Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers.
Maternal exposure to carbamazepine at environmental concentrations can cross intestinal and placental barriers.
复制标题
在环境浓度下，孕产妇接触卡马西平可以横穿肠道和胎盘屏障。
DOI：
10.1016/j.bbrc.2016.04.088
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发表时间：
2016-05-27
影响因子：
3.1
通讯作者：
Thomas MA
中科院分区：
文献类型：
--
作者：
Kaushik G;Huber DP;Aho K;Finney B;Bearden S;Zarbalis KS;Thomas MA
精神活性药物已被发现在怀孕期间的临床剂量致畸。这些药物也在美国的饮用水中检测到微量（ppb）浓度，并且是可能在遗传易感个体中引发神经系统疾病的环境污染物。以前的研究已经确定，精神活性药物（氟西汀，文拉法辛和卡马西平）在环境相关浓度丰富的基因组调节的发育和功能的黑头呆鱼的神经系统。改变的基因组也与潜在的神经系统疾病有关，包括自闭症谱系障碍（ASD）。随后的体外研究表明，精神活性药物改变了人类神经元细胞中ASD相关突触蛋白的表达和基因表达。然而，目前尚不清楚这些药物的环境相关浓度是否能够通过母体到胎儿的生物屏障，从而对神经系统发育构成潜在风险。本研究的主要目的是测试是否精神活性药物（氟西汀，文拉法辛，卡马西平）通过饮用水在环境中的浓度给孕鼠可以通过跨越肠道和胎盘屏障到达发育中的胚胎的大脑。我们通过将2H同位素标记的药物添加到雌性小鼠的饮用水中20天（受孕前10天和受孕后10天），并使用同位素比质谱法定量发育胚胎的母体肝脏和大脑中的2H同位素富集信号来解决这个问题。在卡马西平处理的小鼠的胚胎和肝脏的大脑中检测到显著水平的2H富集，但在对照母鼠或氟西汀或文拉法辛应用中未检测到。这些结果提供了第一个证据，饮用水中的卡马西平和典型的环境浓度是从母亲传递给胚胎。我们的研究结果，结合以前的证据表明，卡马西平可能与ASD的婴儿，值得仔细检查精神药物在饮用水和他们的潜在关联与神经发育障碍。
Psychoactive pharmaceuticals have been found as teratogens at clinical dosage during pregnancy. These pharmaceuticals have also been detected in minute (ppb) concentrations in drinking water in the US, and are environmental contaminants that may be complicit in triggering neurological disorders in genetically susceptible individuals. Previous studies have determined that psychoactive pharmaceuticals (fluoxetine, venlafaxine and carbamazepine) at environmentally relevant concentrations enriched sets of genes regulating development and function of the nervous system in fathead minnows. Altered gene sets were also associated with potential neurological disorders, including autism spectrum disorders (ASD). Subsequent in vitro studies indicated that psychoactive pharmaceuticals altered ASD-associated synaptic protein expression and gene expression in human neuronal cells. However, it is unknown if environmentally relevant concentrations of these pharmaceuticals are able to cross biological barriers from mother to fetus, thus potentially posing risks to nervous system development. The main objective of this study was to test whether psychoactive pharmaceuticals (fluoxetine, venlafaxine, and carbamazepine) administered through the drinking water at environmental concentrations to pregnant mice could reach the brain of the developing embryo by crossing intestinal and placental barriers. We addressed this question by adding 2H-isotope labeled pharmaceuticals to the drinking water of female mice for 20 days (10 pre-and 10 post-conception days), and quantifying 2H-isotope enrichment signals in the dam liver and brain of developing embryos using isotope ratio mass spectrometry. Significant levels of 2H enrichment was detected in the brain of embryos and livers of carbamazepine-treated mice but not in those of control dams, or for fluoxetine or venlafaxine application. These results provide the first evidence that carbamazepine in drinking water and at typical environmental concentrations is transmitted from mother to embryo. Our results, combined with previous evidence that carbamazepine may be associated with ASD in infants, warrant the closer examination of psychoactive pharmaceuticals in drinking water and their potential association with neurodevelopmental disorders.