Ameliorative effect of docosahexaenoic acid on 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced histological changes,oxidative stress,and DNA damage in rat liver
Restricted accessResearch articleFirst published online September, 2012
Ameliorative effect of docosahexaenoic acid on 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced histological changes,oxidative stress,and DNA damage in rat liver
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that leads to the development of hepatotoxicity. Docosahexaenoic acid (DHA) has been proposed to counteract oxidative stress and improve antioxidant status, and several studies suggest that supplementations with antioxidants can influence hepatotoxicity. The aim of the current study was to explore the role of DHA in modulating the toxicity of TCDD in the liver of Sprague-Dawley rats. Animals were assigned to four groups (n = 5): control (only dimethyl sulfoxide (DMSO)), 8 μg/kg body weight (b.w.) TCDD in DMSO solution; 250 mg/kg b.w. DHA and TCDD plus DHA; respectively. Rats were intraperitoneally administered their respective doses daily for 21 days. On day 21, the animals were killed, and then biochemical tests, pathological examination, and micronucleus (MN) assay were performed in the liver. Our results showed that the activities of antioxidant enzymes were significantly decreased and serious pathological findings were established in rats that received TCDD. Beside the rate of MNs in hepatocytes was increased after the treatment with dioxin. In rats treated with DHA alone, MNs were not changed and the activities of antioxidant enzymes were significantly increased. The presence of DHA with TCDD alleviated its pathological effects in hepatic tissue. DHA also prevented the suppression of antioxidant enzymes in the livers of animals exposed to TCDD and displayed a strong protective effect against MNs. It can be concluded that DHA has beneficial influences and could be able to antagonize TCDD toxicity in liver.
AebiH (1984) Catalase in vitro. In: PackerL (ed.) Methods in enzymology. New York: Academic Press, 1–126.
2.
AkerboomTPMSiesH (1981) Assay of glutathione, glutathione disulfide and glutathione mixed disulfides in biological samples. Methods in Enzymology77: 373–382.
3.
AlyHAKhafagyRM (2011) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced cytotoxicity accompanied by oxidative stress in rat sertoli cells: possible role of mitochondrial fractions of sertoli cells. Toxicology and Applied Pharmacology252(3): 273–780.
4.
AmbrozovaGPekarovaMLojekA (2010) Effect of polyunsaturated fatty acids on the reactive oxygen and nitrogen species production by raw 264.7 macrophages. European Journal of Nutrition49(3): 133–139.
5.
ArnalEMirandaMJohnsen-SorianıSAlvarez-NöltingRDíaz-LlopisMAraizJ (2009) Beneficial effect of docosahexanoic acid and lutein on retinal structural, metabolic, and functional abnormalities in diabetic rats. Current Eye Research34(11): 928–938.
6.
BanudeviSArunkumarASharmilaMSenthilkumarJBalasubramanianKSrinivasanN (2005) Diallyl disulfide-induced modulation of a few phase I and II drug metabolizing enzymes on Aroclor 1254 toxicity in Rattus norvegicus liver and ventral prostate. Journal of Clinical Biochemistry and Nutrition36: 59–65.
7.
BergèJPBarnathanG (2005) Fatty acids from lipids of marine organisms: molecular biodiversity, roles as biomarkers, biologically active compounds, and economical aspects. Advances in Biochemical Engineering/Biotechnology96: 49–125.
8.
BockKW (1994) Aryl hydrocarbon or dioxin receptor: biologic and toxic responses. Reviews of Physiology, Biochemistry & Pharmacology125: 1–42.
9.
BoverhofDRBurgoonLDTashiroCSharrattBChittimBHarkemaJR (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicological Sciences94(2): 398–416.
10.
BukowskaB (2004) Effects of 2,4-D and its metabolite 2,4-dichlorophenol on antioxidant enzymes and level of glutathione in human erythrocytes. Comparative Biochemistry and Physiology-Part C: Toxicology andPharmacology135(4): 435–441.
11.
CastilloRRodrigoRPerezFCerecedaMAsenjoRZamoranoJ (2011) Antioxidant therapy reduces oxidative and inflammatory tissue damage in patients subjected to cardiac surgery with extracorpocal circulation. Basic & Clinical Pharmacology & Toxicology108(4): 256–262.
12.
CeruttiPGhoshROyaYAmstadP (1994) The role of the cellular antioxidant defense in oxidant carcinogenesis. Environmental Health Perspectives102(suppl 10): 123–129.
13.
ChenWYLinSYPanHCLiaoSLChuangYHYenYJ (2011) Beneficial effect of docosahexaenoic acid on cholestatic liver injury in rats. The Journal of Nutritional Biochemistry. doi:10.1016/j.jnutbio.2010.11.022..
14.
CiftciOOzdemirITanyildiziSYildizSOguzturkH (2011) Antioxidative effects of curcumin, {beta}-myrcene and 1,8-cineole against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced oxidative stress in rats liver. Toxicology and Industrial Health27(5): 447–453.
15.
CzepielJBiesiadaGGajdaMSzczepańskiWSzypułaKDabrowskiZ (2010) The effect of TCDD dioxin on the rat liver in biochemical and histological assessment. Folia Biologica (Kraków)58(1-2): 85–90.
16.
DereELeeAWBurgonLDZacharewskiTR (2011) Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells. BMC Genomics15: 12–193.
17.
DeVitoMJBirnbaumLSFarlandWHGasiewiczTA (1995) Comparisons of estimated human body burdens of dioxin like chemicals and TCDD body burdens in experimentally exposed animals. Environmental Health Perspectives103(9): 820–831.
18.
DeVitoMJDilibertoJJRossDGMenacheMGBirnbaumLS (1997) Dose–response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I. CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin. Toxicology and Applied Pharmacology147(2): 267–280.
19.
DupertuisYMMeguidMMPichardC (2007) Coloncancer therapy: new perspectives of nutritional manipulations using polyunsaturated fatty acids. Current Opinion in Clinical Nutrition & Metabolic Care10(4): 427–432.
20.
EicherSDMcVeyDS (1995) Dietary modulation of Kupffer cell and splenocyte function during a Salmonella typhimurium challenge in mice. Journal of Leukocyte Biology58(1): 32–39.
21.
El-TawilOSElsaieedEM (2005) Induction of oxidative stress in the reproductive system of rats after subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Bulletin of Environmental Contamination and Toxicology75(1): 15–22.
22.
ForgacsALBurgoonLDLynnSGLaPresJJZacharewskiT (2010) Effects of TCDD on the expression of nuclear encoded mitochondrial genes. Toxicology and Applied Pharmacology246(1-2): 58–65.
23.
FouchecourtMRiviereJ (1995) Activities of cytochrome P450-dependent monooxyganases and antioxidant enzymes in different organs of Norwayrats (Rattus norvegicus) inhabiting reference and contaminated sites. Chemosphere31(11-12): 4375–4386.
24.
GanLQFuYXLiuXQiuLWuSDTianXF (2009) Transforming growth factor-beta3 expression up-regulates on cleft palates induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. Toxicology and Industrial Health25(7): 473–478.
25.
GapeyevABKulaginaTPAripovskyAVChemerisNK (2011) The role of fatty acids in anti-inflammatory effects of low-intensity extremely high-frequency electromagnetic radiation. Bioelectromagnetics32(5): 388–395.
26.
GrassmanJAMastenNAWalkerNJLucierGW (1998) Animal models of human response to dioxins. Environmental Health Perspectives106(suppl 2): 761–775.
27.
HalliwellBGutteridgeJMC (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods in Enzymology186: 1–85.
28.
HarperKNHibbelnJRDeckelbaumRQuesenberryCPJr, SchaeferCABrownAS (2011) Maternal serum docosahexaenoic acid and schizophrenia spectrum disorders in adult offspring. SchizophreniaResearch128(1-3): 30–36.
29.
HassounEALiFAbushabanAStohsSJ (2000) The relative abilities of TCDD and its congeners to induce oxidative stress in the hepatic and brain tissues of rats after subchronic exposure. Toxicology145(2-3): 103–113.
30.
HassounEALiFAbushabanAStohsSJ (2001) Production of superoxide anion, lipid peroxidation and DNA damage in the hepatic and brain tissues of rats after subchronic exposure to mixtures of TCDD and its congeners. Journal of Applied Toxicology21(3): 211–219.
31.
HuffJLucierGTritscherA (1994) Carcinogenicity of TCDD: experimental, mechanistic, and epidemiologic evidence. Annual Review of Pharmacology and Toxicology34: 343–372.
32.
HungYCHuangGSSavaVMBlagodarskyVAHongMY (2006) Protective effects of tea melanin against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity: antioxidant activity and aryl hydrocarbon receptor suppressive effect. Biological and Pharmaceutical Bulletin29(11): 2284–2291.
33.
IARC (1997) Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans. IARC monographs on the evaluation of carcinogenic risk of chemicals to humans, vol. 69. Lyon, France: International Agency for Research on Cancer, 666.
34.
JinMHHongCHLeeHYKangHJHanSW (2008) Enhanced TGF-β1 is involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced oxidative stress in C57BL/6 mouse testis. Toxicology Letters178(3): 202–209.
35.
JinXLokEBondyGCaldwellDMuellerRKapalK (2007) Modulating effects of dietary fats on methylmercury toxicity and distribution in rats. Toxicology230(1): 22–44.
36.
KakarlaPVadluriGReddyKS (2005) Response of hepatic antioxidant system to exercise training in aging female rat. Journal of Experimental Zoology Part A: Comparative Experimental Biology303(3): 203–208.
37.
KiddPM (1997) Glutathione: systemic protectant against oxidative and free radical damage. Alternative Medicine Review1: 155–176.
38.
KimYJChungHY (2007) Antioxidative and anti-inflammatory actions of docosahexaenoic acid and eicosapentaenoic acid in renal epithelial cells and macrophages. Journal of Medicinal Food10(2): 225–231.
39.
KonoYFridovichI (1982) Superoxide radicals inhibit catalase. The Journal of Biological Chemistry257(10): 5751–5754.
40.
KopecAKLyleDBDaherIABryanDMColleenTPotterD (2010) PCB153-elicited hepatic responses in the immature, ovariectomized C57BL/6 mice: comparative toxicogenomic effects of dioxin and non-dioxin-like ligands. Toxicology and Applied Pharmacology243(3): 359–371.
41.
KrugerMCCoetzeeMHaagMWeilerH (2010) Long-chain polyunsaturated fatty acids: selected mechanisms of action on bone. Progress in Lipid Research49(4): 438–449.
42.
LatchoumycandaneCChitraKCMathurPP (2003) 2,3,7,8-tetrachlorodibenze-p-dioxin (TCDD) induces oxidative stress in the epididymis and epididymal sperm of adult rats. Archives of toxicology77(5): 280–284.
43.
LawrenceRABurkRF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochemical and Biophysical Research Communications71(4): 952–958.
44.
LeeJHWadaTFebbraioMHeJMatsubaraTLeeMJ (2010) A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology139(2): 653–663.
45.
LiCHShiBHeWMengT (2010) Is it possible to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cleft palate by prenatal administration of folic acid? An experimental study. Toxicology and Industrial Health26(5): 281–286.
46.
LowryOHRosebroughNJFarrALRandallRJ (1951) Protein measurement with folin phenol reagent. The Journal of Biological Chemistry193(1): 265–275.
47.
MartinezJGWaldonMHuangQAlvarezSOrenASandovalN (2009) Membrane-targeted synergistic activity of docosahexaenoic acid and lysozyme against Pseudomonas aeruginosa. Biochemical Journal419(1): 193–200.
48.
MeisterAAndersonME (1983) Glutathione. Biochemistry-Annual Review of Biochemistry52: 711–760.
49.
MisraHPFridovichK (1972) The generation of superoxide radical during the autooxidation of hemoglobin. The Journal of Biological Chemistry247: 6960–6962.
50.
MoffatIDBoutrosPCChenHOkeyABPohjanvirtaR (2010) Aryl hydrocarbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities. BMC Genomics11: 263.
51.
NaderMAel-AgamyDSSuddekGM (2010) Protective effects of propolis and thymoquinone on development of atherosclerosis in cholesterol-fed rabbits. Archives of Pharmacal Research33(4): 637–643.
52.
National Research Council (1996) Guide for the care and use of laboratory animals. Washington: National Academy Press.
53.
NguyenKACarboneJMSilvaVMChenCHennigGEWhiteleyHE (1999) The PPAR activator docosahexaenoic acid prevents cetaminophen hepatotoxicity in male CD-1 mice. Journal of Toxicology and Environmental Health58(3): 171–186.
54.
PriyaSVijayalakshmiPVivokanandanPKarthikeyanS (2011) Influence of N-acetylcysteine against dimethylnitrosamine induced hepatotoxicity in rats. Toxicology and Industrial Health. doi:10.1177/0748233711399323.
55.
RegoliFWinstonGW (1999) Quantification of total oxidant scavenging capacity of antioxidants for peroxynitrite, peroxyl radicals, and hydroxyl radicals. Toxicology and Applied Pharmacology156(2): 96–105.
56.
Reyes-HernándeODMejía-GarcíaASánchez-OcampoEMCabañas-CortésMARamírezPChávez-GonzálezL (2010) Ube2l3 gene expression is modulated by activation of the aryl hydrocarbon receptor: implications for p53 ubiquitination. Biochemical Pharmacology80(6): 932–940.
57.
RoyRChandrasekharDPujariP (2007) Dietary fish oil as hepatoprotective agent in Mus musculus. The Journal of Experimental Biology45(4): 367–370.
58.
SafeS (1990) Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Critical Reviews in Toxicology21(1): 51–88.
59.
SakamotoMKMimaSTanimuraT (1995) A morphological study of liver lesions in Xenopus larvae exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with special reference to apoptosis of hepatocytes. Journal of Environmental Pathology14(2): 69–82.
60.
ShertzerHG (2010) Protective effects of the antioxidant 4b,5,9b,10-tetrahydroindeno[1,2-b]indole against TCDD toxicity in C57BL/6J mice. International Journal of Toxicology29(1): 40–48.
61.
ShertzerHGNebertDWPugaAAryMSonntagDDixonK (1998) Dioxin causes a sustained oxidative stress response in the mouse. Biochemical and Biophysical Research Communications253(1): 44–48.
62.
ShiizakiKOhsakoSKawanishiMYagiT (2008) Omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. Basic & Clinical Pharmacology & Toxicology103(5): 468–475.
63.
ShimazawaMNakajimaYMashimaYHaraH (2009) Docosahexaenoic acid (DHA) has neuroprotective effects against oxidative stress in retinal ganglion cells. Brain Research1251: 269–275.
64.
SkrzydlewskaEFarbiszewskiR (1997) Decreased antioxidant defense mechanisms in rat liver after methanol intoxication. Free Radical Research27(4): 369–375.
65.
SlagsvoldJEPettersenCHStørvoldGLFollestadTKrokanHESchonbergSA (2010) DHA alters expression of target proteins of cancer therapy in chemotherapy resistant SW620 colon cancer cells. Nutrition in Cancer Care62(5): 611–621.
66.
SlezakBPHatchGEDeVitoMJDilibertoJJSladeRCrissmanK (2000) Oxidative stress in female B6C3F1 mice following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD). Toxicological Sciences54(2): 390–398.
67.
SuHM (2010) Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. The Journal of Nutritional Biochemistry21(5): 364–373.
68.
SuzukiHTakasawaHKobayashiK (2009) Evaluation of a liver micronucleus assay with 12 chemicals using young rats (II): a study by the Collaborative Study Group for the Micronucleus Test/Japanese Environmental Mutagen Society–Mammalian Mutagenicity Study Group. Mutagenesis24(1): 9–16.
69.
SvistunenkoDA (2005) Reaction of haem containing proteins and enzymes with hydroperoxides: the radical view. Biochimica et Biophysica Acta1707(1): 127–155.
70.
TakayamaFNakamotoKTotaniNYamanushiTKabutoHKaneyukiT (2010) Effects of docosahexaenoic acid in an experimental rat model of nonalcoholic steatohepatitis. Journal of Oleo Science59(8): 407–414.
71.
TapieroHTownsendDMTewKD (2004) The role of carotenoids in the prevention of human pathologies. Biomedicine & Pharmacotherapy58(2): 100–110.
72.
Tung-KwangLO’BrienKFWangWJohnkeRMShengCBenhabibSM (2010) Radioprotective effect of American ginseng on human lymphocytes at 90 minutes post-irradiation: a study of 40 cases. Journal of Alternative and Complementary Medicine16(5): 561–567.
73.
TurkezHYousefMIGeyikogluF (2010) Propolis prevents aluminum-induced genetic and hepatic damages in rat liver. Food and Chemical Toxicology48(10): 2741–2746.
74.
TwaroskiLWO’BrienMLRobertsonLW (2001) Effects of selected polychlorinated biphenyl (PCB) congeners on hepatic glutathione, glutathione-related enzymes and selenium status: implications for oxidative stress. Biochemical Pharmacology62(3): 273–278.
75.
ValkoMMorrisHCroninMT (2005) Metals, toxicity and oxidative stress. Current Medicinal Chemistry12(10): 1161–1208.
76.
Van den BergMBirnbaumLBosveldATCBrunstromBCookPFeeleyM, et al. (1998) Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives106(12): 775–792.
WangHXMaXCDengQ (2002) Cytotoxicity of flutamide and 2-hydroxyflutamide and their effects on CYP1A2 mRNA in primary rat hepatocytes. Acta Pharmacologica Sinica23(6): 562–566.
79.
WeitzDWeintraubHFisherESchwartzbardAZ. (2010) Fish oil for the treatment of cardiovascular disease. Cardiology in Review18(5):258–263.
80.
WertzPW (2009) Essential fatty acids and dietary stress. Toxicology and Industrial Health25(4-5): 279–283.
XuJPYinZPZhouXQ (2008) Effect of vitamin E on reproductive function in the mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Industrial Health24(9): 595–601.
83.
YilmazDAydemirNCVatanOTüzünEBilalogluR (2011) Influence of naringin on cadmium-induced genomic damage in human lymphocytes in vitro. Toxicology and Industrial Health. doi:10.1177/0748233711407241..
84.
YilmazSAksoyHUnalFCelikMYüzbaşioğluD (2008) Genotoxic action of fungicide Conan 5FL (hexaconazole) on mammalian cells in vivo and in vitro. Genetika44(3): 323–328.
85.
YinHPXuJPZhouXQWangY (2011) Effects of Vitamin E on reproductive hormones and testis structure in chronic dioxin-treated mice. Toxicology and Industrial Health. doi:10.1177/0748233711408381..
