Toxicokinetics of Domoic Acid (DA) in Pregnant and Non-pregnant Mice After Repeated Oral Administrations

Abstract

Domoic acid (DA), a neurotoxin produced by harmful algal blooms of Pseudo Nitzschia, has been a public health concern. Developmental exposures to DA are believed to result in brain alterations and behavioral disturbances that may persist into adulthood. Therefore, consumption of DA contaminated seafood by pregnant women is particularly concerning as it could affect the neurodevelopment of a developing fetus. In this study, pregnant and non-pregnant C57BL/6 mice were exposed to DA for 8 consecutive days (from gestational days 10 to 17) via oral gavage. Toxicokinetic data were obtained by quantifying DA concentrations in maternal and fetal plasma, maternal and fetal brain (limit of quantification (LOQ) of 0.25 ng/g tissue), and amniotic fluid (LOQ of 0.5 ng/mL) with liquid chromatography-mass spectrometry (LC/MS) multiple reaction monitoring (MRM). Non-pregnant mice were treated with 1, 3, 5, or 15 mg/kg DA repeatedly, where 5 and 15 mg/kg caused neurotoxicity and mortality. The highest plasma concentrations found in non-pregnant mice at 1, 3, 5, and 15 mg/kg were 6, 19, 34, and 166 ng/mL, respectively. Pregnant mice were treated with maternal non-symptomatic dose of 1 or 3 mg DA/kg. As dose of DA increased, the DA absorption rate for both pregnant and non-pregnant mice increased, and a higher absorption rate was observed in pregnant mice plasma when comparing pregnant and non-pregnant mice treated with same dose of DA. Using a combined model, we found that pregnant and non-pregnant mice have redistribution rate (95% CI) of 3.8 (3.3, 4.3) per hour, uptake rate (95% CI) of 1.9 (0.9, 3.8) per hour, and T_cmax of 1.2 hours after the lase dose. In fetal units, fetal brain and amniotic fluid had significant accumulations over time after last dose on GD17. Fetal plasma showed increase, but without any significance. Based on results from our in vivo study, a maternal-fetal PBTK model for DA was then developed to evaluate potential links between chronic, low-level DA exposure and relative health impacts during pregnancy. The developed PBTK model illustrated that the concentration of DA in maternal blood increases and peaks around 1 hour after last dose on GD17 while DA is retained in fetal brain and amniotic fluid over time after lase dose on GD17. Most of the DA was excreted over time based on our developed PBTK model.