND: Human exposure to brevetoxins produced by the red tide organism, Karenia brevis, is an increasing public health concern. Using in vitro exposure of rat liver cells to brevetoxin B (PbTx-2), the primary toxin product of K. brevis, we previously showed that it formed [C.sub.27,28]-epoxy brevetoxin metabolites capable of covalendy binding to nucleic acids, a common initiation step for carcinogenesis.

OBJECTIVE: This study was undertaken to evaluate nucleic acid adduction in lung following in vitro and in vivo brevetoxin exposures.

METHODS: To clarify reactions of brevetoxin epoxide with DNA, we analyzed reaction products of PbTx-6 (a [C(27),(28) epoxide metabolite of brevetoxin B) with nucleosides. We also analyzed adducts from nucleic acid hydrolysates of isolated rat lung cells treated with PbTx-2 or PbTx-6 in vitro and lung tissue from rats after intratracheal exposure to PbTx-2 or PbTx-6 at 45 [micro] toxin/kg body weight.

RESULTS: Our results indicate that PbTx-2 forms DNA adducts with cytidine after treatment of isolated lung cells, and forms DNA adducts with adenosine and guanosine after intratracheal exposure. CONCLUSIONS: These results are consistent with metabolic activation of highly reactive brevetoxin intermediates that bind to nucleic acid. These findings provide a basis for monitoring exposure and assessing the hazard associated with depurination of brevetoxm-nucleotide adducts in lung tissue.

Key WORDS: brevetoxin, DNA adducts, epoxidation, harmful algal bloom, Karenia brevis, lung, metabolism. Environ Health Perspect 116:930-936 (2008). doi:10.1289/ehp.11068 available via [Online 24 March 2008]

Karenia brevis, formerly Gymnodinium breve, a brevetoxin-producing dinoflagellate, is recognized as the major harmful algae forming the red tide blooms in the Gulf of Mexico (Davis 1948). Two classes of brevetoxins were originally isolated ftom K. brevis by high pressure liquid chromatography (Risk et al. 1979). Structural analysis of these fractions identified two backbone structures, containing either 11 (brevetoxin-B) or 10 (brevetoxin-A) fused cyclic ether rings (Lin et al. 1981; Shimizu et al. 1986). Each backbone structure has similar functional groups and is subject to similar metabolic modifications (Wang et al. 2004). Brevetoxins bind to voltage-gated sodium channels to alter gating transitions interfering with the sensitive movements that transition the channel's closed, open, and inactivated states (Catterall and Risk 1981). The initial actions of brevetoxins lead to nerve activation; within a few seconds of nerve activation, transient repetitive neuronal discharges are followed by action potential depression and eventually by a complete blockade of neuronal excitability (Huang et al. 1984).

The direct consumption of brevetoxin-laden shellfish causes the food poisoning referred to as neurotoxic shellfish poisoning (NSP) in humans (McFarren et al. 1965). NSP has become a rare phenomenon, even with the frequent occurrence of red tide events, in large part due to effective monitoring and management of shellfish harvest. However, inhalation of airborne brevetoxins at beaches remains common, and the occupational and recreational hazards have been the subject of recent investigations (Backer et al. 2003, 2005). Experimental exposure of brevetoxin aerosols was first demonstrated by Woodcock (1948), and in the last decade several studies have characterized the toxicokinetics and adverse effects of brevetoxins after intratracheal exposure of rats or sheep (Abraham et al. 2005; Benson et al. 1999). During this time, various animal and tissue explant models have been used to discriminate the molecular actions of brevetoxins on voltage-gated sodium channels in lung smooth muscle, autonomic nerve, and central respiratory centers (Ramsdell 2008). Exposure to brevetoxin-containing aerosols has also been shown to cause severe allergic reactions in asthmatic patients (Fleming et al. …

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