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Evaluation of Oral Anatoxin-a Health Effects in Mice
Citation:
Jenkins-Hill, D. Evaluation of Oral Anatoxin-a Health Effects in Mice. Society of Toxicology, Salt Lake City, UT, March 10 - 14, 2024.
Impact/Purpose:
This presentation will be part of a Harmful Algal Bloom (HAB) session at SOT 2024. The abstract was given to NIEHS coordinators for the session in April 2023. It is an oversight on my part that I did not get the abstract cleared prior to adding it to the session proposal. The session was accepted on 9/27/23. The presentation will be highlighting preliminary data from an ongoing anatoxin study in mice and may include toxicokinetic analysis, ototoxicity screening, and possibly some of the 5-day dose-response data.
Description:
Abstract for Harmful Algal Blooms Session at SOT 2024 Anatoxins are small, water-soluble molecules produced by cyanobacteria in fresh and marine waters globally. They are known to cause prolonged depolarization at the neuromuscular junctions leading to generalized paralysis and can cause death through respiratory paralysis within minutes. Anatoxins have been associated with animal intoxications causing deaths in livestock, pets, and wildlife. In recent years, benthic harmful algal blooms (HABS) have gained attention as producers of anatoxins which often produce larger toxin concentrations than surface HABS. Anatoxin-a is an irreversible nicotinic acetylcholine receptor agonist that acts in the central and peripheral nervous system and is more potent than acetylcholine and nicotine. The World Health Organization has provisional human health guidelines for anatoxin-a in recreational and drinking water, but more definitive regulations require additional health effects data. Environmental Protection Agency’s (EPA) Strategic Plan to Address Harmful Algal Blooms prioritizes data that can inform drinking water health advisories and recreational criteria for anatoxins as needed for health effects of cyanotoxins. Toxicological evaluation of anatoxin-a has shown this to be a neurotoxin with rapid onset, complete recovery if not fatal, and a steep dose response, but little is known about effects of ongoing, sublethal exposures. The EPA Office of Water has identified repeat-dose and non-lethal oral exposures of anatoxin as an important data gap. A study evaluating bioavailability and the toxicokinetics of a single, oral exposure of anatoxin-a will address this information deficit and inform pharmacokinetic modeling for risk assessment. Presence and identification of metabolism by-products will be investigated. The maximum dose will likely be 6.15-10.6 mg/kg. A 5-day oral exposure of anatoxin-a will follow with endpoints of neurobehavioral assessment, ototoxicity screening, genomics, and metabolomics. Histology and serum chemistry endpoints have often been normal with anatoxin-a, with one exception. Mice dosed with 50-150 μg/kg anatoxin-a daily for 7 days by intraperitoneal injection (Yavasoglu et al., 2008) exhibited dose-dependent histological changes in testicular structure and sperm count. Our studies will utilize similar endpoints in males after exposure.