Association between susceptibility to dibenzanthracene-induced fibrosarcoma formation and the Ah locus.

Abstract

The relationship between the Ah locus and the induction of subcutaneous fibrosarcomas by dibenz[a,h]anthracene and dibenz[a,c]anthracene was investigated in C57BL/6J (Ahb/Ahb), (C57BL/6J)(DBA/2J)F1 (Ahb/Ahd) and (Ahd/Ahd) mice. Ahb/Ahb and Ahb/Ahd mice have the high-affinity Ah receptor and therefore the polycyclic hydrocarbon induction of aryl hydrocarbon hydroxylase activity (cytochrome P1-450) proceeds with ease; Ahd/Ahd mice have the poor-affinity Ah receptor and this induction process proceeds more poorly, by a factor of at least 10-fold. Dibenz[a,c]anthracene proved to be a relatively weak carcinogen, producing less than 3% tumor incidence at doses up to 300 micrograms per mouse. In contrast, dibenz[a,h]anthracene caused an almost 50% tumor incidence in Ahb/Ahb and Ahb/Ahd mice, while causing approximately 2% tumor incidence in Ahd/Ahd mice. Both isomers bind avidly to the cytosolic Ah receptor, and both chemicals induce aryl hydrocarbon hydroxylase activity in Ahb/Ahb and Ahd/Ahd animals. Among progeny of the (C57BL/6J) (DBA/2J) F1 X DBA/2J backcross, 63 of 100 Ahb/Ahd mice and none of 75 Ahd/Ahd mice developed tumors. These data demonstrate a strict correlation between susceptibility to dibenz[a,h]anthracene-induced subcutaneous tumors and expression of the Ahb allele, i.e. presence of the high-affinity Ah receptor and therefore readily inducible P1-450.