Harmful blooms of domoic acid-producing algae are a growing problem. Species affected include some that are threatened or endangered. Humans are at risk, and consequences can be severe. Despite established seafood testing mechanisms, concerns about potential human exposures persist, including in utero exposure, which might go undetected initially but have detrimental long-term consequences. Previous rodent studies suggest in utero exposure to domoic acid might cause neuropathological changes in the hippocampus and the development of epilepsy, but direct evidence of spontaneous seizures is lacking. The investigators will attempt to fill this critical gap. The proposed project is an interdisciplinary collaboration among wildlife veterinarians and biomedical scientists to test the hypothesis that in utero exposure to domoic acid causes temporal lobe epilepsy, albeit a milder form than that caused by adult exposure.
Aim 1 is to test whether in utero exposure to domoic acid causes temporal lobe epilepsy in mice and to compare the neuropathology to that of mice exposed as adults.
Aim 2 is to test the hypothesis in California sea lions by evaluating brain tissue from animals euthanized because of domoic acid toxicosis with a poor prognosis. Results will indicate whether or not in utero exposure can cause temporal lobe epilepsy to develop, and if so, whether it is as severe as that which develops after adult exposure. Findings will inform future decisions on whether and how to further evaluate risks of in utero exposure to domoic acid in humans. In addition, Aim 2 will generate rare, perfusion-fixed, quantitative whole-brain data from animals that have a large, gyrencephalic brain and naturally occurring temporal lobe epilepsy, which could provide insight into mechanisms of epileptogenesis.

Public Health Relevance

The proposed project addresses growing concerns that human embryos might be at risk when pregnant women consume seafood containing naturally occurring toxins at levels below current regulatory limits. The investigators will determine whether or not exposure during pregnancy can cause temporal lobe epilepsy in laboratory mice and naturally exposed sea lions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
4R01ES021960-05
Application #
9116156
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Tyson, Frederick L
Project Start
2012-09-24
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Demars, Fanny; Clark, Kristen; Wyeth, Megan S et al. (2018) A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice. Neurotoxicology 66:128-137
Buckmaster, Paul S; Wen, Xiling; Toyoda, Izumi et al. (2014) Hippocampal neuropathology of domoic acid-induced epilepsy in California sea lions (Zalophus californianus). J Comp Neurol 522:1691-706