Toxicokinetics of domoic acid in the fetal rat.
Domoic acid (DA) is a potent neurotoxin that has both marine wildlife and human health impacts, including developmental effects during prenatal exposure in rodent models. However, little is known regarding DA toxicokinetics in the fetal unit during maternal-fetal transfer. Tissue distribution and toxicokinetics of DA were investigated in pregnant rats and their pups just prior to birth at gestational day 20. Pregnant Sprague Dawley rats were given an intravenous dose of 1.0 mg DA/kg and samples of maternal plasma, fetal plasma, placenta, amniotic fluid and fetal brain were taken at intervals over 24 h. Toxicokinetic parameters were determined using WinNonLin software analysis. Maternal plasma DA log concentration-time curves fit a two compartment pharmacokinetic profile, with alpha and beta half-lives of elimination of 26.9 and 297 min, respectively. Placenta had a C(max) of 752 ng/mL and a terminal half-life of 577 min. Maternal-fetal transfer between the plasma compartments was 31% with a fetal plasma C(max) of 86 ng/mL at 60 min and terminal half-life of 553 min. Amniotic fluid and fetal brain had overall averages of 27±12 ng/mL and 8.12 ng/g, respectively, and did not show evidence of elimination over 24 h. The longer fetal retention of DA, particularly in amniotic fluid, indicates that the fetus may be continually re-exposed during gestation, which could potentially lead to a disease state even at small exposure dose. This has implications for the California sea lions (Zalophus californianus), which exhibit an epilepsy-like disease that arises months after DA producing blooms.
National Oceanographic and Atmospheric Administration, Center for Coastal Environmental Health and Biomolecular Research, Charleston, SC 29412, USA.
Jennifer
J
Maucher Fuquay
Noah
N
Muha
Zhihong
Z
Wang
John S
JS
Ramsdell
D000653:Amniotic Fluid / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000196:embryology; D001923:Brain Chemistry; D005260:Female; D005333:Fetus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D010920:Placenta / Q000737:chemistry; D011247:Pregnancy; D051381:Rats / Q000196:embryology; D017207:Rats, Sprague-Dawley; D046070:Sea Lions
C012301:domoic acid; D007608:Kainic Acid