Domoic acid is a potent neurotoxin to neonatal rats

Marine Biotoxins Program, NOAA Southeast Fisheries Science Center Charleston Laboratory, South Carolina, USA.
Natural Toxins 01/1997; 5(2):74-9. DOI: 10.1002/(SICI)(1997)5:2<74::AID-NT4>3.0.CO;2-I
Source: PubMed


Domoic acid induces a time-dependent neuroexcitotoxic effect in neonatal rats characterized by hyperactivity, stereotypic scratching, convulsions, and death with observable behaviors occurring at exposures 40 times lower by body weight in neonates than reported in adults. Low doses of domoic acid (0.1 mg/kg) induced c-fos in the central nervous system which was inhibited in part by 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist. Domoic acid caused no evidence of structural alteration in the brain of neonates as assessed by Nissel staining and cupric silver histochemistry. Domoic acid induced reproducible behavioral effects at doses as low as 0.05 mg/kg and induced seizures doses as low as 0.2 mg/kg. Determination of serum domoic acid levels after 60 min exposure indicated that serum levels of domoic acid in the neonates corresponded closely to the serum levels that induce similar symptoms in adult rats and mice. We conclude that neonatal rats are highly sensitive to the neuroexcitatory and lethal effects of domoic acid and that the increased sensitivity results from higher than expected serum levels of domoic acid. These findings are consistent with other findings that reduced serum clearance of domoic acid is a predisposing factor to domoic acid toxicity.

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    • "Although well below the lethal dose, if this was ingested more than just once, it is possible that this low dose exposure may have effects on development, as studies in laboratory rodents have shown perinatal animals are sensitive to effects of DA when exposed both pre-and postnatally (Xi et al. 1997, Maucher and Ramsdell 2007, Stewart 2010). While many laboratory experiments are based on a one-time dosage (Xi et al. 1997, Maucher and Ramsdell 2007), nursing marine mammals may be continually exposed to a low dose of DA for the duration of their nursing period, so the cumulative exposure could be well above the single dose determined to have effects in experimental exposure studies. Milk may also act as a reservoir of DA as it is not removed from the body without nursing. "
    Marine Mammal Science 02/2014; 30(3). DOI:10.1111/mms.12117 · 1.94 Impact Factor
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    • "Based on these few experiments, neonates have been shown to be more sensitive to DomA per body weight than adults [1] [2] [3] [4] [5]. The reduced serum clearance has been proposed as a contributing factor to their increased vulnerability as well as greater access of DomA through the undeveloped blood-brain barrier [1] [4]. DomA has also been shown to cross the placenta and can reach the brain tissue of the fetus and accumulate in the amniotic fluid [6]. "
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    ABSTRACT: Domoic acid (DomA) is a naturally occurring shellfish toxin that can induce brain damage in mammalians. Neonates have shown increased sensitivity to DomA-induced toxicity, and prenatal exposure has been associated with e.g. decreased brain GABA levels, and increased glutamate levels. Here, we evaluated DomA-induced toxicity in immature and mature primary cultures of neurons and glial cells from rat cerebellum by measuring the mRNA levels of selected genes. Moreover, we assessed if the induced toxicity was mediated by the activation of the AMPA/KA and/or the NMDA receptor. The expression of all studied neuronal markers was affected after DomA exposure in both immature and mature cultures. However, the mature cultures seemed to be more sensitive to the treatment, as the effects were observed at lower concentrations and at earlier time points than for the immature cultures. The DomA effects were completely prevented by the antagonist of the AMPA/KA receptor (NBQX), while the antagonist of the NMDA receptor (APV) partly blocked the DomA-induced effects. Interestingly, the DomA-induced effect was also partly prevented by the neurotransmitter GABA. DomA exposure also affected the mRNA levels of the astrocytic markers in mature cultures. These DomA-induced effects were reduced by the addition of NBQX, APV, and GABA.
    Journal of Toxicology 11/2011; 2011(1687-8191):543512. DOI:10.1155/2011/543512
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    • "Postnatal (single exposure) 0.05 -0.1 Xi et al. 1997; Wang et al. 2000; Doucette et al. 2000; Levin et al. 2006 Postnatal (repeated exposures) Table 7 Summary of proposed oral ARfDs or TDIs for DomA "
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    ABSTRACT: Domoic acid (DomA) is an excitatory amino acid which can accumulate in shellfish and finfish under certain environmental conditions. DomA is a potent neurotoxin. In humans and in non-human primates, oral exposure to a few mg/kg DomA elicits gastrointestinal effects, while slightly higher doses cause neurological symptoms, seizures, memory impairment, and limbic system degeneration. In rodents, which appear to be less sensitive than humans or non-human primates, oral doses cause behavioral abnormalities (e.g. hindlimb scratching), followed by seizures and hippocampal degeneration. Similar effects are also seen in other species (from sea lions to zebrafish), indicating that DomA exerts similar neurotoxic effects across species. The neurotoxicity of DomA is ascribed to its ability to interact and activate the AMPA/KA receptors, a subfamily of receptors for the neuroexcitatory neurotransmitter glutamate. Studies exploring the neurotoxic effects of DomA on the developing nervous system indicate that DomA elicits similar behavioral, biochemical and morphological effects as in adult animals. However, most importantly, developmental neurotoxicity is seen at doses of DomA that are one to two orders of magnitude lower than those exerting neurotoxicity in adults. This difference may be due to toxicokinetic and/or toxicodynamic differences. Estimated safe doses may be exceeded in adults by high consumption of shellfish contaminated with DomA at the current limit of 20 microg/g. Given the potential higher susceptibility of the young to DomA neurotoxicity, additional studies investigating exposure to, and effects of this neurotoxin during brain development are warranted.
    NeuroToxicology 09/2010; 31(5):409-23. DOI:10.1016/j.neuro.2010.05.003 · 3.38 Impact Factor
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