Rutin mitigates perfluorooctanoic acid-induced liver injury via modulation of oxidative stress, apoptosis, and inflammation

Document Type : Original Article

Authors

1 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

2 Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

3 Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

4 Department of Anatomy, Molecular, and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

5 Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran

Abstract

Objective(s): Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP), broadly present in the environment. Due to long biological half-life, it is accumulated in the body, especially the liver, causing hepatocellular damage. This study was designed to assess the effects of rutin on PFOA-induced liver damage in rats.
Materials and Methods: Male Wistar rats were exposed to PFOA (10 mg/kg/day) alone, or in combination with different doses of rutin (25, 50, and 100 mg/kg/day) by oral gavage for 4 weeks. 
Results: PFOA altered the levels of liver enzymes, induced a notable change in the tissue structure of the liver, caused some levels of mitochondrial dysfunction, and increased the expression of pro-apoptotic and pro-inflammatory genes. Co-treatment with rutin mitigated the PFOA-induced elevation of liver enzymes, histopathological defects, oxidative damage, and mitochondrial dysfunction. In addition, rutin declined the stimulatory effects of PFOA on the Bax: Bcl2 ratio and reduced the PFOA-induced gene expression of TNF-α, IL-6, NF-ƙB, and JNK.
Conclusion: These findings suggest rutin as a protective agent for PFOA-induced liver injury, albeit the protection was partial. Possible mechanisms are inhibition of oxidative stress, mitochondrial dysfunction, and inflammatory response.

Keywords

Main Subjects

References

1. Li D, Zhang L, Zhang Y, Guan S, Gong X, Wang X. Maternal exposure to perfluorooctanoic acid (PFOA) causes liver toxicity through PPAR-α pathway and lowered histone acetylation in female offspring mice. Environ Sci Pollut Res Int 2019; 26:18866-18875.
2. Yang G, Zhang N, Yang J, Fu Q, Wang Y, Wang D, et al. Interaction between perfluorooctanoic acid and aerobic granular sludge. Water Res 2020; 169:115249-115259.
3. Yang B, Zou W, Hu Z, Liu F, Zhou L, Yang S, et al. Involvement of oxidative stress and inflammation in liver injury caused by perfluorooctanoic acid exposure in mice. Biomed Res Int 2014; 2014:409837-409843.
4. Erdemli M, Yigitcan B, Gul M, Bag HG, Gul S, Aksungur Z. Thymoquinone is protective against 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity. Biotech Histochem 2018; 93:453-462.
5. Meyer JN, Leung MC, Rooney JP, Sendoel A, Hengartner MO, Kisby GE, et al. Mitochondria as a target of environmental toxicants. Toxicol Sci 2013; 134:1-17.
6. Mashayekhi V, Tehrani KHME, Hashemzaei M, Tabrizian K, Shahraki J, Hosseini M. Mechanistic approach for the toxic effects of perfluorooctanoic acid on isolated rat liver and brain mitochondria. Hum Exp Toxicol 2015; 34:985-996.
7. Suh KS, Choi EM, Kim YJ, Hong SM, Park SY, Rhee SY, et al. Perfluorooctanoic acid induces oxidative damage and mitochondrial dysfunction in pancreatic β-cells. Mol Med Rep 2017; 15:3871-3878.
8. Gedik S, Erdemli ME, Gul M, Yigitcan B, Bag HG, Aksungur Z, et al. Hepatoprotective effects of crocin on biochemical and histopathological alterations following acrylamide-induced liver injury in Wistar rats. Biomed Pharmacother 2017; 95:764-770.
9. Bilgic Y, Akbulut S, Aksungur Z, Erdemli ME, Ozhan O, Parlakpinar H, et al. Protective effect of dexpanthenol against cisplatin‑induced hepatotoxicity. Exp Ther Med 2018; 16:4049-4057.
10. Lebda MA, Sadek KM, Abouzed TK, Tohamy HG, El-Sayed YS. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes. Life Sci 2018; 192:136-143.
11. Brieger A, Bienefeld N, Hasan R, Goerlich R, Haase H. Impact of perfluorooctanesulfonate and perfluorooctanoic acid on human peripheral leukocytes. Toxicol in Vitro 2011; 25:960-968.
12. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12:1-15.
13. Sadek K, Saleh E, Nasr S. Molecular hepatoprotective effects of lipoic acid against carbon tetrachloride-induced liver fibrosis in rats: Hepatoprotection at molecular level. Hum Exp Toxicol 2018; 37:142-154.
14. Workman LM, Habelhah H. TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification. Cell Signal 2013; 25:1654-1664.
15. Lan HY, Nikolic-Paterson DJ. Advances in mechanisms of renal fibrosis. Front Physiol 2018; 9:284-285.
16. Kim JH, Kim BB, Lee KW, Kang NJ. Protective effect of rutin against ultraviolet B-induced cyclooxygenase-2 expression in mouse epidermal cells. Food Sci Biotechnol 2013; 22:1-6.
17. Liang W, Zhang D, Kang J, Meng X, Yang J, Yang L, et al. Protective effects of rutin on liver injury in type 2 diabetic db/db mice. Biomed Pharmacother 2018; 107:721-728.
18. Zargar S, Wani TA, Alamro AA, Ganaie MA. Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin. Int J Immunopathol Pharmacol 2017; 30:207-214.
19. Abdel-Ghaffar O, Mahmoud ST, Said AA, Sanad FA-AY. Hepatoprotective effect of rutin against oxidative stress of isoniazid in albino rats. Int J Pharmacol 2017; 13:516-528.
20. Guruge KS, Yeung LW, Yamanaka N, Miyazaki S, Lam PK, Giesy JP, et al. Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA). Toxicol Sci 2006; 89:93-107.
21. Naderi M, Seyedabadi M, Amiri FT, Mohammadi E, Akbari S, Shaki F. Taurine protects against perfluorooctanoic acid-induced hepatotoxicity via inhibition of oxidative stress, inflammatory, and apoptotic pathways. Toxicol Res 2023; 12:124-132.
22.  Hamzeh M, Hosseinimehr SJ, Khalatbary AR, Mohammadi HR, Dashti A, Amiri FT. Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model. Res Pharm Sci 2018; 13:440-449.
23. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.
24. Arab-Nozari M, Mohammadi E, Shokrzadeh M, Ahangar N, Amiri FT, Shaki F. Co-exposure to non-toxic levels of cadmium and fluoride induces hepatotoxicity in rats via triggering mitochondrial oxidative damage, apoptosis, and NF-kB pathways. Environ Sci Pollut Res Int 2020; 27:24048-24058.
25. Owagboriaye F, Dedeke G, Aladesida A, Bamidele J, Olooto W. Assessment of the effect of gasoline fume on stress hormones, anti-oxidant status and lipid peroxidation in albino rat. J king Saud Univ Sci 2018; 30:393-399.
26. Akbari S, Amiri FT, Naderi M, Shaki F, Seyedabadi M. Sodium arsenite accelerates D-galactose-induced aging in the testis of the rat: Evidence for mitochondrial oxidative damage, NF-kB, JNK, and apoptosis pathways. Toxicology 2022; 470:153148.
27. Ashari S, Karami M, Shokrzadeh M, Ghandadi M, Ghassemi-Barghi N, Dashti A, et al. The implication of mitochondrial dysfunction and mitochondrial oxidative damage in di (2-ethylhexyl) phthalate induced nephrotoxicity in both in vivo and in vitro models. Toxicol Mech Methods 2020; 30:427-437.
28. Seyedabadi M, Ghahremani MH, Ostad SN. ATP depletion as a consequence of hypoxia enhances tamoxifen antiproliferative effects in T47D breast carcinoma cells. Oncol Res 2009;18:221-228.
29. Baracca A, Sgarbi G, Solaini G, Lenaz GJBeba-b. Rhodamine 123 as a probe of mitochondrial membrane potential: Evaluation of proton flux through F0 during ATP synthesis. Biochim Biophys Acta 2003; 1606:137-146.
30. Mohammadnejad L, Soltaninejad K, Seyedabadi M, Ghasem Pouri SK, Shokrzadeh M, Mohammadi H. Evaluation of mitochondrial dysfunction due to oxidative stress in therapeutic, toxic and lethal concentrations of tramadol. Toxicol Res 2021; 10:1162-1170.
31. Khedmat S, Seyedabadi M, Ghahremani MH, Ostad SN. Cyclooxygenase 2 plays a role in Emdogain-induced proliferation. J Periodontal Res 2011; 46:67-73.
32. Mandegary A, Torshabi M, Seyedabadi M, Amirheidari B, Sharif E, Ghahremani MH. Indomethacin-enhanced anticancer effect of arsenic trioxide in A549 cell line: Involvement of apoptosis and phospho-ERK and p38 MAPK pathways. Biomed Res Int 2013; 2013:237543-237551.
33. Najafi A, Moradinasab M, Seyedabadi M, Haghighi MA, Nabipour I. First molecular identification of symbiotic archaea in a sponge collected from the Persian Gulf, Iran. Open Microbiol J 2018; 12:323-332.
34. Quist EM, Filgo AJ, Cummings CA, Kissling GE, Hoenerhoff MJ, Fenton SE. Hepatic mitochondrial alteration in CD-1 mice associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA). Toxicol Pathol 2015; 43:546-557.
35. Ojo AF, Xia Q, Peng C, Ng JC. Evaluation of the individual and combined toxicity of perfluoroalkyl substances to human liver cells using biomarkers of oxidative stress. Chemosphere 2021; 281:130808.
36. Liu W, Xu C, Sun X, Kuang H, Kuang X, Zou W, et al. Grape seed proanthocyanidin extract protects against perfluorooctanoic acid-induced hepatotoxicity by attenuating inflammatory response, oxidative stress and apoptosis in mice. Toxicol Res 2016; 5:224-234.
37. Galano A, Alvarez-Idaboy JR. Glutathione: Mechanism and kinetics of its non-enzymatic defense action against free radicals. Rsc Advances 2011; 1:1763-1771.
38. Zeweil MM, Sadek KM, Elsadek MF, Mahmoud SF, Ahmed BM, Khafaga AF. Sidr honey abrogates the oxidative stress and downregulates the hyaluronic acid concentration and gene expression of TGF‐β1 and COL1a1 in rat model of thioacetamide‐induced hepatic fibrosis. Anim Sci J 2020; 91:e13434.
39. Huang Q, Zhang J, Martin FL, Peng S, Tian M, Mu X, et al. Perfluorooctanoic acid induces apoptosis through the p53-dependent mitochondrial pathway in human hepatic cells: A proteomic study. Toxicol Lett 2013; 223:211-220.
40. Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harbor Perspect Biol 2009; 1:a000034-000047.
41. Roy PK, Rashid F, Bragg J, Ibdah JA. Role of the JNK signal transduction pathway in inflammatory bowel disease. World J Gastroenterol 2008; 14:200-202.
42. Grynberg K, Ma FY, Nikolic-Paterson DJ. The JNK signaling pathway in renal fibrosis. Front Physiol 2017; 8:829-840.
43. Sadek KM, Lebda MA, Abouzed TK, Nasr SM, El-Sayed Y. The molecular and biochemical insight view of lycopene in ameliorating tramadol-induced liver toxicity in a rat model: Implication of oxidative stress, apoptosis, and MAPK signaling pathways. Environ Sci Pollut Res Int 2018; 25:33119-33130.
44. Singh TS, Lee S, Kim H-H, Choi JK, Kim S-H. Perfluorooctanoic acid induces mast cell-mediated allergic inflammation by the release of histamine and inflammatory mediators. Toxicol Lett 2012; 210:64-70.
45. Domitrović R, Jakovac H, Vasiljev Marchesi V, Vladimir-Knežević S, Cvijanović O, Tadić Ž, et al. Differential hepatoprotective mechanisms of rutin and quercetin in CCl4-intoxicated BALB/cN mice. Acta Pharmacologica Sinica 2012; 33:1260-1270.
46. AlSharari SD, Al-Rejaie SS, Abuohashish HM, Ahmed MM, Hafez MM. Rutin attenuates Hepatotoxicity in high-cholesterol-diet-fed rats. Oxid Med Cell Longev 2016;2016:5436745-54367455.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 11
November 2023
Pages 1291-1297

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