Immunosuppression following exposure to 7,12-dimethylbenz[ a]anthracene (DMBA) in Ah-responsive and Ah-nonresponsive mice

Abstract

Recent reports suggest that the immunotoxicity of certain polycyclic aromatic hydrocarbons is associated with the Ah locus in mice. To test whether immunosuppression mediated by 7,12-dimethylbenz[ a]-anthracene (DMBA) is regulated by the Ah locus, several endpoints of immune function were measured in Ah-responsive B6C3F 1 and Ah-nonresponsive DBA/2N and in Ah-congenic C57BL/6J (responsive B6-Ah bAh d and nonresponsive B6-Ah dAh d) mice dosed sc with up to 100 μg/g DMBA in corn oil. Some groups of B6C3F 1 and DBA/2N mice were exposed to 100 μg/g benzo[ a]pyrene (B( a)P) or 1 nmol 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) for determination of hepatic microsomal monooxygenase activity. The body weights of all mice were unaffected by DMBA exposure, but thymus weights and spleen cellularity were decreased. Antibody plaque-forming cells (PFC) measured 4 days after iv sheep erythrocyte (SRBC) immunization were suppressed 99% in B6C3F 1 and 96% in DBA/2 mice. Antibody PFC after in vitro immunization to SRBC were similarly suppressed 98% in both B6-Ah bAh d and B6-Ah dAh d Ah-congenic mice exposed to 100 μg/g DMBA. Responses to the T-cell mitogens concanavalin A and phytohemagglutinin were significantly suppressed in both B6C3F 1 and DBA/2N strains, as was mitogenesis to bacterial lipopolysaccharide. The unidirectional mixed lymphocyte responses of the congenic strains were suppressed 76% in B6-Ah bAh d and 85% in B6-Ah dAh d; cytotoxic lymphocyte generation was suppressed 68% in B6-Ah bAh d and 78% in B6-Ah dAh d. The overall differences between immunosuppressive responses in splenocytes from B6-Ah bAh d and B6-Ah dAh d congenics were not significant. Induction of cytochrome P 1-450, a marker of Ah responsiveness, was determined by 7-ethoxycoumarin O-deethylase monooxygenase activity in hepatic microsomes or splenocytes. This monooxygenase activity was not significantly increased in either B6C3F 1 or DBA/2 mice exposed to DMBA, whereas B( a)P and TCDD exposure significantly induced enzyme activity in B6C3F 1 hepatocytes. These data suggest that DMBA has an immunosuppressive action on murine splenocytes which is independent of the Ah locus and associated induction of cytochrome P 1-450 xenobiotic-metabolizing enzymes.