State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
Ecotoxicol Environ Saf. 2019 Jun 15;174:353-362. doi: 10.1016/j.ecoenv.2019.02.091. Epub 2019 Mar 5.
The liver is one of the major targets of hormones, including thyroid hormones (THs), and many industrial chemicals, such as endocrine-disrupting chemicals. Those compounds may permeate the placenta barrier and pose a risk for embryonic development. Therefore, it is necessary to assess the toxic effects of those kind of industrial chemicals during liver development. In this study, to mimic liver specification in vitro, we differentiated human embryonic stem cells (ESCs) into functional hepatocyte-like cells. We performed this differentiation process in presence of two THs, triiodothyronine (T3) and thyroxine (T4), with the purpose of identifying biomarkers for toxicity screening. TH exposure (3, 30 and 300 nM) yielded to hepatocytes with impaired glycogen storage ability and abnormal lipid droplets' accumulation. Global gene expression analysis by RNA-seq identified a number of genes responsible for hepatic differentiation and function which were affected by 30 nM T3 and T4. Those differentially expressed genes were used to assess the potential developmental liver toxicity of two famous environmental pollutants, 2, 2, 4, 4-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209), at 10 nM to 1 μM treatments. Our findings demonstrate that BDE-47 and BDE-209, dysregulated pathways such as "chemical carcinogenesis", "steroid hormone biosynthesis" and "drug metabolism-cytochrome P450". Moreover, we were able to identify a set of 17 biomarkers, very useful to predict the potential developmental hepatotoxicity of industrial chemicals.
肝脏是激素（包括甲状腺激素）和许多工业化学物质（如内分泌干扰化学物质）的主要靶标之一。这些化合物可能穿透胎盘屏障，对胚胎发育构成风险。因此，有必要评估这些工业化学物质在肝脏发育过程中的毒性作用。在这项研究中，为了模拟体外肝脏特化，我们将人胚胎干细胞（hESCs）分化为功能性肝细胞样细胞。我们在两种甲状腺激素（T3 和 T4）的存在下进行了这种分化过程，目的是鉴定毒性筛选的生物标志物。TH 暴露（3、30 和 300 nM）导致糖原储存能力受损和异常脂质滴积累的肝细胞。通过 RNA-seq 进行的全基因表达分析鉴定了许多负责肝脏分化和功能的基因，这些基因受到 30 nM T3 和 T4 的影响。那些差异表达的基因被用于评估两种著名环境污染物 2,2,4,4-四溴二苯醚（BDE-47）和十溴二苯醚（BDE-209）的潜在发育性肝毒性，处理浓度为 10 nM 至 1 μM。我们的研究结果表明，BDE-47 和 BDE-209 失调的途径，如“化学致癌作用”、“甾体激素生物合成”和“药物代谢-细胞色素 P450”。此外，我们能够鉴定出一组 17 个生物标志物，非常有助于预测工业化学物质的潜在发育性肝毒性。
