title: Repeated independent exposures to domoic acid do not enhance symptomatic toxicity in outbred or seizure-sensitive inbred mice.
abstract: Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperitoneally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were compared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.
authors.affiliation: Marine Biotoxins Program, NOAA Southeast Fisheries Science Center Charleston Laboratory, South Carolina, USA.
authors.forename: Y G
authors.initials: YG
authors.lastname: Peng
authors.forename: E C
authors.initials: EC
authors.lastname: Clayton
authors.forename: L W
authors.initials: LW
authors.lastname: Means
authors.forename: J S
authors.initials: JS
authors.lastname: Ramsdell
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists; D005260:Female; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D009422:Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology; D009498:Neurotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D013045:Species Specificity
chemical_list: D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; C012301:domoic acid; D007608:Kainic Acid