TOXICOLOGY AND APPLIED PHARMACOLOGY l&,26-36 (1990) Influence of the Ah Locus on the Humoral lmmunotoxicity of 2,3,7,8- Tetrachlorodibenzo-p-dioxin: Evidence for Ah-Receptor-Dependent and Ah-Receptor-Independent Mechanisms of Immunosuppression’ N. I. KERKVLIET,*‘~‘~ L. B. STEPPAN,* J. A. BRAuNm,*-f J. A. DEYO,* M. C. HENDERSON,? R. S. TOMAR,* AND D. R. BUHLERt *College of Veterinary Medicine, and tEnvironmenta1 Health Sciences Center, Oregon State University, Corvallis, Oregon 97331 Received April 17,1989: accepted May 3, I990 Influence of the Ah Locus on the Humoral Immunotoxicity of 2,3,7,8Tetrachlorodibenzo- pdioxin: Evidence for Ah-Receptor-Dependent and Ah-Receptor-Independent Mechanisms of Immunosuppression. KJ?RKVLIET, N. I., STEPPAN, L. B., BRAUNER, J. A., DEYO, J. A., HEN- DERSON, M. C., TOMAR, R. S., AND BUHLER, D. R. (I 990). Toxicol. Appi. Pharmacol. 105,26- 36. 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 C57B1/6 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 Ahbb mice by a dose of 0.5 &kg TCDD and maximally induced by a dose of 2 &kg. Ahdd mice required I O-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 Ahbb and Ahdd mice exhibited dose- dependent suppression of the anti-TNP response following TCDD exposure. The ID50 was 7.0 &kg in Ahbb mice and 30.8 &kg in Ahdd mice. Suppression ofthe antibody response to SRBC was also dependent on the Ah locus. The ID50 in Ahbb mice was 0.6 &kg TCDD. However, an apparent biphasic dose response for suppression of the anti-SRBC response in Ahdd 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 lym- phoid or nonlymphoid in nature. The possibility that T helper cells represent the Ah-indepen- dent component is discussed. 0 1990 Academic press. inc. Halogenated aromatic hydrocarbons (HAH), ’ These studies were supported by NIEHS Center such as the polychlorinated dibenzo-p-diox- Grant ES00210 and NIEHS Grants ES00040 and ins, dibenzofurans, and biphenyls, comprise ES03966. The data were presented in summary form at the 28th Annual Meeting of the Society of Toxicology, a class of structurally similar, biologically per- Atlanta, GA. sistent, and widespread environmental con- ‘To whom correspondence should be addressed at taminants. The spectrum of toxicological College of Veterinary Medicine, Oregon State Univer- effects produced by different HAH are similar sity, Corvallis, OR 9733 1. within a species, with differences related pri- 0041-008X/90 $3.00 Copyright 0 I990 by Academic Press, Inc. All rights of reproduction in any form reserved 26