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 TGFalpha 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 microg/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.