Possible involvement of arylhydrocarbon receptor variants in TCDD-induced thymic atrophy and XRE-dependent transcriptional activity in Wistar Hannover GALAS rats

Abstract

Wistar Hannover Global Alliance for Laboratory Animal Standardization (WH GALAS) rats have been distributed for international standardization of preclinical and toxicological research. Han/Wistar (Kuopio) rats are exceptionally resistant to acute toxicities caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and mediated by the aryl hydrocarbon receptor (AhR), and they have a mutated AhR, named AhR(hw/hw). We found that the WH GALAS rat has either of the three AhR allele, AhR(wt/wt), AhRwt/hw and AhRhw/hw. We administered TCDD (0, 5 and 10 microg/kg) to Long-Evans (L-E) rats having AhR(wt/wt) and two WH GALAS rat strains having either AhR(wt/wt) or AhR(hw/hw), and examined the weights of their body, liver and thymus 168 hr post-administration. WH GALAS AhR(hw/hw) strain was more resistant to TCDD-induced effects on thymus weight than L-E and WH GALAS AhR(wt/wt) strains. In order to study differences in susceptibility of thymic atrophy among the strains, we examined CYP1A1 mRNA and AhR protein levels between L-E and WH GALAS strains. However, no significant difference was observed in the amount of AhR protein or CYP1A1 mRNA in the thymus. Next, we carried out in vitro assays to examine the transactivation activities of AhR variants and found that the AhR deletion variant (AhRdv) transcribed from AhR(hw/hw) significantly enhanced transactivation activity of the synthesized xenobiotic response element. All AhR variants similarly suppressed the growth of Jurkat T cells upon TCDD exposure. This study suggests that WH GALAS rat having different AhR alleles is an interesting experimental animal model but should be utilized with caution for preclinical research on chemicals having AhR agonistic activities.