Zn and Se supplementation abrogated metals-(metaloids) mixture mediated ocular-thymus toxicity via modulation of oxido-inflammatory and antiapoptotic mechanisms in female Sprague Dawley rats
DOI:
https://doi.org/10.15584/ejcem.2024.4.30Keywords:
ameliorative effects of zinc and selenium, cocktail noxious metal mixture, eye, thymusAbstract
Introduction and aim. This is an evaluation of the protective effects of Zn and Se in the eye and thymus of rats exposed to cock tail noxious metal mixtures (CNMM) (Al, Pb, Hg and Mn) in ameliorating ocular pathologies due to autoimmunity.
Material and methods. Female Sprague rats were grouped into eight (n=5) and orally exposed to various treatments for a period of 60 days: (1): the control group receive deionized water only; (2): the CNMM only group received lead acetate Pb(C2H3O2)2 (20 mg/kg), AlCl3 (35 mg/kg), HgCl2 (0.40 mg/kg) and MnCl2 (0.56 mg/kg); (3) received CNMM+ZnCl2, 0.80 mg/kg; (4) received CNMM+Na2SeO3, 1.50 mg/kg; (5) received CNMM+ZnCl2, 0.80 mg/kg and Na2SeO3, 1.50 mg/kg combination. Oxidative stress markers, nuclear factor erythroid 2-related factor 2, nuclear factor kappa B, interleukin 6, tumor necrosis factor alpha and caspase-3 and histopathological changes were determined.
Results. CNMM decreased antioxidants levels but increased malondialdehyde and nitric oxide concentrations. CNMM in creased levels of nuclear factor erythroid 2- related factor 2, and nuclear factor kappa B, interleukin 6 and tumor necrosis factor alpha and caspase-3. There was moderate retinal degeneration and total cell loss at the ganglionic cell layer in the eye; severe degenerative thymus, lymphocyte depletion and multifocal necrosis in CNMM only.
Conclusion. Supplementation with Zn and Se reduced the biochemical and histopathological changes in the eye and thymus in response to CNMM exposure.
Downloads
References
Arslan OE. Pathophysiology of Vision. In: Nano-Biomaterials For Ophthalmic Drug Delivery. 2016;57-81. doi: 10.1007/978-3-319-29346-2_4
de Paiva CS, St Leger AJ, Caspi RR. Mucosal immunology of the ocular surface. Mucosal Immunol. 2022;15(6):1143-1157. doi: 10.1038/s41385-022-00551-6
Gipson IK. The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture. Invest ophthalmol Vis Sci. 2007;48(10):4391-4398. doi: 10.1167/iovs.07-0770
Ebrahimi M, Ebrahimi M, Vergroesen JE, Aschner M, Sillanpää M. Environmental exposures to cadmium and lead as potential causes of eye diseases. J Trace Elem. Med Biol. 2023;127358. doi: 10.1016/j.jtemb.2023.127358
Vennam S, Georgoulas S, Khawaja A, Chua S, Strouthidis NG, Foster PJ. Heavy metal toxicity and the aetiology of glaucoma. Eye. 2020;34(1):129-137. doi: 10.1038/s41433-019-0672-z
Kamińska A, Romano GL, Rejdak R, et al. Influence of trace elements on neurodegenerative diseases of the eye—The glaucoma model. Int. J. Molecul Sci. 2021;22(9):4323. doi: 10.3390/ijms22094323
Stern ME, Schaumburg CS, Dana R, Calonge M, Niederkorn JY, Pflugfelder SC. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal immunology. 2010;3(5):425-442. doi: 10.1038/mi.2010.26
Knop N, Knop, E. Conjunctiva-associated lymphoid tissue in the human eye. Invest. Ophthalmol. Visual Sci. 2000;41(6):1270-1279.
Knop E, Knop N. Lacrimal drainage–associated lymphoid tissue (LDALT): a part of the human mucosal immune system. Invest. Ophthalmol. Visual Sci. 2001;42(3):566-574.
Chan JH, Amankwah R, Robins RA, Gray T, Dua HS. Kinetics of immune cell migration at the human ocular surface. Br. J. Ophthalmol. 2008;92(7):970. doi: 10.1136/bjo.2007.131003
Oduntan OA, Masige KP. A review of the role of oxidative stress in the pathogenesis of eye diseases. African Vision and Eye Health. 2011;70(4):191-199. doi: 10.4102/aveh.v70i4.116
Liu J, Man R, Ma S, Li J, Wu Q, Peng J. Atmospheric levels and health risk of polycyclic aromatic hydrocarbons (PAHs) bound to PM2. 5 in Guangzhou, China. Mar Pollut Bull. 2015;100(1):134-143. doi: 10.1016/j.marpolbul.2015.09.014
Zheng Q, Ren Y, Reinach PS, et al. Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients. Exp Eye Res. 2015;134:133-140. doi: 10.1016/j.exer.2015.02.013
Erie JC, Butz JA, Good JA, Erie EA, Burritt MF, Cameron JD. Heavy metal concentrations in human eyes. Am. J. Ophthalmol. 2005;139(5):888-893. doi: 10.1016/j.ajo.2004.12.007
Hahn P, Milam AH, Dunaief, JL. Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane. Arch. Ophthalmol. 2003;121(8):1099-1105. doi: 10.1001/archopht.121.8.1099
Ekinci M, Ceylan E, Keleş S, Çağatay HH, Apil A, Tanyıldız B, Uludag G. Toxic effects of chronic mercury exposure on the retinal nerve fiber layer and macular and choroidal thickness in industrial mercury battery workers. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2014;20:1284. doi: 10.12659/MSM.890756
Shu DY, Chaudhary S, Cho KS, et al. Role of oxidative stress in ocular diseases: a balancing act. Metabolites. 2023;13(2):187. doi: 10.3390/metabo13020187
Caspi RR. A look at autoimmunity and inflammation in the eye. J. Clin. Invest. 2010;120(9):3073-3083. doi: 10.1172/JCI42440
Hsu SM, Yang CH, Teng YT, et al. Suppression of the reactive oxygen response alleviates experimental autoimmune uveitis in mice. Int J Mol Sci. 2020;21(9):3261. doi. 10.3390/ijms21093261
Choi Y, Jung K, Kim HJ, et al. Attenuation of experimental autoimmune uveitis in Lewis rats by betaine. Exp. Neurol. 2021;30(4):308. doi: 10.5607/en21011
Nasi, M, Pinti, M, Troiano, L, Cossarizza, A. Physiology and Immunology of the Thymus Gland. In: Thymus Gland Pathology. Lavini C, Moran CA, Morandi U, Schoenhuber R (eds). Milano. Springer; 2008:19-30. doi: 10.1007/978-88-470-0828-1_3
Yan F, Mo X, Liu J, Ye S, Zeng X, Chen D. Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling. Mol Med Rep. 2017;16(5):7175-7184. doi: 10.3892/mmr.2017.7525
Lunin SM, Novoselova EG. Thymus hormones as prospective anti-inflammatory agents. Expert Opin. Ther Targets. 2010;14(8):775-786. doi: 10.1517/14728222.2010.499127
Paust S, Cantor H. Regulatory T cells and autoimmune disease. Immunol. Rev. 2005;204(1):195-207. doi: 10.1111/j.0105-2896.2005.00247.x
Elmore SA. Enhanced histopathology of the thymus. Toxicol. Pathol. 2006;34(5):656-665. doi: 10.1080/01926230600865556
Kim HS, Kim YJ, Seo YR. An overview of carcinogenic heavy metal: molecular toxicity mechanism and prevention. J Cancer Prev. 2015;20(4):232.
Ficek W. Heavy metals and the mammalian thymus: in vivo and in vitro investigations. Toxicology and Industrial Health. 1994;10(3):191-201. doi: 10.1177/074823379401000308
Sharma R, Kantwa SM. Effects of Vitamin C on Lead Induced Developing Thymus in Mice: A review. Un J Envir Res Tech. 2011;1(2):91-102.
Bhattacharyya MH, Wilson AK, Rajan SS, Jonah M. Biochemical pathways in cadmium toxicity. In: Molecular Biology and Toxicology of Metal. RK Zalups, J Koropatnick (eds), London and New York. Taylor and Francis. 2000:34-74.
Hsu PC, Guo, YL. Antioxidant nutrients and lead toxicity. Toxicology 2002;180(1):33-44. doi: 10.1016/s0300-483x(02)00380-3
Dike C, Orish CN, Ezejiofor AN, et al. Selenium and zinc alleviate quaternary metal mixture-induced neurotoxicity in rats by inhibiting oxidative damage and modulating the expressions of NF-kB and Nrf2/Hmox-1 pathway. IBRO Neurosci. Rep. 2023: 1(15):57-67 doi: 10.1016/j.ibneur.2023.06.003
Zhang D, Liu J, Gao J, et al. Zinc supplementation protects against cadmium accumulation and cytotoxicity in Madin-Darby bovine kidney cells. PLoS One. 2014 ;9(8):e103427. doi: 10.1371/journal.pone.0103427
Babaknejad N, Moshtaghie AA, Nayeri H, Hani M, Bahrami S. Protective role of zinc and magnesium against cadmium nephrotoxicity in male Wistar rats. Biol Trace Elem. Res. 2016;174:112-120. doi: 10.1007/s12011-016-0671-x
El-Boshy ME, Risha EF, Abdelhamid FM, Mubarak MS, Hadda TB. Protective effects of selenium against cadmium induced hematological disturbances, immunosuppressive, oxidative stress and hepatorenal damage in rats. J Trace Elem Med Biol. 2015;29:104-110. doi: 10.1016/j.jtemb.2014.05.009
Anyanwu BO, Orish CN, Ezejiofor AN, Nwaogazie IL, Orisakwe OE. Neuroprotective effect of Costus afer on low dose heavy metal mixture (lead, cadmium and mercury) induced neurotoxicity via antioxidant, anti-inflammatory activities. Toxicol Rep. 2020;7:1032-1038.
Messarah M, Klibet F, Boumendjel A, et al. Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats. Exp Pathol. 2012;64(3):167-174.
Okoye EA, Bocca B, Ruggieri, F, et al. Arsenic and toxic metals in meat and fish consumed in Niger delta, Nigeria: employing the margin of exposure approach in human health risk assessment. Food Chem. Toxicol. 2022 ;159:112767. doi: 10.1016/j.fct.2021.112767
Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra W. Selenium: biochemical role as a component of glutathione peroxidase. Science 1973;179(4073):588-590. doi: 10.1126/science.179.4073.588
Ellman GL. Tissue sulfhydryl groups. Arch Biochem. Biophys. 1959;82(1):70-77.
Claiborne AJFCP. Handbook of Methods for Oxygen Radical Research. Florida. CRC Press, Boca Raton. 1985:283-284.
Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-3175. doi. 10.1016/S0021-9258(19)45228-9
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 1979;95(2):351-358. doi: 10.1016/0003-2697(79)90738
Oktem G, Uysal A, Oral O, et al. Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Exp Toxicol Pathol. 2012;64(5):471-479.
Sosroseno W, Musa M, Ravichandran M, Ibrahim MF, Bird PS, Seymour GJ. Effect of inhibition of inducible nitric oxide synthase (iNOS) on the murine splenic immune response induced by Aggregatibacter (Actinobacillus) actinomycetemcomitans lipopolysaccharide. Eur J Oral Sci. 2008;116(1):31-36.
Huang YC, Chang WC, Shan YH, et al. Toxic metals increase serum tumor necrosis factor-α levels, modified by essential elements and different types of tumor necrosis factor-α promoter single-nucleotide polymorphisms. Epidemiology. 2017:28:S113-S120. doi: 10.1097/EDE.0000000000000738
Zhu L, Yi X, Ma C, et al. Betulinic acid attenuates oxidative stress in the thymus induced by acute exposure to T-2 toxin via regulation of the MAPK/Nrf2 signaling pathway. Toxins. 2020 ;12(9):540. doi: 10.3390/toxins12090540
Ferenčík M, Ebringer L. Modulatory effects of selenium and zinc on the immune system. Folia Microbiol. 2003;48:417-426. doi: 10.1007/BF02931378
Ha KN, Chen Y, Cai J, Sternberg P. Increased glutathione synthesis through an ARE-Nrf2–dependent pathway by zinc in the RPE: implication for protection against oxidative stress. Invest Ophthalmol Visual Sci. 2006;47(6):2709-2715. doi: 10.1167/iovs.05-1322
Böhm EW, Buonfiglio F, Voigt AM, et al. Oxidative stress in the eye and its role in the pathophysiology of ocular diseases. Redox Biol. 2023;102967. doi: 10.1016/j.redox.2023.102967
Almeer RS, Soliman D, Kassab RB, et al. Royal jelly abrogates cadmium-induced oxidative challenge in mouse testes: involvement of the Nrf2 pathway. Int J Mol Sci. 2018;19(12):3979. doi: 10.3390/ijms19123979
Brieger K, Schiavone S, Miller Jr FJ, Krause, KH. Reactive oxygen species: from health to disease. Swiss Med Wkly. 2012;142(3334):w13659-w13659. doi: 10.4414/smw.2012.13659
Machoń-Grecka A, Dobrakowski M, Boroń M, Lisowska G, Kasperczyk A, Kasperczyk S. The influence of occupational chronic lead exposure on the levels of selected pro-inflammatory cytokines and angiogenic factors. Hum Exp Toxicol. 2017;36(5):467-473. doi: 10.1177/0960327117703688
Li B, Cui W, Tan Y, et al. Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J Cell Mol Med. 2014;18(5):895-906. doi: 10.1111/jcmm.12239
Buha A, Baralić K, Djukic-Cosic D, et al. The role of toxic metals and metalloids in Nrf2 signaling. Antioxidants. 2021;10(5):630. doi: 10.3390/antiox10050630
Zhou Q, Gu Y, Yue X, et al. Combined toxicity and underlying mechanisms of a mixture of eight heavy metals. Mol Med Rep. 2017;15(2):859-866. doi: 10.3892/mmr.2016.6089
Ahmed S, Khoda SME, Rekha RS, et al. Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Environ. Health Perspect. 2011;119(2):258-264. doi: 10.1289/ehp.1002086
Bao B, Prasad AS, Beck FW, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010;91(6):1634-1641. doi: 10.3945/ajcn.2009.28836
Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat Rev Drug Discovery. 2021;20(9):689-709. doi: 10.1038/s41573-021-00233-1
Vomund S, Schäfer A, Parnham MJ, Brüne B, Von Knethen A. Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci. 2017;18(12):2772. doi: 10.3390/ijms18122772
Turner TT, Lysiak JJ. Oxidative stress: a common factor in testicular dysfunction. J Androl. 2008;29(5):488-498. doi: 10.2164/jandrol.108.005132
Aziz NM, Kamel MY, Mohamed MS, Ahmed SM. Antioxidant, anti-inflammatory, and anti-apoptotic effects of zinc supplementation in testes of rats with experimentally induced diabetes. Appl Physiol Nutr Metab 2018;43(10):1010-1018. doi: 10.1139/apnm-2018-0070
Ruan Y, Jiang S, Musayeva A, Gericke A. Oxidative stress and vascular dysfunction in the retina: Therapeutic strategies. Antioxidants. 2020;9(8):76.
Vallabh NA, Romano V, Willoughby CE. Mitochondrial dysfunction and oxidative stress in corneal disease. Mitochondrion. 2017;36:103-113. doi: 10.1016/j.mito.2017.05.009
Shoeb M, Zhang M, Xiao T, Syed MF, Ansari NH. Amelioration of endotoxin-induced inflammatory toxic response by a metal chelator in rat eyes. Invest Ophthalmol Visual Sci. 2018;59(1):31-38. doi: 10.1167/iovs.17-22172
Hsueh YJ, Chen YN, Tsao YT, Cheng CM, Wu WC, Chen HC. The pathomechanism, antioxidant biomarkers, and treatment of oxidative stress-related eye diseases. Int J Mol Sci. 2022;23(3):1255. doi: 10.3390/ijms23031255
Anka AU, Usman AB, Kaoje AN, et al. Potential mechanisms of some selected heavy metals in the induction of inflammation and autoimmunity. Eur J Inflammation. 2022;20:1721727X221122719. doi: 10.1177/1721727X22112271
Sirivarasai J, Wananukul W, Kaojarern S, et al. Association between inflammatory marker, environmental lead exposure, and glutathione S-transferase gene. BioMed Res Int. 2013;2013(1):474963 doi: 10.1155/2013/474963
Terpiłowska S, Siwicki AK. Review paper The role of selected microelements: selenium, zinc, chromium and iron in immune system. Cent Eur J Immunol. 2011 ;36(4):303-307.
Gera R, Singh V, Mitra S, et al. Arsenic exposure impels CD4 commitment in thymus and suppress T cell cytokine secretion by increasing regulatory T cells. Sci Rep. 2017;7(1):7140. doi: 10.1038/s41598-017-07271-z
Chen Y, Wang S, Alemi H, Dohlman T, Dana, R. Immune regulation of the ocular surface. Exp Eye Res. 2022;218:109007. doi: 10.1016/j.exer.2022.109007
Chauhan SK, Dana R. Role of Th17 cells in the immunopathogenesis of dry eye disease. Mucosal Immunol. 2009;2(4):375-376. doi: 10.1038/mi.2009.21
Amouzegar A, Chauhan SK, Dana R. Alloimmunity and tolerance in corneal transplantation. J Immunol. 2016 ;196(10):3983-3991 doi: 10.4049/jimmunol.1600251
Yin X, Qiu Y, Li Z, et al. Longdan Xiegan Decoction alleviates experimental autoimmune uveitis in rats by inhibiting Notch signaling pathway activation and Th17 cell differentiation. Biomed Pharmacother. 2021;136:111291. doi: 10.1016/j.biopha.2021.111291
Foulsham W, Marmalidou A, Amouzegar A, Coco G, Chen Y, Dana R. The function of regulatory T cells at the ocular surface. The ocular surface 2017;15(4):652-659. doi: 10.1016/j.jtos.2017.05.013
Schwarz M, Lossow K, Kopp JF, Schwerdtle T, Kipp AP. Crosstalk of Nrf2 with the trace elements selenium, iron, zinc, and copper. Nutrients. 2019;11(9):2112. doi: 10.3390/nu11092112
O’Sullivan BJ, Yekollu S, Ruscher R, et al. Autoimmune-mediated thymic atrophy is accelerated but reversible in RelB-deficient mice. Front Immunol. 2018;9:1092. doi: 10.3389/fimmu.2018.01092
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 European Journal of Clinical and Experimental Medicine

This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.




