Mechanistic investigation on the cause for reduced toxicity of TCDD in wa‐1 homozygous TGFα mutant strain of mice as compared its matching wild‐type counterpart, C57BL/6J mice

We investigated the cause for resistance to TCDD toxicity in TGFα mutant wa‐1 mice (wa/wa) as compared to its wild‐type C57BL/6J(+/+) counterpart. For this purpose after 1 or 10 days TCDD (115 μg/kg) exposure, liver samples were isolated. Biochemical investigations revealed that wa/wa mice showed decreased effects of TCDD characterized by reduced triglyceride accumulation and lesser declines in glycogen levels. qRT‐PCR mRNA analysis demonstrated that while the effect of TCDD on EGF receptor and ERK‐1 in wa/wa mice were indistinguishable from +/+ mice, upregulation by TCDD of c‐Src and ERK‐2 and downregulation of PEPCK were less pronounced in the wa/wa mice. To confirm that these differences are due to intrinsic cellular characteristics, mouse embryonic fibroblast (MEF) cells were cultured from embryos and their responses to 10 nM TCDD were assessed. qRT‐PCR analysis showed that MEF from the wa/wa mice was less responsive to TCDD in terms of its stimulatory effect on ERK‐2, but not on ERK‐1. These results indicate that a possible mechanism why wa/wa mice are less responsive to TCDD is that two genes encoding for the growth factor signaling components, c‐Src and ERK‐2, are not readily affected by TCDD. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:151–158, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20131