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

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.