A chimeric aryl hydrocarbon receptor knockout mouse model indicates that aryl hydrocarbon receptor activation in hematopoietic cells contributes to the hepatic lesions induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Pathologic changes associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCD D) exposure have been reported in the livers of a wide range of species. Wh ile these changes have been extensively described, the mechanisms of toxic interaction(s) that produce these lesions remain unclear. Using an aryl hyd rocarbon receptor (Ahr) knockout male mouse chimeric model, we investigated whether the presence of this receptor in hematopoietic and/or parenchymal cells affects TCDD-induced hepatotoxicity. Bone marrow chimeras were produc ed by hematopoietic reconstitution of irradiated mice, Specifically, chimer as were generated with aryl hydrocarbon receptor (AHR) positive hematopoiet ic and parenchymal cells (Ahr(+/+) animal bone marrow cells into irradiated Ahr(+/+) animals), AHR positive hematopoietic and negative parenchymal cel ls (Ahr(+/+) into Ahr(-/-)), AHR negative hematopoietic and positive parenc hymal cells (Ahr(-/-) into Ahr(+/+)), and AHR negative hematopoietic and pa renchymal cells (Ahr(-/-) into Ahr(-/-)). Male wild-type (Ahr(+/+)) and kno ckout (Ahr(-/-)) animals were used as nonchimeric controls. Following TCDD treatment (30 mu g/kg body wt), liver sections from mice in each control an d chimeric group were histologically evaluated for necrotic and inflammator y changes. TCDD treatment produced moderate inflammation in Ahr(+/+) contro ls and Ahr(+/+) into Ahr(+/+) chimeras. This response was mild in TCDD-trea ted Ahr(-/-), Ahr(-/-) into Ahr(-/-), Ahr(+/+) into Ahr(-/-), and Ahr(-/-) into Ahr(+/+) animals and was not different from the corresponding vehicle- treated groups, Moderate necrosis was observed in all TCDD-treated controls or chimeras with AHR-positive parenchyma. No or mild necrosis was observed in TCDD- and vehicle-treated animals containing AHR-negative parenchyma. T hese data indicate that the presence of AHR in hepatic parenchyma alone is sufficient for TCDD induction of hepatic necrosis, and its presence in hema topoietic cells is necessary for the inflammatory response to TCDD-induced hepatic lesions. (C) 1999 Academic Press.