The use of c-src knockout mice for the identification of the main toxic signaling pathway of TCDD to Induce wasting syndrome

✍ Scribed by Christoph F. A. Vogel; Yeuchao Zhao; Patrick Wong; Naomi F. Young; Fumio Matsumura

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 160 KB
• Volume: 17
• Category: Article
• ISSN: 1095-6670
• DOI: 10.1002/jbt.10096

✦ Synopsis

Abstract

The effect of single intraperitoneal injection of 115 μg/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, TGFα, and PDGFa. In contrast, those observed to be consistently suppressed were mRNAs for EGF receptor (EGFR), Ki‐Ras, SAPKK, Sp‐1, C/EBPβ, and NFkB. Elevation of mRNAs for TGFβ 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/EPBβ, NMT‐1, and AP‐2γ 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 TGFα, PDGF~AA~, and C/EBPα, β. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:305–315, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10096