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首页> 外文期刊>Archives of Toxicology >Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells
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Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells

机译：使用来自多能干细胞的肝细胞来模拟胎儿暴露于母体吸烟

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Abstract The liver is a dynamic organ which is both multifunctional and highly regenerative. A major role of the liver is to process both endo and xenobiotics. Cigarettes are an example of a legal and widely used drug which can cause major health problems for adults and constitute a particular risk to the foetus, if the mother smokes during pregnancy. Cigarette smoke contains a complex mixture of thousands of different xenobiotics, including nicotine and polycyclic aromatic hydrocarbons. These affect foetal development in a sex-specific manner, inducing sex-dependant molecular responses in different organs. To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models. While these models have proven to be useful, poor cell phenotype, tissue scarcity, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward human development. Therefore, in this study we have employed hepatoblasts, derived from pluripotent stem cells, to model the effects of xenobiotics from cigarette smoke on human hepatocyte development. Highly pure hepatocyte populations (>90%) were produced in vitro and exposed to factors present in cigarette smoke. Analysis of ATP levels revealed that, independent of the sex, the majority of smoking derivatives tested individually did not deplete ATP levels below 50%. However, following exposure to a cocktail of smoking derivatives, ATP production fell below 50% in a sex-dependent manner. This was paralleled by a loss metabolic activity and secretory ability in both female and male hepatocytes. Interestingly, cell depletion was less pronounced in female hepatocytes, whereas caspase activation was ~twofold greater, indicating sex differences in cell death upon exposure to the smoking derivatives tested.
机译：摘要肝脏是一种动态器官，既有多功能且高度再生。肝脏的主要作用是处理内部和异种学。卷烟是一个合法和广泛使用的药物的一个例子，如果母亲在怀孕期间吸烟，则会对成人产生重大健康问题并对胎儿的危险作出特殊的风险。香烟烟雾含有成千上万的不同Xenobiotics的复杂混合物，包括尼古丁和多环芳烃。这些以性别特异性方式影响胎儿发育，诱导不同器官的性依赖性分子反应。迄今为止，使用细胞系，主要组织和动物模型在体外研究了母亲吸烟对胎儿肝脏的影响。虽然这些模型已被证明是有用的，但细胞表型差，组织短缺，分批变异和物种差异导致数据外推对人类发展的困难。因此，在该研究中，我们使用衍生自多能干细胞的肝细胞，以模拟异鹅对人肝细胞发育的卷烟烟雾的影响。体外产生高纯度肝细胞种群（> 90％）并暴露于香烟烟雾中存在的因素。 ATP水平分析显示，独立于性别，大多数吸烟衍生物都在检测到的单独测试并未耗尽低于50％的ATP水平。然而，在暴露于吸烟衍生物的鸡尾酒之后，ATP产量以性别依赖的方式降低了50％。这通过雌性和雄性肝细胞的损失代谢活性和分泌能力并联。有趣的是，在雌性肝细胞中细胞耗尽不太明显，而Caspase活化〜Twofold大，表明在接触到测试的吸烟衍生物后，表明细胞死亡的性别差异。

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