Toxicological Research

  • 제39권2호
  • /
  • Pages.201-211
  • /
  • 2023
  • /
  • 1976-8257(pISSN)
  • /
  • 2234-2753(eISSN)
한국독성학회 (Korean Society of Toxicology & Korea Environmental Mutagen Society)
권호 표지
DOI QR코드

DOI QR Code

Integrated transcriptomic analysis of liver and kidney after 28 days of thioacetamide treatment in rats

  • Hyoung-Yun Han (Department of Predictive Toxicology, Korea Institute of Toxicology) ;
  • Se-Myo Park (Department of Predictive Toxicology, Korea Institute of Toxicology) ;
  • Je-Won Ko (College of Veterinary Medicine and Institute of Veterinary Science, Chungnam National University) ;
  • Jung-Hwa Oh (Department of Predictive Toxicology, Korea Institute of Toxicology) ;
  • Sang Kyum Kim (College of Pharmacy, Chungnam National University) ;
  • Tae-Won Kim (College of Veterinary Medicine and Institute of Veterinary Science, Chungnam National University)
  • 투고 : 2022.07.20
  • 심사 : 2022.11.15
  • 발행 : 2023.04.15
⟨ 이전 논문 다음 논문 ⟩

초록

Thioacetamide (TAA) was developed as a pesticide; however, it was soon found to cause hepatic and renal toxicity. To evaluate target organ interactions during hepatotoxicity, we compared gene expression profiles in the liver and kidney after TAA treatment. Sprague-Dawley rats were treated daily with oral TAA and then sacrificed, and their tissues were evaluated for acute toxicity (30 and 100 mg/kg bw/day), 7-day (15 and 50 mg/kg bw/day), and 4-week repeated-dose toxicity (10 and 30 mg/kg). After the 4-week repeated toxicity study, total RNA was extracted from the liver and kidneys, and microarray analysis was performed. Differentially expressed genes were selected based on fold change and significance, and gene functions were analyzed using ingenuity pathway analysis. Microarray analysis showed that significantly regulated genes were involved in liver hyperplasia, renal tubule injury, and kidney failure in the TAA-treated group. Commonly regulated genes in the liver or kidney were associated with xenobiotic metabolism, lipid metabolism, and oxidative stress. We revealed changes in the molecular pathways of the target organs in response to TAA and provided information on candidate genes that can indicate TAA-induced toxicity. These results may help elucidate the underlying mechanisms of target organ interactions during TAA-induced hepatotoxicity.

키워드

과제정보

This work was supported by a grant from the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2020R1F1A1054226, NRF-2021M3A9H3016047 and NRF-2015M3A7B6027948), a grant from the Ministry of Food and Drug Safety in 2021 (21162MFDS045), research fund of Chungnam National University, and the Korea Institute of Toxicology (KIT) Research Program (No. 1711159817).

참고문헌

  1. Lee JW, Shin KD, Lee M, Kim EJ, Han SS, Han MY, Ha H, Jeong TC, Koh WS (2003) Role of metabolism by flavin-containing monooxygenase in thioacetamide-induced immunosuppression. Toxicol Lett 136:163-172. https://doi.org/10.1016/s0378-4274(02)00333-8 
  2. Schyman P, Printz RL, Estes SK, O'Brien TP, Shiota M, Wallqvist A (2019) Assessing chemical-induced liver injury in vivo from in vitro gene expression data in the rat: the case of thioacetamide toxicity. Front Genet 10:1233. https://doi.org/10.3389/fgene.2019.01233 
  3. Stankova P, Kucera O, Lotkova H, Rousar T, Endlicher R, Cervinkova Z (2010) The toxic efect of thioacetamide on rat liver in vitro. Toxicol In Vitro 24:2097-2103. https://doi.org/10.1016/j.tiv.2010.06.011 
  4. Fitzhugh OG, Nelson AA (1947) Chronic oral toxicity of alpha-naphthyl thiourea. Proc Soc Exp Biol Med 64:305-310. https://doi.org/10.3181/00379727-64-15776 
  5. Ghosh S, Sarkar A, Bhattacharyya S, Sil PC (2016) Silymarin protects mouse liver and kidney from thioacetamide induced toxicity by scavenging reactive oxygen species and activating PI3K-Akt pathway. Front Pharmacol 7:481. https://doi.org/10.3389/fphar.2016.00481 
  6. Moreira E, Fontana L, Periago JL, Sanchez De Medina F, Gil A (1995) Changes in fatty acid composition of plasma, liver microsomes, and erythrocytes in liver cirrhosis induced by oral intake of thioacetamide in rats. Hepatology 21:199-206. https://doi.org/10.1002/hep.1840210132 
  7. Low TY, Leow CK, Salto-Tellez M, Chung MC (2004) A proteomic analysis of thioacetamide-induced hepatotoxicity and cirrhosis in rat livers. Proteomics 4:3960-3974. https://doi.org/10.1002/pmic.200400852 
  8. Mangipudy RS, Chanda S, Mehendale HM (1995) Tissue repair response as a function of dose in thioacetamide hepatotoxicity. Environ Health Perspect 103:260-267. https://doi.org/10.1289/ehp.95103260 
  9. Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, Balasubramanian KA (2006) Oxidative stress in the development of liver cirrhosis: a comparison of two diferent experimental models. J Gastroenterol Hepatol 21:947-957. https://doi.org/10.1111/j.1440-1746.2006.04231.x 
  10. Okuyama H, Nakamura H, Shimahara Y, Araya S, Kawada N, Yamaoka Y, Yodoi J (2003) Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice. Hepatology 37:1015-1025. https://doi.org/10.1053/jhep.2003.50203 
  11. Chilakapati J, Shankar K, Korrapati MC, Hill RA, Mehendale HM (2005) Saturation toxicokinetics of thioacetamide: role in initiation of liver injury. Drug Metab Dispos 33:1877-1885. https://doi.org/10.1124/dmd.105.005520 
  12. Mehendale HM (2005) Tissue repair: an important determinant of final outcome of toxicant-induced injury. Toxicol Pathol 33:41-51. https://doi.org/10.1080/01926230590881808 
  13. Ansil PN, Nitha A, Prabha SP, Wills PJ, Jazaira V, Latha MS (2011) Protective effect of Amorphophallus campanulatus (Roxb.). Blume tuber against thioacetamideinduced oxidative stress in rats. Asian Pac J Trop Med 4:870-877. https://doi.org/10.1016/S1995-7645(11)60211-3 
  14. Begum Q, Noori S, Mahboob T (2011) Antioxidant effect of sodium selenite on thioacetamide-induced renal toxicity. Pak J Biochem Mol Biol 44:21-26 
  15. Negishi K, Noiri E, Maeda R, Portilla D, Sugaya T, Fujita T (2008) Renal L-type fatty acid-binding protein mediates the bezafibrate reduction of cisplatin-induced acute kidney injury. Kidney Int 73:1374-1384. https://doi.org/10.1038/ki.2008.106 
  16. KFDA (2012) Good laboratory practice regulation for non-clinical laboratory studies (Notification No. 2012-61) 
  17. OECD (1998) OECD Guideline for testing of chemicals, Test No 407: Repeated dose 28-day oral toxicity study in rodents. https://doi.org/10.1787/20745788. 
  18. Son MY, Kim YD, Seol B, Lee MO, Na HJ, Yoo B, Chang JS, Cho YS (2017) Biomarker discovery by modeling Behcet's disease with patient-specific human induced Pluripotent stem cells. Stem Cells Dev 26:133-145. https://doi.org/10.1089/scd.2016.0181 
  19. Derelanko MJ, Auletta CS (2014) Handbook of toxicology. CRC Press, Boca Raton, FL. https://doi.org/10.1201/b16632 
  20. Han ZZ, Xu HD, Kim KH, Ahn T, Bae J, Lee J, Gil K, Lee J, Woo S, Yoo H, Lee H, Kim K, Park C, Zhang H, Song S (2010) Reference data of the main physiological parameters in control Sprague-Dawley rats from pre-clinical toxicity studies. Lab Anim Res 26:153-164. https://doi.org/10.5625/lar.2010.26.2.153 
  21. Delire B, Starkel P, Leclercq I (2015) Animal models for fibrotic liver diseases: what we have, what we need, and what is under development. J Clin Transl Hepatol 3:53-66. https://doi.org/10.14218/JCTH.2014.00035 
  22. Reif S, Aeed H, Shilo Y, Reich R, Kloog Y, Kweon YO, Bruck R (2004) Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. J Hepatol 41:235-241. https://doi.org/10.1016/j.jhep.2004.04.010 
  23. Salguero Palacios R, Roderfeld M, Hemmann S, Rath T, Atanasova S, Tschuschner A, Gressner OA, Weiskirchen R, Graf J, Roeb E (2008) Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. Lab Investig 88:1192-1203. https://doi.org/10.1038/labinvest.2008.91 
  24. Starkel P, Leclercq IA (2011) Animal models for the study of hepatic fbrosis. Best Pract. Res Clin Gastroenterol 25:319-333. https://doi.org/10.1016/j.bpg.2011.02.004 
  25. Li X, Benjamin IS, Alexander B (2002) Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality. J Hepatol 36:488-493. https://doi.org/10.1016/s0168-8278(02)00011-9 
  26. Yang JM, Han DW, Xie CM, Liang QC, Zhao YC, Ma XH (1998) Endotoxins enhance hepatocarcinogenesis induced by oral intake of thioacetamide in rats. World J Gastroenterol. 4:128-132. https://doi.org/10.3748/wjg.v4.i2.128 
  27. Yeh CN, Maitra A, Lee KF, Jan YY, Chen MF (2004) Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis 25:631-636. https://doi.org/10.1093/carcin/bgh037 
  28. Mroueh M, Saab Y, Rizkallah R (2004) Hepatoprotective activity of Centaurium erythraea on acetaminophen-induced hepatotoxicity in rats. Phytother Res 18:431-433. https://doi.org/10.1002/ptr.1498 
  29. Han H, Han K, Ahn J, Park S, Kim S, Lee B, Min B, Yoon S, Oh J, Kim T (2020) Subchronic toxicity assessment of Phytolacca americana L. (Phytolaccaceae) in F344 rats. Nat Prod Commun 15:1-10. https://doi.org/10.1177/1934578X20941656 
  30. Lim KT, Lim V, Chin JH (2012) Subacute oral toxicity study of ethanolic leaves extracts of Strobilanthes crispus in rats. Asian Pac J Trop Biomed 2:948-952. https://doi.org/10.1016/S2221-1691(13)60005-2 
  31. Worasuttayangkurn L, Watcharasit P, Rangkadilok N, Suntararuks S, Khamkong P, Satayavivad J (2012) Safety evaluation of longan seed extract: acute and repeated oral administration. Food Chem Toxicol 50:3949-3955. https://doi.org/10.1016/j.fct.2012.07.068 
  32. Schyman P, Printz RL, Estes SK, Boyd KL, Shiota M, Wallqvist A (2018) Identifcation of the toxicity pathways associated with thioacetamide-induced injuries in rat liver and kidney. Front Pharmacol 9:1272. https://doi.org/10.3389/fphar.2018.01272 
  33. Daujat-Chavanieu M, Gerbal-Chaloin S (2020) Regulation of CAR and PXR expression in health and disease. Cells 9:2395. https://doi.org/10.3390/cells9112395 
  34. Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, Dijke P, Dooley S (2013) Animal models of chronic liver diseases. Am J Physiol-Gastrointest Liver Physiol 304:449-468. https://doi.org/10.1152/ajpgi.00199.2012 
  35. Wang F, Miao MX, Sun BB, Wang ZJ, Tang XG, Chen Y, Zhao KJ, Liu XD, Liu L (2017) Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp. Acta Pharmacol Sinica 38:1554-1565. https://doi.org/10.1038/aps.2017.54 
  36. McIlwain CC, Townsend DM, Tew KD (2006) Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene 25:1639-1648. https://doi.org/10.1038/sj.onc.1209373 
  37. Zhang K, Chen D, Ma K, Wu X, Hao H, Jiang S (2018) NAD (P) H: quinone oxidoreductase 1 (NQO1) as a therapeutic and diagnostic target in cancer. J Med Chem 61:6983-7003. https://doi.org/10.1021/acs.jmedchem.8b00124