EFFECTS OF IN-VIVO EXPOSURE TO BIS(TRI-N-BUTYLTIN)OXIDE, HEXACHLOROBENZENE, AND BENZO(A)PYRENE ON CYTOKINE (RECEPTOR) MESSENGER-RNA LEVELS IN CULTURED RAT SPLENOCYTES AND ON IL-2 RECEPTOR PROTEIN-LEVELS

Analysis of cytokine (receptor) mRNA levels has been suggested to be a sensitive technique for predicting the immunomodulatory potential of drugs and chemicals. Furthermore, this type of analysis is thought to be important in unraveling mechanisms of immunotoxicity. To study thes e issues, male Wistar rats were exposed to the immunotoxic environment al contaminants bis(tri-n-butyltin)oxide (TBTO; 5, 20, or 80 mg/kg die t for 6 weeks), hexachlorobenzene (HCB; 50, 150, or 450 mg/kg diet for 6 weeks), or benzo(a)pyrene (B(a)P; 3, 10, 30, or 90 mg/kg body Wt fo r 5 weeks by a daily (5 times a week) oral intubation). Spleen cells w ere cultured with Con A and analyzed by dot blot hybridization for IL- 2, IFN-gamma, IL-2 receptor a-chain (IL-2R alpha, CD25), and IL-4 mRNA levels, In addition, spleen and thymus sections of TBTO-exposed anima ls were assayed immunohistochemically for CD25 expression, Exposure to TBTO resulted in a dose-dependent decrease in IL-2R alpha mRNA levels from 5 mg/kg, a dose-dependent increase in IFN-gamma mRNA levels from 20 mg/kg, and increased IL-2 mRNA levels at 80 mg/kg diet. Exposure t o HCB resulted in a dose-dependent increase in IL-2 and IFN-gamma mRNA levels from 150 mg/kg and increased IL-2R alpha mRNA levels at 450 mg /kg diet, Exposure to B(a)P resulted in a dose-dependent increase in I L-2 and IFN-gamma mRNA levels from 10 mg/kg and increased IL-2R alpha mRNA levels at 90 mg/kg body wt. No effects were seen on IL-4 mRNA lev els, Spleen and thymus sections of TBTO-exposed animals showed reduced CD25 expression from 5 mg/kg diet. These results show that (1) the co rrelation between altered cytokine (receptor) mRNA levels and function al endpoints is variable, depending on the type of functional endpoint tested and the compound studied, (2) these assays are among the most sensitive ones for TBTO and HCB immunotoxicity, and among the more sen sitive ones for B(a)P immunotoxicity, and (3) for TBTO, these assays p rovide a possible clue to a mechanism for thymus atrophy, resulting fr om exposure to this compound: reduced IL-2R expression may impede thym ocyte maturation, resulting in thymusatrophy. (C) 1998 Academic Press.