You are here:
CYP1A2 DOES NOT PLAY A CRITICAL ROLE IN 2, 3 7, 8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED IMMUNOSUPRESSION
Citation:
Smialowicz, R J., W C. Williams, J J. Diliberto, AND L S. Birnbaum. CYP1A2 DOES NOT PLAY A CRITICAL ROLE IN 2, 3 7, 8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED IMMUNOSUPRESSION. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
CYP1A2 IS NOT REQUIRED FOR 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN-INDUCED IMMUNOSUPPRESSION Smialowicz, Ralph J1; Burgin, Deborah E2; Williams, Wanda C1; Diliberto, Janet J1; Birnbaum, Linda S1
1 Experimental Toxicology Division, US EPA, RTP, NC, USA; 2Curriculum in Toxicology, UNC, Chapel Hill, NC, USA;
One of the most sensitive and reproducible immunotoxic endpoints of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure is suppression of the antibody response to sheep red blood cells (SRBCs) in mice. Immunosuppression occurs in concert with hepatomegaly and associated induction of several hepatic cytochrome P450 enzymes, including CYP1A2 which is responsible for the hepatic sequestration of TCDD. In this study, TCDD-induced immunosuppression was evaluated in CYP1A2 (-/-) knockout mice and compared with that of age-matched female C57/BL/6N CYP1A2 (+/+) wild-type, and CYP1A2 (+/-) heterozygote mice. Groups of mice were given a single gavage dose of 0, 0.03, 0.1, 0.3, 1.0, 3.0 or 10.0 g TCDD/kg, followed seven days later by immunization with SRBCs. Serum was obtained five days after immunization and body, spleen, thymus and liver weights were measured. SRBC antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA). Anti-SRBC titers were suppressed at 1.0, 1.0 and 0.3 g TCDD/kg for CYP1A2 (+/+), CYP1A2 (+/-), and CYP1A2 (-/-) mice, respectively, which indicated a three fold increase in TCDD immuno-sensitivity for the CYP1A2 (-/-) mice. This increase in TCDD-induced immunosuppression may be due to the inability of CYP1A2 (-/-) mice to sequester TCDD in the liver, leading to a higher dose to the immune system. In CYP1A2(+/+) mice a dose of 0.3 g TCDD/kg was sufficient to increase the liver-to-body weight ratio, while in CYP1A2 (-/-) mice a dose of 10 g TCDD/kg was required. Nevertheless, calculated TCDD ED50 values of immunosuppression were no different across the three groups of mice examined (i.e., mean ? SEM of 0.98 ? 0.32, 1.02 ? 0.89 and 0.58 ? 0.71 g TCDD/kg for CYP1A2 (+/+), (+/-), and (-/-) mice, respectively). Thus CYP1A2 is not required for TCDD-induced immunosuppression. (This abstract does not reflect EPA policy.)