Vogel Christoph F A, Zhao Yeuchao, Wong Patrick, Young Naomi F, Matsumura Fumio
Department of Environmental Toxicology and the Center for Environmental Health Sciences, University of California, Davis, CA 95616, USA.
J Biochem Mol Toxicol. 2003;17(6):305-15. doi: 10.1002/jbt.10096.
The effect of single intraperitoneal injection of 115 microg/kg of TCDD (i.e., approximately 1/2 of LD50) to male C57BL/6 mice on the liver mRNA expression changes of several growth factor related genes was assessed at 3 h, 24 h, 10 days, and 30 days posttreatment. The results revealed that the most consistently elevated mRNAs during the entire test period were those of c-Src, TGFalpha, and PDGFa. In contrast, those observed to be consistently suppressed were mRNAs for EGF receptor (EGFR), Ki-Ras, SAPKK, Sp-1, C/EBPbeta, and NFkB. Elevation of mRNAs for TGFbeta and STAT3 was observed only on day 10 and day 30. To assess the role of c-Src in the above action of TCDD, we conducted a parallel study with congenic C57BL/6 male c-src -/- mice. The results showed that in scr -/- mice the effect of TCDD was less in the case of mRNA expression of PDGF(AA), STAT3, C/EPBbeta, NMT-1, and AP-2gamma in addition to c-src as compared to scr +/+ mice. Those affected least by the absence of c-Src were SAPKK, and surprisingly, EGF receptor mRNAs, both of which were consistently downregulated in both strains. In most of the other cases, the extent of TCDD-induced changes were generally less pronounced in src -/- mice as compared to +/+ mice. These observations support the notion that c-Src is an important mediator of the effects of TCDD on TGFalpha, PDGF(AA), and C/EBPalpha, beta.
给雄性C57BL/6小鼠腹腔注射115微克/千克的2,3,7,8-四氯二苯并-对-二恶英（即约为半数致死剂量的1/2），并于给药后3小时、24小时、10天和30天评估其对几种生长因子相关基因肝脏mRNA表达变化的影响。结果显示，在整个测试期间，最持续升高的mRNA是c-Src、转化生长因子α（TGFα）和血小板衍生生长因子α（PDGFa）的mRNA。相比之下，观察到持续被抑制的是表皮生长因子受体（EGFR）、Ki-Ras、丝裂原活化蛋白激酶激酶激酶（SAPKK）、特异性蛋白1（Sp-1）、CCAAT/增强子结合蛋白β（C/EBPβ）和核因子κB（NFkB）的mRNA。仅在第10天和第30天观察到转化生长因子β（TGFβ）和信号转导子和转录激活子3（STAT3）的mRNA升高。为了评估c-Src在2,3,7,8-四氯二苯并-对-二恶英上述作用中的角色，我们对同基因的C57BL/6雄性c-src基因敲除小鼠进行了一项平行研究。结果表明，与c-src基因野生型小鼠相比，在c-src基因敲除小鼠中，除了c-src外，2,3,7,8-四氯二苯并-对-二恶英对血小板衍生生长因子（AA）、信号转导子和转录激活子3、CCAAT/增强子结合蛋白β、N-甲基转移酶1（NMT-1）和活化蛋白2γ（AP-2γ）mRNA表达的影响较小。受c-Src缺失影响最小的是丝裂原活化蛋白激酶激酶激酶和令人惊讶的表皮生长因子受体mRNA，这两种mRNA在两个品系中均持续下调。在大多数其他情况下，与野生型小鼠相比，2,3,7,8-四氯二苯并-对-二恶英诱导的变化程度在c-src基因敲除小鼠中通常不太明显。这些观察结果支持这样一种观点，即c-Src是2,3,7,8-四氯二苯并-对-二恶英对转化生长因子α、血小板衍生生长因子（AA）和CCAAT/增强子结合蛋白α、β作用的重要介质。
