p53-dependent apoptosis contributes to di-(2-ethylhexyl) phthalate-induced hepatotoxicity
p53-dependent apoptosis contributes to di-(2-ethylhexyl) phthalate-induced hepatotoxicity
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DOI：
10.1016/j.envpol.2015.10.009
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发表时间：
2016-01-01
影响因子：
8.9
通讯作者：
Liu, Changjiang
中科院分区：
文献类型：
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作者：
Ha, Mei;Wei, Li;Liu, Changjiang
邻苯二甲酸二（2-乙基己基）酯（DEHP）广泛用于许多个人护理和消费品中，通过多种途径和媒介导致广泛的非职业性人体暴露。DEHP具有多种有害作用，包括肝毒性。p53蛋白是细胞凋亡的中心感受器。为了阐明p53在DEHP诱导的肝毒性中的作用，Sprague道利（SD）大鼠每天灌胃给予DEHP，持续30天; BRL细胞（大鼠肝细胞系）在用NAC或小干扰RNA（siRNA）预处理后用DEHP处理24 h。结果表明，DEHP暴露后，肝组织学变化，如肝细胞水肿，空泡化和肝窦扩张，细胞凋亡指数增加。在肝脏中，DEHP诱导氧化应激和DNA损伤，在体内和体外激活p53。NAC预处理可显著降低BRL细胞ROS水平和p53表达。抑制的Mdm 2也有助于p53积聚。激活的p53通过内在线粒体途径介导肝细胞凋亡，抑制抗凋亡Bcl-2和Bcl-xL，诱导促凋亡Bax、细胞色素c和半胱天冬酶。在p53沉默的BRL细胞中，p53介导的肝细胞凋亡减弱。p53基因沉默后PCNA蛋白表达上调。然而，Fas/FasL凋亡途径并没有表现出激活迹象DEHP引起的肝毒性。总之，DEHP引起的氧化应激和Mdm 2下调有助于p53激活。p53依赖的细胞凋亡通路在DEHP诱导的肝毒性中起着重要的作用，而Fas/FasL通路并不参与DEHP诱导的肝毒性。(C)2015爱思唯尔有限公司版权所有。
Di-(2-ethylhexyl) phthalate (DEHP) is used extensively in many personal care and consumer products, resulting in widespread non-occupational human exposure through multiple routes and media. DEHP has various deleterious effects including hepatotoxicity. p53 protein is a central sensor in cell apoptosis. In order to clarify the roles of p53 in DEHP-induced hepatotoxicity, Sprague Dawley (SD) rats were dosed daily with DEHP by gavage for 30 days; BRL cells (rat liver cell line) were treated with DEHP for 24 h after pretreatment with NAC or small interfering RNA (siRNA). Results indicated that after exposure to DEHP, hepatic histological changes such as hepatocyte edema, vacuolation and hepatic sinusoidal dilation, and increased apoptosis index were observed. In the liver, DEHP induced oxidative stress and DNA damage, which activated p53 in vivo and in vitro. Pretreatment with NAC significantly reduced ROS level and p53 expression in BRL cells. The suppressed Mdm2 also contributed to p53 accumulation. Activated p53 mediated hepatocyte apoptosis via the intrinsic mitochondrial pathway, inhibiting antiapoptotic BcI-2 and Bcl-xL and inducing pro-apoptotic Bax, cytochrome c and caspases. In p53-silenced BRL cells, hepatocyte apoptosis mediated by p53 was attenuated. PCNA protein level was upregulated after p53 gene silencing. However, the Fas/FasL apoptotic pathway did not exhibit activated signs in DEHP-caused hepatotoxicity. Taken together, DEHP-caused oxidative stress and Mdm2 down-regulation contribute to p53 activation. The p53-dependent apoptotic pathway plays critical and indispensable roles in DEHP-induced hepatotoxicity, while the Fas/FasL pathway does not involve in this molecular event. (C) 2015 Elsevier Ltd. All rights reserved.