Maternal‐Fetal Toxicokinetics of the Shellfish Toxin Domoic Acid

Abstract

BackgroundDomoic Acid (DA) is an excitatory neurotoxin produced by harmful algal blooms. Through the marine food web, humans and marine mammals can be exposed to DA and experience DA poisoning. To protect humans, a tolerable daily intake (TDI) of 0.075 mg/kg of DA has been suggested based on acute/short term exposure “no observable adverse effect level” (NOAEL) in animals with a 10‐fold safety factor. However, several studies in model species have suggested that chronic DA exposure at subacute level is also harmful to the central nervous system. Similarly, it has been suggested that in utero exposure to DA adversely affects fetal neurological development which highlights the need to establish safe chronic consumption levels in vulnerable populations. The purpose of this study was to characterize DA disposition during pregnancy following chronic subacute dosing, and to determine whether such chronic DA exposure results in significant fetal exposures and alters infant behavioral outcomes in cynomolgus monkeys.MethodFemale monkeys (n=10) were orally dosed daily with 0.15 mg/kg DA for at least two months prior to and over the course of pregnancy. DA pharmacokinetics were characterized pre‐pregnancy, and on weeks 9 and 17 of gestation. At delivery, the maternal plasma and amniotic fluid DA concentrations were measured. Infant plasma DA concentrations were measured from birth to day 7 and neonatal behavioral outcomes were measured from birth to day 14. Maternal‐fetal pharmacokinetics of DA through pregnancy was simulated using physiologically‐based pharmacokinetic (PBPK) modeling.ResultsThe renal clearance of DA was significantly increased in these monkeys in parallel with increased GFR during pregnancy, but the overall exposure to DA was similar during pregnancy as before pregnancy (Table 1). Average maternal plasma, fetal plasma, and amniotic fluid concentrations at time of delivery were 2.1 ± 1.3 ng/mL (n=9), 1.3 ± 1.0 ng/mL (n=8), and 7.5 ± 5.0 ng/mL (n=5), respectively. Fetal to maternal plasma and amniotic fluid to maternal plasma concentration ratios were 0.6 (95% CI: 0.4, 1.0) and 3.5 (95% CI: 1.8, 7.1). Results from behavioral testing of the infants suggested that in utero exposure to DA at subacute dose levels may be associated with adverse effects on neurocognitive development.ConclusionThe results of this study suggest that mother and fetus exposures are nearly similar following repeated doses of DA during pregnancy. The high amniotic fluid to maternal concentration ratio suggests that amniotic fluid acts as a “deep compartment” of fetal distribution, and may contribute to continuous fetal exposure in utero. Collectively the data suggest that the TDI estimates for DA may need to be lowered to assure maternal‐fetal safety.Support or Funding InformationR01 ES023043‐01 NIH/NIEHSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.