Browse > Article
http://dx.doi.org/10.5487/TR.2011.27.2.061

Molecular Mechanism of Tetrabromobisphenol A (TBBPA)-induced Target Organ Toxicity in Sprague-Dawley Male Rats  

Choi, Jae-Seok (College of Pharmacy, Pusan National University)
Lee, Young-Jun (College of Pharmacy, Pusan National University)
Kim, Tae-Hyung (College of Pharmacy, Pusan National University)
Lim, Hyun-Jung (College of Pharmacy, Pusan National University)
Ahn, Mee-Young (College of Pharmacy, Pusan National University)
Kwack, Seung-Jun (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration)
Kang, Tae-Seok (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration)
Park, Kui-Lea (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration)
Lee, Jae-Won (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration)
Kim, Nam-Deuk (National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration)
Jeong, Tae-Cheon (College of Pharmacy, Yeungnam University)
Kim, Sang-Geum (College of Pharmacy, Chungnam National University)
Jeong, Hye-Gwang (College of Pharmacy, Chungnam National University)
Lee, Byung-Mu (College of Pharmacy, Sungkyunkwan University)
Kim, Hyung-Sik (College of Pharmacy, Pusan National University)
Publication Information
Toxicological Research / v.27, no.2, 2011 , pp. 61-70 More about this Journal
Abstract
Brominated flame retardants (BFRs) are present in many consumer products ranging from fabrics to plastics and electronics. Wide use of flame retardants can pose an environmental hazard, which makes it important to determine the mechanism of their toxicity. In the present study, dose-dependent toxicity of tetrabromobisphenol A (TBBPA), a flame retardant, was examined in male prepubertal rats (postnatal day 18) treated orally with TBBPA at 0, 125, 250 or 500 mg/kg for 30 days. There were no differences in body weight gain between the control and TBBPA-treated groups. However, absolute and relative liver weights were significantly increased in high dose of TBBPA-treated groups. TBBPA treatment led to significant induction of CYP2B1 and constitutive androstane receptor (CAR) expression in the liver. In addition, serum thyroxin (T4) concentration was significantly reduced in the TBBPA treated group. These results indicate that repeated exposure to TBBPA induces drug-metabolising enzymes in rats through the CAR signaling pathway. In particular, TBBPA efficiently produced reactive oxygen species (ROS) through CYP2B1 induction in rats. We measured 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage, in the kidney, liver and testes of rats following TBBPA treatment. As expected, TBBPA strongly induced the production of 8-OHdG in the testis and kidney. These observations suggest that TBBPA-induced target organ toxicity may be due to ROS produced by metabolism of TBBPA in Sprague-Dawley rats.
Keywords
Tetrabromobisphenol A; Target organ; CAR; CYP2B1; Thyroid hormone;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Jakobsson, K., Thuresson, K., Rylander, L., Sjödin, A., Hagmar, L. and Bergman, A. (2002). Exposure to polybrominated diphenyl ethers and tetrabromobisphenol A among computer technicians. Chemosphere, 46, 709-716.   DOI   ScienceOn
2 Kang, M.J., Kim, J.H., Shin, S., Choi, J.H., Lee, S.K., Kim, H.S., Kim, N.D., Kang, G.W., Jeong, H.G., Kang, W., Chun, Y.J. and Jeong, T.C. (2009). Nephrotoxic potential and toxicokinetics of tetrabromobisphenol A in rat for risk assessment. J. Toxicol. Environ. Health A., 72, 1439-1445.   DOI   ScienceOn
3 Kasai, H., Crain, P.F., Kuchino, Y., Nishimura, S., Ootsuyama, A. and Tanooka, H. (1986). Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis, 7, 1849-1851.   DOI   ScienceOn
4 Alaee, M., Arias, P., Sjödin, A. and Bergman, A. (2003). An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release. Environ. Int., 29, 683-689.   DOI   ScienceOn
5 Cariou, R., Antignac, J.P., Zalko, D., Berrebi, A., Cravedi, J.P., Maume, D., Marchand, P., Monteau, F., Riu, A., Andre, F. and Le Bizec, B. (2008). Exposure assessment of French women and their newborns to tetrabromobisphenol-A: occurrence measurements in maternal adipose tissue, serum, breast milk and cord serum. Chemosphere, 73, 1036-1041.   DOI   ScienceOn
6 Chu, S., Haffner, G.D. and Letcher, R.J. (2005). Simultaneous determination of tetrabromobisphenol A, tetrachlorobisphenol A, bisphenol A and other halogenated analogues in sediment and sludge by high performance liquid chromatography-electrospray tandem mass spectrometry. J. Chromatogr. A., 1097, 25-32.   DOI   ScienceOn
7 Darnerud, P.O. (2003). Toxic effects of brominated flame retardants in man and in wildlife. Environ. Int., 29, 841-853.   DOI   ScienceOn
8 de Wit, C.A. (2002). An overview of brominated flame retardants in the environment. Chemosphere, 46, 583-624.   DOI   ScienceOn
9 EU-Report. (2005). European Union Risk Assessment Report on 2,2,6,6-tetrabromo-4,4 isopropylene diphenol (tetrabromobisphenol-A). CAS No. 79-94-7, EINECS No. 201-236-9, European Chemicals Bureau, Ispra, Italy.
10 Fernandes, A., Dicks, P., Mortimer, D., Gem, M., Smith, F., Driffield, M., White, S. and Rose, M. (2008). Brominated and chlorinated dioxins, PCBs and brominated flame retardants in Scottish shellfish: methodology, occurrence and human dietary exposure. Mol. Nutr. Food Res., 52, 238-249.   DOI   ScienceOn
11 Tasaki, T., Takasuga, T., Osako, M. and Sakai, S. (2004). Substance flow analysis of brominated flame retardants and related compounds in waste TV sets in Japan. Waste Manag., 24, 571-580.   DOI   ScienceOn
12 WHO/ICPS. (1995). Environmental Health Criteria 172: Tetrabromobisphenol A and Derivatives. World Health Organization, Geneva, Switzerland.
13 Shi, H., Wang, X., Luo, Y. and Su, Y. (2005). Electron paramagnetic resonance evidence of hydroxyl radical generation and oxidative damage induced by tetrabromobisphenol A in carassius auratus. Aquat. Toxicol., 74, 365-371.   DOI   ScienceOn
14 Sjodin, A., Patterson, D.G. Jr. and Bergman, A. (2003). A review on human exposure to brominated flame retardants--particularly polybrominated diphenyl ethers. Environ. Int., 29, 829-839.   DOI   ScienceOn
15 Swales, K. and Negishi, M. (2004). CAR, driving into the future. Mol. Endocrinol., 18, 1589-1598.   DOI   ScienceOn
16 Szymanska, J.A., Piotrowski, J.K. and Frydrych, B. (2000). Hepatotoxicity of tetrabromobisphenol A: effect of repeated dosage in rats. Toxicology, 142, 87-95.
17 Uchiyama, M. and Mihara, M. (1978). Determination of malondialdehyde precursor in tissues by thiobarbituric acid test. Anal. Biochem., 86, 271-278.   DOI   ScienceOn
18 Vranckx, R., Rouaze, M., Savu, L., Nunez, E.A., Beaumont, C. and Flink, I.L. (1990). The hepatic biosynthesis of rat thyroxine binding globulin (TBG): demonstration, ontogenesis, and up-regulation in experimental hypothyroidism. Biochem. Biophys. Res. Commun., 167, 317-322.   DOI   ScienceOn
19 Xia, J., Liao, L., Sarkar, J., Matsumoto, K., Reddy, J.K., Xu, J. and Kemper, B. (2007). Redundant enhancement of mouse consititutive androstane receptor transactivation by p160 coactivator family members. Arch. Biochem. Biophys., 468, 49-57.   DOI   ScienceOn
20 Xie, W., Yeuh, M.F., Radomionska-Pandya, A., Saini, S.P., Neglishi, Y., Bottroff, B.S., Cabrera, G.Y., Tukey, R.H. and Evans, R.M. (2003). Control of steroid, heme, and carcinogen metabolism by nuclear pregnae X receptor and constitutive androstane receprtor. Proc. Natl. Acad. Sci. U.S.A., 100, 4150-4155.   DOI   ScienceOn
21 Mikamo, E., Harada, S., Nishikama, J. and Nishihara, T. (2003). Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor. Toxicol. Appl. Pharmacol., 193, 66-72.   DOI   ScienceOn
22 Morris, S., Allchin, C.R., Zegers, B.N., Haftka, J.J., Boon, J.P., Belpaire, C., Leonards, P.E., van Leeuwen, S.P. and de Boer, J. (2004). Distribution and fate of HBCD and TBBPA brominated flame retardants in North Sea estuaries and aquatic food webs. Environ. Sci. Technol., 38, 5497-5504.   DOI   ScienceOn
23 Nelson, D.R., Koymans, L., Kamataki, T., Stegeman, J.J., Feyereisen, R., Waxman, D.J., Waterman, M.R., Gotoh, O., Coon, M.J., Estabrook, R.W., Gunsalus, I.C. and Nebert, D.W. (1996). P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 6, 1-42.   DOI
24 Omura, T. and Sato, R. (1964). The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J. Biol. Chem., 239, 2370-2378.
25 Ronisz, D., Finne, E.F. and Karlsson, H. (2004). Effects of the brominated flame retardants hexabromocyclododecane (HBCCD), and tetrabromobisphenol A (TBBPA), on hepatic enzymes and other biomarkers in juvenile rainbow trout and feral eelpout. Aquat. Toxicol., 69, 229-245.   DOI   ScienceOn
26 Schauer, U.M., Volkel, W. and Dekant, W. (2006). Toxicokinetics of tetrabromobisphenol A in humans and rats after oral administration. Toxicol. Sci., 91, 49-58.   DOI   ScienceOn
27 Schussler, G.C. (2000). The thyroxine-binding proteins. Thyroid, 10, 141-149.   DOI   ScienceOn
28 Kawamoto, T., Sueyoshi, T., Zelko, I., Moore, R., Washburn, K. and Negishi, M. (1999). Phenobarbotal-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol. Cell. Biol., 19, 6318-6322.
29 Sedlak, J. and Lindsay, R.H. (1968). Estimation of total protein-bound and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Arch. Biochem., 25, 192-205.   DOI   ScienceOn
30 Shen, H.M., Yang, C.F., Ding, W.X., Liu, J. and Ong, C.N. (2001). Superoxide radical-initiated apoptotic signalling pathway in selenite-treated HepG(2) cells: mitochondria serve as the main target. Free. Radic. Biol. Med., 30, 9-21.   DOI   ScienceOn
31 Kawashiro, Y., Fukata, H., Omori-Inoue, M., Kubonoya, K., Jotaki, T., Takigami, H., Sakai, S. and Mori, C. (2008). Perinatal exposure to brominated flame retardants and polychlorinated biphenyls in Japan. Endocr. J., 55, 1071-1084.   DOI   ScienceOn
32 Kitamura, S., Jinno, N., Ohta, S., Kuroki, H. and Fujimoto, N. (2002). Thyroid hormonal activity of the flame retardants tetrabromobisphenol A and tetrachlorobisphenol A. Biochem. Biophys. Res. Commun., 293, 554-559.   DOI   ScienceOn
33 Kitamura, S., Suzuki, T., Sanoh, S., Kohta, R., Jino, N., Sugihara, K., Yoshihara, S., Fujimoto, N., Watanabe, H. and Ohta, S. (2005). Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds. Toxicol. Sci., 84, 249-259.   DOI   ScienceOn
34 Lee, B.M. and Santella, R.M. (1988). Quantitation of protein adducts as a marker of genotoxic exposure: immunologic detection of $benzo({\alpha})pyrene--globin$ adducts in mice. Carcinogenesis, 9, 1773-1777.   DOI   ScienceOn
35 Legler, J. and Brouwer, A. (2003). Are brominated flame retardants endocrine disruptors? Environ. Int., 29, 879-885.   DOI   ScienceOn
36 Fukuda, N., Ito, Y., Yamaguchi, M., Mitumori, K., Koizumi, M., Hasegawa, R., Kamata, E. and Ema, M. (2004). Unexpected nephrotoxicity induced by tetrabromobisphenol A in newborn rats. Toxicol. Lett., 150,145-155.   DOI   ScienceOn
37 Maglich, J.M., Watson, J., McMillen, P.J., Goodwin, B., Willson, T.M. and Moore, J.T. (2004). The nuclear receptor CAR is regulator of thyroid hormone metabolism during caloric restriction. J. Biol. Chem., 279, 19832-19838.   DOI   ScienceOn
38 Meerts, I.A., van Zanden, J.J., Luijks, E.A., van Leeuwen-Bol, I., Marsh, G., Jakobssen, E., Bergman, A. and Brouwer, A. (2000). Potent competitive interations of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol. Sci., 56, 95-104.   DOI   ScienceOn
39 Mihara, M. and Uchiyama, M. (1978) Determination of malondialdehyde precursor in tissues by thiobarbituric acid test. Anal. Biochem., 86, 271-278.   DOI   ScienceOn
40 Germer, S., Piersma, A.H., van der Ven, L., Kamyschnikow, A., Fery, Y., Schmitz, H.J. and Schrenk, D. (2006). Subacute effects of the brominated flame retardants hexabromocyclododecane and tetrabromobisphenol A on hepatic cytochrome P450 levels in rats. Toxicology, 218, 229-236.   DOI   ScienceOn
41 Hakk, H. and Letcher, R.J. (2003). Metabolism in the toxicokinetics and fate of brominated flame retardants--a review. Environ. Int., 29, 801-828.   DOI   ScienceOn
42 Hattori-Nakakuki, Y., Nishigori, C., Okamoto, K., Imamura, S., Hiai, H. and Toyokuni, S. (1994). Formation of 8-hydroxy-2'-deoxyguanosine in epidermis of hairless mice exposed to near-UV. Biochem. Biophys. Res. Commun., 201, 1132-1139.   DOI   ScienceOn
43 Imaoka, S., Osada, M., Minamiyama, Y., Yukimura, T., Toyokuni, S., Takemura, S., Hiroi, T. and Funae, Y. (2004). Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation. Cancer Lett., 203, 117-125.   DOI   ScienceOn