Influence of the Ah locus on the humoral immunotoxicity of 2,3,7,8-tetrachlorodibenzo- p-dioxin: Evidence for Ah-receptor-dependent and Ah-receptor-independent mechanisms of immunosuppression

Abstract

There are conflicting reports in the literature regarding the role of the Ah locus in 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) immunotoxicity. The present studies have utilized two congenic strains of C57Bl 6 mice that differ only at this locus to assess its influence on TCDD-induced suppression of antibody responses. Mice were given a single oral dose of TCDD 2 days prior to challenge with sheep red blood cells (SRBC) or trinitrophenyl-lipopolysaccharide (TNP-LPS). The subsequent dose-dependent effects of TCDD on the amount of antibody produced by splenic plasma cells were measured using the hemolytic antibody isotope release assay. In addition, the relative importance of the Ah genotype of lymphoid versus nonlymphoid tissue was examined in adoptive transfer experiments. Aryl hydrocarbon hydroxylase (AHH) activity was significantly induced in Ah bb mice by a dose of 0.5 μg/kg TCDD and maximally induced by a dose of 2 μg/kg. Ah dd mice required 10-fold higher doses of TCDD to induce comparable levels of AHH. The degree of thymic involution and liver hypertrophy induced by TCDD was also influenced by the Ah genotype of the animals. Both Ah bb and Ah dd mice exhibited dose-dependent suppression of the anti-TNP response following TCDD exposure. The ID50 was 7.0 μg/kg in Ah bb mice and 30.8 μg/kg in Ah dd mice. Suppression of the antibody response to SRBC was also dependent on the Ah locus. The ID50 in Ah bb mice was 0.6 μg/kg TCDD. However, an apparent biphasic dose response for suppression of the anti-SRBC response in Ah dd mice suggested the involvement of an Ah-independent component of suppression as well. In adoptive transfer studies, lymphocytes were identified as an Ah-dependent component of the response. The Ah-independent component of the response was not identified, and could be either lymphoid or nonlymphoid in nature. The possibility that T helper cells represent the Ah-independent component is discussed.