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.
Vogel
Christoph F A
CF
Department of Environmental Toxicology and the Center for Environmental Health Sciences, University of California, Davis, CA 95616, USA.
Zhao
Yeuchao
Y
Wong
Patrick
P
Young
Naomi F
NF
Matsumura
Fumio
F
D000217:Acyltransferases / Q000096:biosynthesis; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis; D000081247:CSK Tyrosine-Protein Kinase; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D016391:Genes, src / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics; D019282:Wasting Syndrome / Q000139:chemically induced* / Q000235:genetics; D019061:src-Family Kinases
D022763:CCAAT-Enhancer-Binding Protein-alpha; D000072317:Polychlorinated Dibenzodioxins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D019363:Cytochrome P-450 CYP1A1; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases