The flame retardants tetrabromobisphenol A and tetrabromobisphenol A-bisallylether suppress the induction of interleukin-2 receptor alpha chain (CD25) in murine splenocytes.

Polybrominated flame retardants (PBF) are frequently used additives in electronical equipment. They are ubiquitous environmental contaminants which bioaccumulate with several health effects for humans and the environment. This study investigated immunotoxic effects of the PBF tetrabromobisphenol A (TBBP A), tetrabromobisphenol A-bisallylether (TBBP A-AE), tetrabromobisphenol A-bis-(2,3-dibromopropyl-ether) (TBBP A-PE), decabromodiphenylether (DBDE), and 2,4,6-tribromophenol (TBP) in vitro. The structurally related polychlorinated aromatic hydrocarbon 3,4,3',4'-tetrachlorobiphenyl (PCB77) and dioxins mediate their immunotoxicity via the Ah-receptor gene complex. A highly relevant function of the Ah receptor, the induction of CYP 1A1 in hepatocytes of C57BL/6 mice by the established inducers 3-methylcholanthrene (MC) and PCB77 was compared to the effect of PBF by measurement of ethoxyresorufin-o-deethylase (EROD) activity. The PBF did not show any induction of CYP 1A1, while EROD activity of hepatocytes exposed to MC and PCB77 was induced 10.8- and 8.7-fold, respectively. To investigate immunotoxic effects of the flame retardants, splenocytes of C57BL/6 mice were incubated with subtoxic doses of the flame retardants and PCB77 and activated by concanavalin A (Con A). The flame retardants TBBP A and TBBP A-AE significantly inhibited the expression of interleukin-2 receptor alpha chain (CD25) in contrast to TBBP A-PE, DBDE, TBP, and PCB77 as shown by immunohistochemistry and quantitative analysis by laser scanning cytometry. None of the substances had any effect on the Con A-induced production of cytokines. Hence, TBBP A and TBBP A-AE may act as immunotoxic compounds by specifically inhibiting the expression of CD25.

[1]  P. Seglen.  Preparation of rat liver cells. 3. Enzymatic requirements for tissue dispersion. , 1973, Experimental cell research.

[2]  K. Bock.  Aryl hydrocarbon or dioxin receptor: biologic and toxic responses. , 1994, Reviews of physiology, biochemistry and pharmacology.

[3]  J. Descotes.  An introduction to immunotoxicology , 1998 .

[4]  T. Helleday,et al.  Brominated flame retardants induce intragenic recombination in mammalian cells. , 1999, Mutation research.

[5]  S. Safe.  Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs): biochemistry, toxicology, and mechanism of action. , 1984, Critical reviews in toxicology.

[6]  L. Schwarz,et al.  Cytochrome P450 in Primary and Permanent Liver Cell Cultures , 1993 .

[7]  V. Vasiliou,et al.  Role of the Ah Receptor and the Dioxin‐Inducible [Ah] Gene Battery in Toxicity, Cancer, and Signal Transduction a , 1993, Annals of the New York Academy of Sciences.

[8]  Y. Fujii‐Kuriyama,et al.  Ah receptor: a novel ligand-activated transcription factor. , 1994, Experimental and clinical immunogenetics.

[9]  R. House.  Theory and practice of cytokine assessment in immunotoxicology. , 1999, Methods.

[10]  T. Strom,et al.  Anti-interleukin 2 receptor antibody suppresses murine diabetic insulitis and lupus nephritis. , 1988, Journal of immunology.

[11]  T. Pineau,et al.  Thymocyte development in Ah-receptor-deficient mice is refractory to TCDD-inducible changes. , 1999, International journal of immunopharmacology.

[12]  J. Lester,et al.  Polybrominated diphenyl ether (PBDE) flame retardants. , 2001, The Science of the total environment.

[13]  J. Kupiec-Weglinski,et al.  Agonistic and antagonistic interactions of anti-interleukin 2 receptor monoclonal antibodies in rat recipients of cardiac allografts. , 1989, Transplantation.

[14]  N. Rothman,et al.  Breast cancer among women exposed to polybrominated biphenyls. , 1995, Epidemiology.

[15]  C. Esser,et al.  Generation of αβ T‐cell receptor+ CD4– CD8+ cells in major histocompatibility complex class I‐deficient mice upon activation of the aryl hydrocarbon receptor by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin , 2000 .

[16]  J. Boer,et al.  Do flame retardants threaten ocean life? , 1998, Nature.

[17]  Cancer among a Michigan Cohort Exposed to Polybrominated Biphenyls in 1973 , 1998, Epidemiology.

[18]  G. Maliji,et al.  Immunotoxic effects of prolonged dietary exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 1995, European journal of pharmacology.

[19]  R. Mayer,et al.  Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. , 1985, Biochemical pharmacology.

[20]  L. Kaminsky,et al.  Correlations between polychlorinated biphenyl immunotoxicity, the aromatic hydrocarbon locus, and liver microsomal enzyme induction in C57BL/6 and DBA/2 mice. , 1984, Toxicology and applied pharmacology.

[21]  Eva Jakobsson,et al.  Flame retardant exposure: polybrominated diphenyl ethers in blood from Swedish workers. , 1999 .

[22]  H. van Loveren,et al.  In vitro exposure effects of cyclosporin A and bis(tri-n-butyltin)oxide on lymphocyte proliferation, cytokine (receptor) mRNA expression, and cell surface marker expression in rat thymocytes and splenocytes. , 1999, Toxicology.

[23]  H. Tryphonas.  Immunotoxicity of polychlorinated biphenyls: present status and future considerations. , 1994, Experimental and clinical immunogenetics.

[24]  T. Waldmann,et al.  Advances in interleukin 2 receptor targeted treatment , 2000, Annals of the rheumatic diseases.

[25]  T. Fujita,et al.  PCBs: structure–function relationships and mechanism of action , 1985, Environmental health perspectives.

[26]  J. Szymańska,et al.  Hepatotoxicity of tetrabromobisphenol-A: effects of repeated dosage in rats. , 1999, Toxicology.