Strain differences in the proteome of dioxin-sensitive and -resistant mice treated with 2,3,7,8-tetrabromodibenzo-p-dioxin
Strain differences in the proteome of dioxin-sensitive and -resistant mice treated with 2,3,7,8-tetrabromodibenzo-p-dioxin
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用 2,3,7,8-四溴二苯并-对-二恶英处理的二恶英敏感和耐药小鼠蛋白质组的菌株差异
DOI：
10.1007/s00204-016-1834-4
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发表时间：
2017
影响因子：
6.1
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Nguyen;H.T.;Lauan Tsuchiya;M.C.;Yoo;J.;Iida;M.;Agusa;T.;Hirano;M.;Kim;E.-Y.;Miyazaki;T.;Nose;M.;Iwata;H.
二恶英通过脊椎动物的芳烃受体（AHR）引起各种毒性效应，在敏感性方面存在巨大的物种和菌株差异。尽管近交系小鼠品系C3 H/HeJ-lpr/lpr（C3 H/lpr）和MRL/MpJ-lpr/lpr（MRL/lpr）分别被称为二恶英敏感小鼠和二恶英抗性小鼠，但这种差异背后的分子机制仍不清楚。采用双向电泳结合基质辅助激光解吸电离飞行时间/飞行时间串联质谱（MALDI-TOF/TOF）技术，研究了溶剂和2，3，7，8-四溴二苯并对二恶英（TBDD）处理后两种小鼠肝脏蛋白质组的差异。为了确认菌株对TBDD处理的响应差异，在两种菌株中测量细胞色素P450（CYP 1A 1）1A 1和1A 2蛋白水平。10 µg/kg体重剂量的TBDD诱导两种品系的肝脏CYP 1A 1和CYP 1A 2表达，但C3 H/lpr小鼠中两种CYP 1A蛋白的表达水平均高于MRL/lpr小鼠，支持C3 H/lpr小鼠比MRL/lpr小鼠对二恶英更敏感。通过2-DE和MALDI-TOF/TOF成功地鉴定了C3 H/lpr小鼠中TBDD处理更诱导或抑制的蛋白质，包括通过产生内源性配体（如天冬氨酸氨基转移酶、吲哚乙胺N-甲基转移酶和乙醛脱氢酶）负责AHR激活的蛋白质，以及减少氧化应激的蛋白质（如超氧化物歧化酶和过氧化物还原酶）。两者合计，我们的研究结果提供了深入了解的分子机制，潜在的高二恶英的敏感性的C3 H/lpr株，其中AHR激活TBDD是更多地促使生产的内源性配体，但适应氧化应激也收购。
Dioxins cause various toxic effects through the aryl hydrocarbon receptor (AHR) in vertebrates, with dramatic species and strain differences in susceptibility. Although inbred mouse strains C3H/HeJ-lpr/lpr(C3H/lpr) and MRL/MpJ-lpr/lpr(MRL/lpr) are known as dioxin-sensitive and dioxin-resistant mice, respectively, the molecular mechanism underlying this difference remains unclear. The difference in the hepatic proteome of the two mouse strains treated with vehicle or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) was investigated by a proteomic approach of two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF). To confirm the strain-difference in response to TBDD treatment, cytochrome P450 (CYP) 1A1 and 1A2 protein levels were measured in both strains. A dose of 10 µg/kg body weight of TBDD induced hepatic CYP1A1 and CYP1A2 expression in both strains, but the expression levels of both CYP1A proteins were higher in C3H/lprmice than in MRL/lprmice, supporting that C3H/lprmice are more sensitive to dioxins than MRL/lprmice. Proteins that were more induced or suppressed by TBDD treatment in C3H/lprmice were successfully identified by 2-DE and MALDI-TOF/TOF, including proteins responsible for AHR activation through production of endogenous ligands such as aspartate aminotransferase, indolethylamineN-methyltransferase, and aldehyde dehydrogenases, as well as proteins reducing oxidative stress, such as superoxide dismutase and peroxiredoxins. Taken together, our results provide insights into the molecular mechanism underlying the high dioxin susceptibility of the C3H/lprstrain, in which AHR activation by TBDD is more prompted by the production of endogenous ligands, but the adaptation to oxidative stress is also acquired.