Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity

Abstract

Acute exposure of mammals to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a diverse set of toxicologic and pathologic effects. The mechanism of some of these effects has been studied extensively in vitro and correlative studies have indicated the involvement of a transcription factor known as the aryl hydrocarbon receptor (AHR). However, a definitive association of the AHR with TCDD-mediated toxicity has been difficult to establish due to the diversity of effects and the ubiquitous expression of this receptor. In an effort to distinguish AHR-mediated TCDD toxicities from those resulting from alternative pathways, we have made use of the recently described AHR-deficient mouse that was generated by locus-specific homologous recombination in embryonic stem cells. Present studies demonstrate that AHR-deficient mice are relatively unaffected by doses of TCDD (2000 micrograms/kg) 10-fold higher than that found to induce severe toxic and pathologic effects in littermates expressing a functional AHR. Analyses of liver, thymus, heart, kidney, pancreas, spleen, lymph nodes, and uterus from AHR-deficient mice identified no significant TCDD-induced lesions. The resistance of AHR-deficient mice to TCDD-induced thymic atrophy appears restricted to processes involving AHR since the corticosteroid dexamethasone rapidly and efficiently induced cortical depletion in both AHR-deficient and normal littermate control mice. Taken together these results suggest that the pathological changes induced by TCDD in the liver and thymus are mediated entirely by the AHR. However, it is important to note that at high doses of TCDD, AHR-deficient mice displayed limited vasculitis and scattered single cell necrosis in their lungs and livers, respectively. The mechanism(s) responsible for these apparently receptor-independent processes remain unclear but may involve novel, alternative pathways for TCDD-induced toxicity.