Domoic acid (DA), the cause of Amnesic Shellfish Poisoning, is a naturally occurring marine excitotoxin that can contaminate shellfish and finfish living in marine waters. Produced by toxic algae, elevated levels of DA are becoming more frequent and human exposure has become a significant public health concern for populations who consume high levels of shellfish. Acute high-dose symptomology in humans includes vomiting, cramping, coma and death. Experimental animal studies and human neuropsychological/autopsy medical reports have collectively shown that DA exposure primarily affects the hippocampal regions of the brain and is associated with seizures and the disruption of cognitive processes (e.g. hallucinations, confusion and both transient and permanent memory loss). The route of DA exposure is important and influences the severity of effects. While some information on developmental exposure is known, studies are few, limited to rodent models and have not used oral exposure, the route most relevant to human health concerns. Domoic Acid readily crosses the placenta and enters the fetal brain. Domoic acid is not associated with congenital dysmorphia in exposed offspring but is linked to persistent neurobehavioral changes such as hyperreactivity, hyperactivity, reduced social contact, increased withdrawal and emotionality and deficits in spatial learning and memory. The functional losses associated with developmental DA can be persistent and injuries to the CNS after a single exposure can be progressive and severe. We propose the first study using a nonhuman primate model to study maternal and infant effects associated with chronic, low-level oral exposure to DA during pregnancy. Our experimental approach includes studies of maternal-fetal toxicokinetics, neurobehavioral assessments of infants and offspring imaging studies to evaluate DA-induced changes in the developing brain. Our nonhuman primate model provides an unmatched opportunity to study this emerging excitotoxin at subtoxic levels in a controlled laboratory setting.
Our specific aims are to: 1) characterize the maternal-fetal transfer and disposition of DA during pregnancy 2) determine the offspring postnatal neurobehavioral effects of maternal DA exposure prior to and during pregnancy with special emphasis on evaluation of behavioral reactivity, emotionality, physical activity, social behavior and spatial memory and 3) characterize the relationship between the offspring neurobehavioral effects and structural and functional changes in the CNS with measures of brain electrophysiology (EEG) and state-of-the-art neuroimaging techniques. Results will fill significant data gaps in our knowledge of this marine compound and the danger that low-level maternal exposure may pose to the developing fetus for high shellfish consumers.
The study proposed in this application will be the first to examine the effects of low-level, oral DA exposure on maternal-fetal kinetics and infant development in the nonhuman primate model. Results will fill significant data gaps in our knowledge of this marine compound and the danger that low-level maternal exposure may pose to the developing fetus for high shellfish consumers.
|Shum, Sara; Kirkwood, Jay S; Jing, Jing et al. (2018) Validated HPLC-MS/MS Method To Quantify Low Levels of Domoic Acid in Plasma and Urine after Subacute Exposure. ACS Omega 3:12079-12088|
|Jing, Jing; Petroff, Rebekah; Shum, Sara et al. (2018) Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates. Drug Metab Dispos 46:155-165|