Abstract
Metallothionein-3 (MT3) is an antioxidant protein that alters after exposure to heavy metals. In this study, we investigated the hepatic and renal expression of MT3 gene following exposure to lead acetate (PbAc) alone and PbAc plus CoQ10 as an adjuvant antioxidant. Twenty-four rats were allocated into three groups, including control, PbAc (free access to drinking water contaminated with PbAc at 1 g/100 ml), and PbAc plus CoQ10 (10 mg/kg/day Oral). After 28 consecutive days of treatment, the mRNA expression of MT3 and Cyt-c genes and MT3 protein levels were assessed using real-time PCR and immunosorbent assay. The serum lipid profile was also monitored in the three groups. PbAc exposure significantly reduced the hepatic and renal MT3 mRNA and protein expression compared to the control group. This reduction was significantly increased with addition of CoQ10 to levels near those of the control group. The hepatic and renal expression of Cyt-c mRNA increased after treatment with PbAc, while such effect was reversed after addition of CoQ10. Alteration in lipid profile including increased cholesterol and low-density lipoprotein levels were observed after PbAc exposure which were counteracted by CoQ10. Our results confirm the cytotoxic effects of acute lead exposure manifested as changes in the serum lipid profile and cellular levels of Cyt-c mRNA. These cytotoxic effects may have been caused by decreased MT3 gene expression and be reduced by the protective role of CoQ10.
Similar content being viewed by others
References
Togao M, Nakayama SM, Ikenaka Y, Mizukawa H, Makino Y, Kubota A, Matsukawa T, Yokoyama K, Hirata T, Ishizuka M (2020) Bioimaging of Pb and STIM1 in mice liver, kidney and brain using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) and immunohistochemistry. Chemosphere 238:124581. https://doi.org/10.1016/j.chemosphere.2019.124581
Ericson B, Landrigan P, Taylor MP, Frostad J, Caravanos J, Keith J, Fuller R (2016) The global burden of lead toxicity attributable to informal used lead-acid battery sites. Ann Glob Health 82(5):686–699. https://doi.org/10.1016/j.aogh.2016.10.015
S Yousef AO, A Fahad A, Abdel Moneim AE, Metwally DM, El-Khadragy MF, Kassab RB (2019) The neuroprotective role of coenzyme Q10 against lead acetate-induced neurotoxicity is mediated by antioxidant, anti-inflammatory and anti-apoptotic activities. Int J Environ Res Public Health 16(16):2895. https://doi.org/https://doi.org/10.3390/ijerph16162895
Dai S, Yin Z, Yuan G, Lu H, Jia R, Xu J, Song X, Li L, Shu Y, Liang X (2013) Quantification of metallothionein on the liver and kidney of rats by subchronic lead and cadmium in combination. Environ Toxicol Pharmacol 36(3):1207–1216. https://doi.org/10.1016/j.etap.2013.10.003
Abdelhamid FM, Mahgoub HA, Ateya AI (2020) Ameliorative effect of curcumin against lead acetate–induced hemato-biochemical alterations, hepatotoxicity, and testicular oxidative damage in rats. Environ Sci Pollut Res. https://doi.org/10.1007/s11356-020-07718-3
Thirumoorthy N, Kumar KM, Sundar AS, Panayappan L, Chatterjee M (2007) Metallothionein: an overview. World J Gastroenterol WJG 13(7):993. https://doi.org/10.3748/wjg.v13.i7.993
Rahman A, Khan KM, Rao MS (2018) Exposure to low level of lead during preweaning period increases metallothionein-3 expression and dysregulates divalent cation levels in the brain of young rats. Neurotoxicology 65:135–143. https://doi.org/10.1016/j.neuro.2018.02.008
Sabolić I, Breljak D, Škarica M, Herak-Kramberger CM (2010) Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23(5):897–926. https://doi.org/10.1007/s10534-010-9351-z
Thirumoorthy N, Sunder AS, Kumar KM, Ganesh G, Chatterjee M (2011) A review of metallothionein isoforms and their role in pathophysiology. World J Surg Oncol 9(1):1–7. https://doi.org/10.1186/1477-7819-9-54
Juárez-Rebollar D, Rios C, Nava-Ruíz C, Méndez-Armenta M (2017) Metallothionein in brain disorders. Oxid Med Cell Longev. https://doi.org/10.1155/2017/5828056
Al-Waeli A, Pappas A, Zoidis E, Georgiou C, Fegeros K, Zervas G (2012) The role of selenium in cadmium toxicity: interactions with essential and toxic elements. Br Poult Sci 53(6):817–827. https://doi.org/10.1080/00071668.2012.751523
Sabolić I, Škarica M, Ljubojević M, Breljak D, Herak-Kramberger CM, Crljen V, Ljubešić N (2018) Expression and immunolocalization of metallothioneins MT1, MT2 and MT3 in rat nephron. J Trace Elem Med Biol 46:62–75. https://doi.org/10.1016/j.jtemb.2017.11.011
Zoidis E, Papadomichelakis G, Pappas AC, Theodorou G, Fegeros K (2019) Effects of selenium and cadmium on breast muscle fatty-acid composition and gene expression of liver antioxidant proteins in broilers. Antioxidants 8(5):147. https://doi.org/10.3390/antiox8050147
Shen X, Liu W, Chen Y, Guo Y, Gao M, Chen W, Liu Y, Liu S (2019) Diagnostic significance of metallothionein members in recognizing cadmium exposure in various organs under low-dose exposure. Chemosphere 229:32–40. https://doi.org/10.1016/j.chemosphere.2019.04.192
Carpenter M, Shami Shah A, DeSilva S, Gleaton A, Su A, Goundie B, Croteau M, Stevenson M, Wilcox D, Austin R (2016) Thermodynamics of Pb (II) and Zn (II) binding to MT-3, a neurologically important metallothionein. Metallomics 8(6):605–617. https://doi.org/10.1039/c5mt00209e
Pérez-Zúñiga C, Leiva-Presa À, Austin RN, Capdevila M, Palacios Ò (2019) Pb (ii) binding to the brain specific mammalian metallothionein isoform MT3 and its isolated αMT3 and βMT3 domains. Metallomics 11(2):349–361. https://doi.org/10.1039/c8mt00294k
Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE (2001) Metallothionein III is reduced in Alzheimer’s disease. Brain Res 894(1):37–45. https://doi.org/10.1016/s0006-8993(00)03196-6
Chetcuti A, Adams LJ, Mitchell PB, Schofield PR (2008) Microarray gene expression profiling of mouse brain mRNA in a model of lithium treatment. Psychiatr Genet 18(2):64–72. https://doi.org/10.1097/YPG.0b013e3282fb0051
Chander K, Vaibhav K, Ahmed ME, Javed H, Tabassum R, Khan A, Kumar M, Katyal A, Islam F, Siddiqui MS (2014) Quercetin mitigates lead acetate-induced behavioral and histological alterations via suppression of oxidative stress, Hsp-70, Bak and upregulation of Bcl-2. Food Chem Toxicol 68:297–306. https://doi.org/10.1016/j.fct.2014.02.012
Dewanjee S, Dua TK, Khanra R, Das S, Barma S, Joardar S, Bhattacharjee N, Zia-Ul-Haq M, Jaafar HZ (2015) Water spinach, Ipomoea aquatic (Convolvulaceae), ameliorates lead toxicity by inhibiting oxidative stress and apoptosis. PLoS ONE 10(10):e0139831. https://doi.org/10.1371/journal.pone.0139831
Flora G, Gupta D, Tiwari A (2012) Toxicity of lead: a review with recent updates. Interdiscip Toxicol 5(2):47–58. https://doi.org/10.2478/v10102-012-0009-2
Khanra R, Dewanjee S, Dua TK, Sahu R, Gangopadhyay M, De Feo V, Zia-Ul-Haq M (2015) Abroma augusta L.(Malvaceae) leaf extract attenuates diabetes induced nephropathy and cardiomyopathy via inhibition of oxidative stress and inflammatory response. J Transl Med 13(1):1–14. https://doi.org/10.1186/s12967-014-0364-1
Dua TK, Dewanjee S, Khanra R, Joardar S, Barma S, Das S, Zia-Ul-Haq M, De Feo V (2016) Cytoprotective and antioxidant effects of an edible herb, Enhydra fluctuans Lour.(Asteraceae), against experimentally induced lead acetate intoxication. PLoS ONE 11(2):148757. https://doi.org/10.1371/journal.pone.0148757
Tomasetti M, Littarru G, Stocker R, Alleva R (1999) Coenzyme Q10 enrichment decreases oxidative DNA damage in human lymphocytes. Free Radical Biol Med 27(9–10):1027–1032. https://doi.org/10.1016/s0891-5849(99)00132-x
Xu Z, Huo J, Ding X, Yang M, Li L, Dai J, Hosoe K, Kubo H, Mori M, Higuchi K (2017) Coenzyme Q10 improves lipid metabolism and ameliorates obesity by regulating CaMKII-mediated PDE4 inhibition. Sci Rep 7(1):1–12. https://doi.org/10.1038/s41598-017-08899-7
Rivara MB, Yeung CK, Robinson-Cohen C, Phillips BR, Ruzinski J, Rock D, Linke L, Shen DD, Ikizler TA, Himmelfarb J (2017) Effect of coenzyme Q10 on biomarkers of oxidative stress and cardiac function in hemodialysis patients: the CoQ10 biomarker trial. Am J Kidney Dis 69(3):389–399. https://doi.org/10.1053/j.ajkd.2016.08.041
Omar HA, Almalki WH, Shamardl H, Mahdy AY, Abd El-Latif HA (2016) Lipoic acid and coenzyme Q10 protect against lead-induced toxicity in rats with metabolic syndrome. Int J Pharmacol 12(3):146–153
Baranowska-Bosiacka I, Strużyńska L, Gutowska I, Machalińska A, Kolasa A, Kłos P, Czapski G, Kurzawski M, Prokopowicz A, Marchlewicz M (2013) Perinatal exposure to lead induces morphological, ultrastructural and molecular alterations in the hippocampus. Toxicology 303:187–200. https://doi.org/10.1016/j.tox.2012.10.027
Rauscher FM, Sanders RA, Watkins JB III (2001) Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 15(1):41–46. https://doi.org/10.1002/1099-0461(2001)15:1%3c41::aid-jbt5%3e3.0.co;2-z
Amanpour P, Khodarahmi P, Salehipour M (2020) Protective effects of vitamin E on cadmium-induced apoptosis in rat testes. Naunyn Schmiedebergs Arch Pharmacol 393(3):349–358. https://doi.org/10.1007/s00210-019-01736-w
Alian NS, Khodarahmi P, Naseh V (2018) The effect of cadmium on apoptotic genes mRNA expression of Bax and Bcl-2 in small intestine of rats. Iran J Pathol 13(4):408–414
Rouhani F, Khodarahmi P, Naseh V (2019) NGF, BDNF and Arc mRNA expression in the hippocampus of rats after administration of morphine. Neurochem Res 44(9):2139–2146. https://doi.org/10.1007/s11064-019-02851-z
Abdou HM, Hassan MA (2014) Protective role of omega-3 polyunsaturated fatty acid against lead acetate-induced toxicity in liver and kidney of female rats. Biomed Res Int. https://doi.org/10.1155/2014/435857
Kojima M, Masui T, Nemoto K, Degawa M (2004) Lead nitrate-induced development of hypercholesterolemia in rats: sterol-independent gene regulation of hepatic enzymes responsible for cholesterol homeostasis. Toxicol Lett 154(1–2):35–44. https://doi.org/10.1016/j.toxlet.2004.06.010
Tarugi P, Calandra S, Borella P, Vivoli G (1982) Heavy metals and experimental atherosclerosis: effect of lead intoxication on rabbit plasma lipoproteins. Atherosclerosis 45(2):221–234. https://doi.org/10.1016/0021-9150(82)90140-x
Newairy A-SA, Abdou HM (2009) Protective role of flax lignans against lead acetate induced oxidative damage and hyperlipidemia in rats. Food Chem Toxicol 47(4):813–818. https://doi.org/10.1016/j.fct.2009.01.012
El-Boshy ME, Refaat B, Qasem AH, Khan A, Ghaith M, Almasmoum H, Mahbub A, Almaimani RA (2019) The remedial effect of Thymus vulgaris extract against lead toxicity-induced oxidative stress, hepatorenal damage, immunosuppression, and hematological disorders in rats. Environ Sci Pollut Res 26(22):22736–22746. https://doi.org/10.1007/s11356-019-05562-8
Ohara Y, Peterson TE, Harrison DG (1993) Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 91(6):2546–2551. https://doi.org/10.1172/JCI116491
Paunović MG, Matić MM, Ognjanović BI, Saičić ZS (2017) Antioxidative and haematoprotective activity of coenzyme Q10 and vitamin E against cadmium-induced oxidative stress in Wistar rats. Toxicol Ind Health 33(10):746–756. https://doi.org/10.1177/0748233717725480
Tarry-Adkins JL, Fernandez-Twinn DS, Hargreaves IP, Neergheen V, Aiken CE, Martin-Gronert MS, McConnell JM, Ozanne SE (2016) Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth. Am J Clin Nutr 103(2):579–588. https://doi.org/10.3945/ajcn.115.119834
Vašák M, Meloni G (2017) Mammalian metallothionein-3: New functional and structural insights. Int J Mol Sci 18(6):1117. https://doi.org/10.3390/ijms18061117
Sens MA, Somji S, Garrett SH, Beall CL, Sens DA (2001) Metallothionein isoform 3 overexpression is associated with breast cancers having a poor prognosis. Am J Pathol 159(1):21–26. https://doi.org/10.1016/S0002-9440(10)61668-9
Tsui K-H, Hou C-P, Chang K-S, Lin Y-H, Feng T-H, Chen C-C, Shin Y-S, Juang H-H (2019) Metallothionein 3 is a hypoxia-upregulated oncogene enhancing cell invasion and tumorigenesis in human bladder carcinoma cells. Int J Mol Sci 20(4):980. https://doi.org/10.3390/ijms20040980
Bonaventura G, La Cognata V, Iemmolo R, Zimbone M, Contino A, Maccarrone G, Failla B, Barcellona ML, Conforti FL, D’Agata V (2018) Ag-NPs induce apoptosis, mitochondrial damages and MT3/OSGIN2 expression changes in an in vitro model of human dental-pulp-stem-cells-derived neurons. Neurotoxicology 67:84–93. https://doi.org/10.1016/j.neuro.2018.04.014
Tahmasbpour E, Ghanei M, Qazvini A, Vahedi E, Panahi Y (2016) Gene expression profile of oxidative stress and antioxidant defense in lung tissue of patients exposed to sulfur mustard. Mutat Res 800:12–21. https://doi.org/10.1016/j.mrgentox.2016.03.006
Somji S, Garrett SH, Sens MA, Gurel V, Sens DA (2004) Expression of metallothionein isoform 3 (MT-3) determines the choice between apoptotic or necrotic cell death in Cd+ 2-exposed human proximal tubule cells. Toxicol Sci 80(2):358–366. https://doi.org/10.1093/toxsci/kfh158
Bousleiman J, Pinsky A, Ki S, Su A, Morozova I, Kalachikov S, Wiqas A, Silver R, Sever M, Austin RN (2017) Function of metallothionein-3 in neuronal cells: do metal ions alter expression levels of MT3? Int J Mol Sci 18(6):1133. https://doi.org/10.3390/ijms18061133
Wong DL, Merrifield-MacRae ME, Stillman MJ (2017) Lead (II) binding in metallothioneins. Metal Ionsin Life Sciences, ed A Sigel, H Sigel and RKO Sigel 17:241. https://doi.org/10.1515/9783110434330-009
La Guardia PG, Alberici LC, Ravagnani FG, Catharino RR, Vercesi AE (2013) Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation. Front Physiol 4:103. https://doi.org/10.3389/fphys.2013.00103
El-Tantawy WH (2016) Antioxidant effects of Spirulina supplement against lead acetate-induced hepatic injury in rats. J Tradit Complement Med 6(4):327–331. https://doi.org/10.1016/j.jtcme.2015.02.001
Acknowledgments
The results described in this paper were based on a student thesis.
Author information
Authors and Affiliations
Contributions
PK designed the research. PK and AAM conducted the studies. PK analyzed the data. PK interpreted the results. PK and AAM wrote the manuscript. All authors read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflicts of interest.
Ethical approval
The Ethics Committee of the Islamic Azad University-Parand Branch approved and oversaw this study (IR.IAU.PIAU.REC.1399.003).
Research involving human participants
No human sample was used.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Mazandaran, A.A., Khodarahmi, P. The protective role of Coenzyme Q10 in metallothionein-3 expression in liver and kidney upon rats’ exposure to lead acetate. Mol Biol Rep 48, 3107–3115 (2021). https://doi.org/10.1007/s11033-021-06311-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-021-06311-2