Abstract
The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.
Similar content being viewed by others
References
Chen Y, Santella RM, Kibriya MG, Wang Q, Kappil M, Verret WJ, Graziano JH, Ahsan H (2007) Association between arsenic exposure from drinking water and plasma levels of soluble cell adhesion molecules. Environ Health Perspect 115:1415–1420. doi:10.1289/ehp.1027
Chowdhury UK, Biswas BK, Chowdhury TR, Samanta G, Mandal BK, Basu GC, Chanda CR, Lodh D, Saha KC, Mukherjee SK, Roy S, Kabir S, Quamruzzaman Q, Chakraborti D (2000) Groundwater arenic contamination in Bangladesh and West Bengal, India. Environ Health Perspect 108:393–397. doi:10.2307/3454378
Brinkel J, Khan MH, Kraemer A (2009) A systematic review of arsenic exposure and its social and mental health effects with special reference to Bangladesh. Int J Environ Res Public Health 6:1609–1619. doi:10.3390/ijerph6051609
Bhattacharya R, Chatterjee D, Nath B, Jana J, Jacks G, Vahter M (2003) High arsenic groundwater: mobilization, metabolism and mitigation: an overview in the Bengal delta plain. Mol Cell Biochem 253:347–355. doi:10.1023/A:1026001024578
Paul S, Das N, Bhattacharjee P, Banerjee M, Das JK, Sarma N, Sarkar A, Bandyopadhyay AK, Sau TJ, Basu S, Banerjee S, Majumder P, Giri AK (2013) Arsenic-induced toxicity and carcinogenicity: a two-wave cross-sectional study in arsenicosis individuals in West Bengal, India. J Expo Sci Environ Epidemiol 23:156–162. doi:10.1038/jes.2012.91
Flora SJ (2011) Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med 51:257–281. doi:10.1016/j.freeradbiomed.2011.04.008
Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, Rhodesd CJ, Valkoc M (2011) Arsenic: toxicity, oxidative stress and human disease. J Appl Toxicol 31:95–107. doi:10.1002/jat.1649
Santra A, Das GJ, De BK, Roy B, Guha Mazumder DN (1999) Hepatic manifestations in chronic arsenic toxicity. Indian J Gastroenterol 18:152–155
Guha Mazumder DN (2005) Effect of chronic intake of arsenic contaminated water on liver. Toxicol Appl Pharmacol 206:169–175. doi:10.1016/j.taap.2004.08.025
Muthumani M, Miltonprabu S (2012) Silibinin potentially protects arsenic-induced oxidative hepatic dysfunction in rats. Toxicol Mech Methods 22:277–288. doi:10.3109/15376516.2011.647113
Nutt LK, Gogvadze V, Uthaisang W, Mirnikjoo B, McConkey DJ, Orrenius S (2005) Indirect effects of Bax and Bak initiate the mitochondrial alterations that lead to cytochrome c release during arsenic trioxide-induced apoptosis. Cancer Biol Ther 4:459–467. doi:10.4161/cbt.4.4.1652
Brouillet E, Conde F, Beal MF, Hantraye P (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog Neurobiol 59:427–468. doi:10.1016/S0301-0082(99)00005-2
Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646–653. doi:10.1002/ana.410410514
Santra A, Chowdhury A, Ghatak S, Biswas A, Dhali GK (2007) Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine. Toxicol Appl Pharmacol 220:146–155. doi:10.1016/j.taap.2006.12.029
Das J, Ghosh J, Manna P, Sil PC (2010) Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCdelta-JNK pathway. PLoS One 5:e12602. doi:10.1371/journal.pone.0012602
Mishra D, Mehta A, Flora SJ (2008) Reversal of arsenic-induced hepatic apoptosis with combined administration of DMSA and its analogues in guinea pigs: role of glutathione and linked enzymes. Chem Res Toxicol 21:400–407. doi:10.1021/tx700315a
Namgung U, Xia Z (2001) Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase. J Neurosci 20:6442–6451
Ramjiawan A, Bagchi RA, Albak L, Czubryt MP (2013) Mechanism of cardiomyocyte PGC-1a gene regulation by ERRa. Cell Biol 91:148–154. doi:10.1139/bcb-2012-0080
Gleyzer N, Vercauteren K, Scarpulla RC (2005) Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol 25:1354–1366. doi:10.1128/MCB.25.4.1354-1366.2005
Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–1124. doi:10.1016/S0092-8674(00)80611-X
Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271. doi:10.1016/j.cmet.2005.03.002
Sharma DR, Sunkaria A, Wani WY, Sharma RK, Kandimalla RJ, Bal A, Gill KD (2013) Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression. Toxicol Appl Pharmacol 273:365–380. doi:10.1016/j.taap.2013.09.012
Prakash C, Kamboj VK, Ahlawat P, Kumar V (2015) Structural and molecular alterations in arsenic-induced hepatic oxidative stress in rats: a FTIR study. Toxicol Environ Chem 97:1408–1421. doi:10.1080/02772248.2015.1102425
Majumdar S, Karmakar S, Maiti A, Choudhury M, Ghosh A, Das AS, Mitra C (2011) Arsenic-induced hepatic mitochondrial toxicity in rats and its amelioration by dietary phosphate. Environ Toxicol Pharmacol 31:107–118. doi:10.1016/j.etap.2010.09.011
Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J (2013) Toxicity of arsenic (III) on isolated liver mitochondria: a new mechanistic approach. Iran J Pharm Res 12:121–138
Flora SJ, Chouhan S, Kannan GM, Mittal M, Swarnkar H (2008) Combined administration of taurine and monoisoamyl DMSA protects arsenic induced oxidative injury in rats. Oxidative Med Cell Longev 1:39–45. doi:10.4161/oxim.1.1.6481
Prakash C, Soni M, Kumar V (2015) Biochemical and molecular alterations following arsenic-induced oxidative stress and mitochondrial dysfunction in rat brain. Biol Trace Elem Res 167:121–129. doi:10.1007/s12011-015-0284-9
Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in isolated brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137. doi:10.1046/j.1471-4159.1999.0731127.x
Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357
Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676
Kumar V, Bal A, Gill KD (2009) Susceptibility of mitochondrial superoxide dismutase to aluminium induced oxidative damage. Toxicology 255:117–123. doi:10.1016/j.tox.2008.10.009
Lowry OH, Rosenbrough NJ, Farr A, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Jain A, Yadav A, Bozhkov AI, Padalko VI, Flora SJ (2011) Therapeutic efficacy of silymarin and naringenin in reducing arsenic-induced hepatic damage in young rats. Ecotoxicol Environ Saf 74:607–614. doi:10.1016/j.ecoenv.2010.08.002
Miltonprabu S, Sumedha NC (2014) Arsenic-induced hepatic mitochondrial toxicity in rats and its amelioration by diallyl trisulfide. Toxicol Mech Methods 24:124–135. doi:10.3109/15376516.2013.869778
Naranmandura H, Xu S, Sawata T, Hao WH, Liu H, Bu N, Ogra Y, Lou YJ, Suzuki N (2011) Mitochondria are the main target organelle for trivalent monomethylarsonous acid (MMA(III))-induced cytotoxicity. Chem Res Toxicol 24:1094–1103. doi:10.1021/tx200156k
Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488. doi:10.1126/science.283.5407.1482
Dispersyn G, Nuydens R, Connors R, Borgers M, Geerts H (1999) Bcl-2 protects against FCCP-induced apoptosis and mitochondrial membrane potential depolarization in PC12 cells. Biochim Biophys Acta 1428:357–3571. doi:10.1016/S0304-4165(99)00073-2
Yang L, Matthews RT, Schulz JB, Klockgether T, Liao AW, Martinou JC, Penney JBJr, Hyman BT, Beal MF (1998) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2. J Neurosci 18:8145–8152
Andersson U, Scarpulla RC (2001) PGC-1 related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription I mammalian cells. Mol Cell Biol 21:3738–3749. doi:10.1128/MCB.21.11.3738-3749.2001
Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266:6–11. doi:10.1016/j.canlet.2008.02.026
Kim HK, Song IS, Lee SY, Jeong SH, Lee SR, Heo HJ, Thu VT, Kim N, Ko KS, Rhee BD, Jeong DH, Kim YN, Han J (2014) B7-H4 downregulation induces mitochondrial dysfunction and enhances doxorubicin sensitivity via the cAMP/CREB/PGC1-a signaling pathway in HeLa cells. Pflugers Arch-Eur J Physiol 466:2323–2338. doi:10.1007/s00424-014-1493-3
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Jama 297:842–857. doi:10.1001/jama.297.8.842
Vijayasarathy C, Damle S, Prabu SK, Otto CM, Avadhani NG (2003) Adaptive changes in the expression of nuclear and mitochondrial encoded subunits of cytochrome c oxidase and the catalytic activity during hypoxia. Eur J Biochem 270:871–879. doi:10.1046/j.1432-1033.2003.03447.x
Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426. doi:10.1146/annurev-pharmtox-011112-140320
Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T, Fujiwara T, Hamasaki N, Takeshita A, Sunagawa K, Tsutsui H (2005) Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 112:683–690. doi:10.1161/CIRCULATIONAHA.104.524835
Acknowledgments
The financial assistance for the present work was provided by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), New Delhi, India (Grant no. SR/FT/LS-25/2012), in the form of Fast Track Young Scientist project sanctioned to Vijay Kumar. Authors also acknowledge DST, New Delhi, for providing research infrastructural facilities in the form of FIST program (Grant no. SR/FST/LSI-534/2012) to the department.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical clearance for killing of animals was duly obtained from the Institute Animal Ethical Committee. All study protocols were performed following the guidelines of the Committee for the Purpose of Control and Supervision on Experiments on Animals, India.
Rights and permissions
About this article
Cite this article
Prakash, C., Kumar, V. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver. Biol Trace Elem Res 173, 87–95 (2016). https://doi.org/10.1007/s12011-016-0622-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-016-0622-6