Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
Toxicol Appl Pharmacol. 2020 Jul 1;398:115027. doi: 10.1016/j.taap.2020.115027. Epub 2020 May 1.
Domoic acid (DA) is a marine algal toxin that causes acute and chronic neurotoxicity in animals and humans. Prenatal exposure to DA has been associated with neuronal damage and cognitive and behavioral deficits in juvenile California sea lions, cynomolgus monkeys and rodents. Yet, the toxicokinetics (TK) of DA during pregnancy and the maternal-fetal disposition of DA have not been fully elucidated. In this study, we investigated the TK before, during, and after pregnancy and the maternal-fetal disposition of DA in 22 cynomolgus monkeys following daily oral doses of 0.075 or 0.15 mg/kg/day of DA. The AUC of DA was not changed while the renal clearance of DA was increased by 30-90% during and after pregnancy when compared to the pre-pregnancy values. DA was detected in the infant plasma and in the amniotic fluid at delivery. The infant plasma concentrations correlated positively with both the maternal plasma and the amniotic fluid concentrations. The paired infant-to-maternal plasma DA concentration ratios ranged from 0.3 to 0.6 and increased as a function of time which suggests placental efflux and longer apparent fetal half-life than the maternal half-life. The paired amniotic fluid-to-infant plasma DA concentration ratios ranged from 4.5 to 7.5 which indicates significant accumulation of DA in the amniotic fluid. A maternal-fetal TK model was developed to explore the processes that give the observed maternal-fetal disposition of DA. The final model suggests that placental transport and recirculation of DA between the fetus and amniotic fluid are major determining factors of the maternal-fetal TK of DA.
软骨藻酸（DA）是一种海洋藻类毒素，可导致动物和人类急性和慢性神经毒性。产前暴露于 DA 与加利福尼亚海狮、食蟹猴和啮齿动物的神经元损伤以及认知和行为缺陷有关。然而，DA 在怀孕期间的毒代动力学（TK）以及 DA 的母体-胎儿分布尚未完全阐明。在这项研究中，我们在 22 只食蟹猴中研究了怀孕前、期间和之后每日口服 0.075 或 0.15mg/kg/天 DA 后的 TK 以及 DA 的母体-胎儿分布。与怀孕前相比，DA 的 AUC 没有改变，而肾清除率在怀孕期间和之后增加了 30-90%。DA 在婴儿血浆和分娩时的羊水。婴儿血浆浓度与母体血浆和羊水浓度呈正相关。婴儿与母体血浆 DA 浓度比值的配对范围为 0.3 至 0.6，并随时间增加，这表明胎盘外排和比母体半衰期更长的胎儿表观半衰期。配对羊水与婴儿血浆 DA 浓度比值范围为 4.5 至 7.5，这表明 DA 在羊水中有明显的积累。建立了母体-胎儿 TK 模型，以探讨导致观察到的 DA 母体-胎儿分布的过程。最终模型表明，胎盘转运和胎儿与羊水之间 DA 的再循环是 DA 母体-胎儿 TK 的主要决定因素。
