QUERCETIN MITIGATES TOXICITY AND OXIDATIVE STRESS MOTIVATED BY BISPHENOL A IN LIVER OF MALE RATS
Objective: Epidemiological reports have indicated a correlation between the increasing of bisphenol A (BPA) levels in the environment and the incidence of hepatotoxicity. The present study aimed to evaluate the protective effect of quercetin on oxidative stress, inflammatory markers, apoptotic and antiapoptotic markers in the liver tissue of the bisphenol A treated rats.
Methods: Forty-eight male Wistar rats were divided into six groups; Group(1): Negative control group (Con), Group(2): Corn oil control group orally administered 1 ml of corn oil/rat daily for two months (Corn), Group(3): Olive oil control group orally administered 1 ml olive oil/rat daily for two months (Olive), Group(4): Quercetin (Qu) control group orally received Qu dissolved in olive oil (50 mg/kg b. wt.) daily for two months (Qu). Group(5): Positive control group orally received Bisphenol A (BPA) dissolved in corn oil in a dose of 50 mg/kg b. wt. daily for two months (BPA), Group(6): Quercetin treated group orally administered 50 mg/kg b. wt. of BPA and treated with Qu (50 mg/kg b. wt. Orally) daily for two months (BPA+Qu).
Results: BPA exposure resulted in significant elevations of oxidative stress, as evidenced by the increased malondialdehyde level and glutathione-S-transferase activity associated with significant decrease in glutathione peroxidase activity in the liver tissue. Moreover, BPA caused an up regulation in the values of liver function enzymes. Also, BPA produced a significant elevation in the hepatic Interleuckin-6 (IL-6) and caspase-3 levels with a significant decline in antiapoptotic protein B-cell lymphoma 2 (Bcl2) level in liver tissue. Quercetin significantly attenuated the BPA-evoked liver oxidative stress and modulated the activities of liver function enzymes. In addition, treatment of quercetin with BPA resulted in an improvement of IL-6 and caspase-3 levels associated with a significant increase in hepatic protein Bcl2 expression.
Conclusion: These data suggest that quercetin protects rat liver from BPA-induced oxidative stress, probably via its antioxidant activity, anti-inflammatory and antiapoptotic effects. So, Quercetin is a promising pharmacological agent for preventing the potential hepatotoxicity of BPA following occupational or environmental exposures.
Keywords: Bisphenol A, Quercetin, hepatotoxicity, Antioxidant, Anti-inflammatory effect, Antiapoptotic effect
Ranjit N, Siefert K, Padmanabhan V. Bisphenol-A and disparities in birth outcomes: a review and directions for future research. J Perinatol 2010;30:2-9.
Bae B, Jeong JH, Lee SJ. The quantification and characterization of endocrine disruptor bisphenol-A leaching from epoxy resin. Water Sci Technol 2002;46:381-7.
Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol 2007;24:139-77.
Sasaki N, Okuda K, Kato T. Salivary bisphenol-A levels detected by ELISA after restoration with composite resin. J Mater Sci Mater Med 2005;16:297-300.
Joskow R, Barr DB, Barr DB, Calafat AM, Needham LL, Rubin C. Exposure to bisphenol A from bis-glycidyl dimethacrylate-based dental sealants. J Am Dent Assoc 2006;137:353-62.
Carwile JL, Luu HT, Bassett LS. Polycarbonate bottle use and urinary bisphenol A concentrations. Environ Health Perspect 2007;117:1368-72.
Loganathan SN, Kannan K. Occurrence of bisphenol a in indoor dust from two locations in the EasternUnited States and implications for human exposures. Arch Environ Contam Toxicol 2011;61:68-73.
Lang IA, Galloway TS, Scarlett A. Association of urinary bisphenol a concentration with medical disorders and laboratory abnormalities in adults. J Am Med Assoc 2008;300:1303-10.
Kabuto H, Hasuike S, Minagawa N, Shishibori T. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ Res 2003;93:31-5.
Bindhumol V, Chitra KC, Mathur PP. Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology 2003;188:117-24.
Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci 2004;74:2931-40.
Korkmaz A, Aydogan M, Kolankaya D, Barlas N. Influence of vitamin C on bisphenol A, nonylphenol and octyl phenol induced oxidative damages in the liver of male rats. Food Chem Toxicol 2010;48:2865-71.
Halliwell B. Antioxidant defense mechanisms: from the beginning to the end (of the beginning). Free Radical Res 1999;31:261-72.
Ji L, Sheng Y, Zheng Z, Shi L, Wang Z. The involvement of p62â€“Keap1â€“Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radical Biol Med 2015;85:12-23.
Wang J, Pan Y, Hong Y, Zhang Q, Wang X, Kong L. Quercetin protects against cadmium-induced renal uric acid transport system alteration and lipid metabolism disorder in rats. J Evidence-Based Complementary Altern Med 2012;1-14. Doi:10.1155/2012/548430. [Article in Press]
Sofie C, Axelstad PM, Julie B, Anne Marie V, Gitte Alsing P, Ulla H. Low-dose effects of bisphenol A on early sexual development in male and female rats. Reproduction 2014;147:477-87.
Young DS. Effect of drugs on clinical laboratory tests. Third edition 1990;3:6-12.
Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 1978;90:37-43.
Habig W, Jakoby PM. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974;249:7130-9.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-69.
Andrade RJ, Lucena MI, FernÃ¡ndez MC. Drug-induced liver injury: an analysis of 461 incidences subÂ¬mitted to the Spanish registry over a 10-year period. GastroÂ¬enterology 2005;192:512-21.
Reuben A, Koch DG, Lee WM. Drug-inÂ¬duced acute liver failure: results of a U. S. multicenter, proÂ¬spective study. Hepatology 2010;52:2065-76.
Nandi D, Patra RC, Swarup D. Effect of cysteine, methionine, ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats. Toxicology 2005;211:26-35.
AydoË‡gan M, Korkmaz A, Barlas N, Kolankaya D. Prooxidant effect of vitamin C coadministration with bisphenol A, nonylphenol, and octyl phenol on the reproductive tract of male rats. Drug Chem Toxicol 2010;33:193-203.
Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi YC. Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis. Antioxid Redox Signaling 2004;6:289-300.
Pinkus R, Weiner LM, Daniel V. Role of oxidants and antioxidants in the induction of AP-1, NF-ÎºB, and glutathione S-transferase gene expression. J Biol Chem 1996;271:13422-9.
Huang J, Tan PH, Tan BK, Bay BH. GST-pi expression correlates with oxidative stress and apoptosis in breast cancer. Oncol Reports 2004;12:921-5.
Hassan ZK, Elobeid MA, Virk P, Omer SA, ElAmin M, Daghestani MH, et al. Bisphenol a induces hepatotoxicity through oxidative stress in a rat model. Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity; 2012. p. 1-6.
Moon MK, Kim MJ, Jung IK, Koo YD, Ann HY, Lee KJ, et al. Bisphenol a impairs mitochondrial function in the liver at doses below the no observed adverse effect level. J Korean Med Sci 2012;27:644-52.
Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 2008;585:325-37.
Muthukumaran S, Sudheer AR, Menon VP, Nalini N. Protective effect of quercetin on nicotine-induced prooxidant and antioxidant imbalance and DNA damage in wistar rats. Toxicology 2008;243:207-15.
Rohrdanz E, Obertrifter B, Ohler S, Tran-Thi QH, Kahl R. Influence of adriamycin and paraquat on antioxidant enzyme expression in primary rat hepatocytes. Arch Toxicol 2000;74:23-37.
Olsvik PA, Kristensen T, Waagb R, Rosseland BO, Tollefsen KE, Baeverfjord G, et al. mRNA expression of antioxidant enzymes (SOD, CAT and GSH-Px) and lipid peroxidative stress in liver of Atlantic salmon(Salmo salar) exposed to hyperoxic water during smoltification. Comp Biochem Physiol Part C: Toxicol Pharmacol 2005;141:314-23.
Rohrdanz E, Bittner A, Tran-Thi QH, Kahl R. The effect of quercetin on the mRNA expression of different antioxidant enzymes in hepatoma cells. Arch Toxicol 2003;77:506-10.
Crespo I, Garcia-Mediavilla MV, Almar M, Gonzalez P, TuËœnon MJ, Sanchez-Campos S, et al. Differential effects of dietary flavonoids on reactive oxygen and nitrogen species generation and changes in antioxidant enzyme expression induced by proinflammatory cytokines in chang liver cells. Food Chem Toxicol 2008;46:1555-69.
Mathuria N, Verma RJ. Ameliorative effect of curcumin on aflatoxin-induced toxicity in the serum of mice. Acta Poloniae Pharm Drug Res 2008;65:339-43.
Sangai NP, Verma RJ. Quercetin ameliorates bisphenol A-induced toxicity in mice. Acta Poloniae Pharm Drug Res 2012;69:557-63.
Dong W, Simeonova PP, Gallucci R, Matheson J, Flood L, Wang S, et al. Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms. Toxicol Appl Pharmacol 1998;151:359-66.
Babbar N, Casero RA. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis. Cancer Res 2006;66:11125-30.
Broker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res 2005;11:3155-62.
Li YC, Kuan YH, Huang FM, Chang YC. The role of DNA damage and caspase activation in cytotoxicity and genotoxicity of macrophages induced by bisphenol-A-glycidyl methacrylate. Int Endodontic J 2012;45:499-507.
Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis 2002;7:313-9.
Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999;399:483-7.
Yamaguchi H, Wang HG. Bcl-XL protects Bim E L induced Bax conformational change and cytochrome c release independent of interacting with Bax or BimEL. J Biol Chem 2002;277:41604-12.
Wu KJ, Chen YF, Tsai HY, Wu CR, Wood WG. Guizhi-Fuling-Wan, a traditional Chinese herbal medicine, ameliorates memory deficits and neuronal apoptosis in the streptozotocin-induced hyper glycemic rodents via the decrease of Bax/Bcl2 ratio and caspase-3 expression. J Evidence-Based Complementary Altern Med 2012;1-11. Doi.org/10.1155/2012/656150. [Article in Press]
Tasyriq M, Najmuldeen IA, In LLA, Mohamad K, Awang K, Hasima N. 7Î±-Hyd roxy-Î²-Sitosterol from chisocheton tomentosus induces apoptosis via dysregulation of cellular Bax/Bcl-2 Ratio and cell cycle arrest by downregulating ERK1/2 activation. J Evidence-Based Complementary Altern Med 2012;2012:1-12. Doi.org/ 10.1155/2012/765316. [Article in Press]
Iida H, Maehara K, Doiguchi M, Mori T, Yamada F. Bisphenol A-induced apoptosis of cultured rat sertoli cells. Reprod Toxicol 2003;17:457-64.
Li YJ, Song TB, Cai YY, Zhou JS, Song X, Zhao X. Bisphenol an exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol Sci 2009;108:427-36.
Wang Q, Zhao XF, Ji YL, Wang H, Liu P, Zhang C. Mitochondrial signaling pathway is also involved in bisphenol A-induced germ cell apoptosis in testes. Toxicol Lett 2010;199:129-35.
Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reprod Toxicol 2010;30:532-9.
Wu HJ, Liu C, Duan WX, Xu SC, He MD, Chen CH. Melatonin ameliorates bisphenol A-induced DNA damage in the germ cells of adult male rats. Mutat Res 2013;752:57-67.
Shen HM, Liu ZG. JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radical Biol Med 2006;40:928-39.
Matsumaru K, Ji C, Kaplowitz N. Mechanisms for sensitization to TN Find used apoptosis by acute glutathione depletion in murine hepatocytes. Hepatology 2003;37:1425-34.
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000;103:239-52.
Chao CL, Hou YC, Chao PD, Weng CS, Ho FM. The antioxidant effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells. Br J Nutr 2009;101:1165-70.
Shi C, Zhao L, Zhu B, Li Q, Yew DT, Yao Z, et al. Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against Î²-amyloid peptide-induced toxicity in SH-SY5Y cells. Chem Biol Interact 2009;181:115-23.
Kim BM, Choi YJ, Han Y, Yun YS, Hong SH. N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. Toxicol Appl Pharmacol 2009;239:87-97.