Investigation of the Effect of hUC-MSCs on Autophagy and Apoptosis in Cadmium-Induced Mice Thyroid
DOI:
https://doi.org/10.58600/eurjther3091Keywords:
apoptosis, autophagy, cadmium, hUC-MSCs, mice, thyroidAbstract
Objective: Previous studies have showed that cadmium (Cd) induces structural changes in thyroid follicles. Various disorders are treated with human umbilical cord MSCs (hUC-MSCs), which are easily cultured, grown, purified, harvested, and separated. This study aimed to assess how cadmium affects autophagic and apoptotic pathways and protective effects of hUC-MSCs on thyroid gland.
Methods: Four groups (n = 6) of C57BL/6 mice were established: control, hUC-MSCs, Cadmium, and Cadmium + hUC-MSCs. Blood samples were collected and analyzed to measure levels of thyroid-stimulating hormone (TSH), triiodothyronine (fT3), and thyroxine (fT4). Hematoxylin-eosin (H&E) and Masson trichrome staining were used to determine histopathological changes. Additionally, the expression levels of apoptotic marker Caspase-3 and autophagic markers Beclin-1, LC3B, p62 were analyzed by immunohistochemistry.
Results: The histopathological results showed that Cd exposure resulted in damaged thyroid follicles, vacuoles in follicles, flattening of follicular epithelium, vascular congestion in thyroid tissues, and invasion of follicular connective tissue by mononuclear cells. The histologic structures improved when hUC-MSCs were used to treat thyroid tissues from mice induced with cadmium. There was a difference in degeneration in fibrosis (p < 0.05), and mononuclear cell infiltration (p < 0.05) between the Cd and Cd+hUC-MSCs groups. The findings demonstrated that, in contrast to control mice, Cd exposure raised serum levels of TSH while decreasing the levels of fT3 (p < 0.05) and fT4 (p < 0.01). Furthermore, immunoexpression of Caspase-3 (p < 0.01), Beclin-1 (p < 0.01), LC3B (p < 0.01) was increased; conversely, p62 (p < 0.05) was decreased in Cd-treated thyroid tissue of mice compared to control and hUC-MSCs groups.
Conclusions: We conclude that exposure to cadmium induces cellular-level damage in thyroid tissue. Cadmium can also induce apoptosis and is associated with alterations in autophagy-related pathways. hUC-MSCs may mitigate the adverse effects of Cd.
References
[1] Zoeller TR, Dowling AL, Herzig CT, Iannacone EA, Gauger KJ, Bansal R (2002) Thyroid hormone, brain development, and the environment. Environ Health Perspect. 110 Suppl 3 (Suppl 3):355-361. https://doi.org/10.1289/ehp.02110s3355
[2] Sakai K, Yamada S, Yamada K (2000) Effects of ovariectomy on parafollicular cells in the rat. Okajimas Folia Anat. Jpn. 76(6):311-319. https://doi.org/10.2535/ofaj1936.76.6_311
[3] Sawicki B (1995) Evaluation of the role of mammalian thyroid parafollicular cells. Acta Histochem. 97(4):389-399. https://doi.org/10.1016/S0065-1281(11)80064-4
[4] Yazbeck CF, Sullivan SD (2012) Thyroid disorders during pregnancy. Med Clin North Am. 96(2):235-56. https://doi.org/10.1016/j.mcna.2012.01.004
[5] Williams GR. (2008) Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol. 20(6):784-794. https://doi.org/10.1111/j.1365-2826.2008.01733.x
[6] Danzi S, Klein I (2012) Thyroid hormone and the cardiovascular system. Med Clin North Am. 96(2):257-268. https://doi.org/10.1016/j.mcna.2012.01.006
[7] Kelly GS (2000) Peripheral metabolism of thyroid hormones: a review. Altern Med Rev. 5(4):306-333. https://pubmed.ncbi.nlm.nih.gov/10956378/
[8] Harvey CB, Williams GR (2002) Mechanism of thyroid hormone action. Thyroid. 12(6):441-446. https://doi.org/10.1089/105072502760143791
[9] Järup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol. 238(3):201-208. https://doi.org/10.1016/j.taap.2009.04.020
[10] Faroon O, Ashizawa A, Wright S, Tucker P, Jenkins K, Ingerman L, Rudisill C (2012) Toxicological Profile for Cadmium. Atlanta (GA): ATSDR. https://www.ncbi.nlm.nih.gov/books/NBK158838/
[11] Matović V, Buha A, Bulat Z, Dukić-Ćosić D (2011) Cadmium toxicity revisited: focus on oxidative stress induction and interactions with zinc and magnesium. Arh Hig Rada Toksikol. 62(1):65-76. https://doi.org/10.2478/10004-1254-62-2011-2075
[12] Jancic SA, Stosic BZ (2014) Cadmium effects on the thyroid gland. Vitam Horm. 94:391-425. https://doi.org/10.1016/B978-0-12-800095-3.00014-6
[13] Abbaspanah B, Momeni M, Ebrahimi M, Mousavi SH (2018) Advances in perinatal stem cells research: a precious cell source for clinical applications. Regen Med. 13(5):595-610. https://doi.org/10.2217/rme-2018-0019
[14] Fan C, Wang D, Zhang Q, Zhou J (2013) Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo. Neural Regen Res 8:2093-2102. https://doi.org/10.3969/j.issn.1673-5374.2013.22.009
[15] Hsieh MJ, Tsai TL, Hsieh YS, Wang CJ, Chiou HL (2013) Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines. Arch Toxicol. 87(11):1927-1937. https://doi.org/10.1007/s00204-013-1047-z
[16] Funderburk SF, Wang QJ, Yue Z (2010) The Beclin 1-VPS34 complex--at the crossroads of autophagy and beyond. Trends Cell Biol. 20(6):355-362. https://doi.org/10.1016/j.tcb.2010.03.002
[17] Chiarelli R, Roccheri MC (2012) Heavy metals and metalloids as autophagy inducing agents: focus on cadmium and arsenic. Cells. 1(3):597-616. https://doi.org/10.3390/cells1030597
[18] Saidi RF, Rajeshkumar B, Shariftabrizi A, Bogdanov AA, Zheng S, Dresser K, Walter O (2014) Human adipose-derived mesenchymal stem cells attenuate liver ischemia-reperfusion injury and promote liver regeneration. Surgery. 156(5):1225-1231. https://doi.org/10.1016/j.surg.2014.05.008
[19] Benvenga S, Micali A, Ieni A, Antonelli A, Fallahi P, Pallio G, Irrera N, Squadrito F, Picciolo G, Puzzolo D, Minutoli L (2021) The Association of Myo-Inositol and Selenium Contrasts Cadmium-Induced Thyroid C Cell Hyperplasia and Hypertrophy in Mice. Front Endocrinol. 12:608697. https://doi.org/10.3389/fendo.2021.608697
[20] John T, Liu G, Tsao MS (2009) Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene. 28(S1): S14–S23. https://doi.org/10.1038/onc.2009.197
[21] Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremnes RM, Baron AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 21(20):3798-3807. https://doi.org/10.1200/JCO.2003.11.069
[22] Marcano LB, Carruyo IM, Montiel XM, Morales CB, de Soto PM (2009) Effect of cadmium on cellular viability in two species of microalgae (Scenedesmus sp. and Dunaliella viridis). Biol Trace Elem Res. 130(1):86-93. https://doi.org/10.1007/s12011-009-8316-y
[23] Hogervorst J, Plusquin M, Vangronsveld J, Nawrot T, Cuypers A,Van Hecke E, Roels HA, Carleer R, Staessen JA (2007) House dust as possible route of environmental exposure to cadmium and lead in the adult general population. Environ Res. 103(1):30-37. https://doi.org/10.1016/j.envres.2006.05.009
[24] Centeno JA, Finkelman RB, Selinus O (2016) Medical Geology: Impacts of the Natural Environment on Public Health. Geosciences. 6(1):8. https://doi.org/10.3390/geosciences6010008
[25] Nordberg GF, Nogawa K, Nordberg M, Friberg L (2007) Cadmium. In: Nordberg GF, Fowler BF, Nordberg M, Friberg L, editors. Chapter 23 in Handbook of the Toxicology of Metals. 3rd edition. Amsterdam, The Netherlands: Elsevier; 445–486.
[26] Tsutsumi R, Hiroi H, Momoeda M, Hosokawa Y, Nakazawa F, Yano T, Tsutsumi O, Taketani Y (2009) Induction of early decidualization by cadmium, a major contaminant of cigarette smoke. Fertil Steril. 91(4):1614–1617. https://doi.org/10.1016/j.fertnstert.2008.12.055
[27] Andujar P, Bensefa-Colas L, Descatha A (2010) Intoxication aiguë et chronique au cadmium [Acute and chronic cadmium poisoning]. Rev Med Interne. 31(2):107-115. https://doi.org/10.1016/j.revmed.2009.02.029
[28] Jin YH, Clark AB, Slebos RJ, Al-Refai H, Taylor JA, Kunkel TA, Resnick MA, Gordenin DA (2003) Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet. 34(3):326-329. https://doi.org/10.1038/ng1172
[29] Koçak M, Akçil E (2006) The effects of chronic cadmium toxicity on the hemostatic system. Pathophysiol Haemost Thromb. 35(6):411-416. https://doi.org/10.1159/000102047
[30] Piłat-Marcinkiewicz B, Brzóska MM, Sawicki B, Moniuszko-Jakoniuk J (2003) Structure and function of thyroid follicular cells in female rats chronically exposed to cadmium. Bull. Vet. Inst. Pulawy. 47:157–163.
[31] Bekheet SH (2011) Comparative effects of repeated administration of cadmium chloride during pregnancy and lactation and selenium protection against cadmium toxicity on some organs in immature rats' offsprings. Biol Trace Elem Res. 144(1-3):1008-1023. https://doi.org/10.1007/s12011-011-9084-z
[32] Benvenga S, Marini HR, Micali A, Freni J, Pallio G, Irrera N, Squadrito F, Altavilla D, Antonelli A, Ferrari SM, Fallahi P, Puzzolo D, Minutoli L (2020) Protective Effects of Myo-Inositol and Selenium on Cadmium-Induced Thyroid Toxicity in Mice. Nutrients. 12(5):1222. https://doi.org/10.3390/nu12051222
[33] Yoshizuka M, Mori N, Hamasaki K, Tanaka I, Yokoyama M, Hara K, Doi Y, Umezu Y, Araki H, Sakamoto Y, Miyazaki M, Fujimoto S (1991) Cadmium toxicity in the thyroid gland of pregnant rats. Exp Mol Pathol. 55(1): 97-104. https://doi.org/10.1016/0014-4800(91)90021-o
[34] Prakash P, Kumar PG, Laloraya M, Javeri T, Parihar MS (1997) Superoxide anion radical production as a cadmium-mediated mechanism of toxicity in avian thyroid: an electron spin resonance study by spin trapping. Comp Biochem Physiol C Toxicol Pharmacol. 118(1):89–95. https://doi.org/10.1016/S0742-8413(97)00082-0
[35] Hammouda F, Messaoudi I, El Hani J, Baati T, Saïd K, Kerkeni A (2008) Reversal of cadmium-induced thyroid dysfunction by selenium, zinc, or their combination in rat. Biol Trace Elem Res. 126(1-3):194–203. https://doi.org/10.1007/s12011-008-8194-8
[36] Buha A, Antonijević B, Bulat Z, Jaćević V, Milovanović V, Matović V (2013) The impact of prolonged cadmium exposure and co-exposure with polychlorinated biphenyls on thyroid function in rats. Toxicol Lett. 221(2):83-90. https://doi.org/10.1016/j.toxlet.2013.06.216
[37] Park JD, Liu Y, Klaassen CD (2001) Protective effect of metallothionein against the toxicity of cadmium and other metals (1). Toxicology. 163(2-3):93-100. https://doi.org/10.1016/s0300-483x(01)00375-4
[38] Baoxia HE, Yequan FU, Jinlong LI, Shiwen XU (2008) Effect of cadmium on the expression of Fas and caspase-3 mRNA in chicken anterior pituitary. Acta Scientiae Circumstantiae. 7:1419-1424.
[39] Belyaeva EA, Korotkov SM, Saris NE (2011) In vitro modulation of heavy metal-induced rat liver mitochondria dysfunction: a comparison of copper and mercury with cadmium. J Trace Elem Med Biol. 25(Suppl 1):S63-S73. https://doi.org/10.1016/j.jtemb.2010.10.007
[40] Cannino G, Ferruggia E, Luparello C, Rinaldi AM (2009) Cadmium and mitochondria. Mitochondrion. 9(6):377-384. https://doi.org/10.1016/j.mito.2009.08.009
[41] Xie Q, Liu R, Jiang J, Peng J, Yang C, Zhang W, Wang S, Song J (2020) What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Res Ther. Dec. 1;11(1):519. https://doi.org/10.1186/s13287-020-02011-z
[42] Gao J, Hu J, Li P, Che K, Wang F, Yan S (2022) Human umbilical cord mesenchymal stem cells alleviate the imbalance of CD4+ T cells via protein tyrosine phosphatase non-receptor type 2/signal transducer and activator of transcription 3 signaling in ameliorating experimental autoimmune thyroiditis in rats. Endocr J. 69(6):613-625. https://doi.org/10.1507/endocrj.EJ20-0695
[43] Ma Y, Su Q, Yue C, Zou H, Zhu J, Zhao H, Song R, Liu Z (2022) The Effect of Oxidative Stress-Induced Autophagy by Cadmium Exposure in Kidney, Liver, and Bone Damage, and Neurotoxicity. Int J Mol Sci. 23(21):13491. https://doi.org/10.3390/ijms232113491
[44] Hempel N, Trebak M (2017) Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium. 63:70-96. https://doi.org/10.1016/j.ceca.2017.01.007
[45] Lee WK, Probst S, Santoyo-Sánchez MP, Al-Hamdani W, Diebels I, von Sivers JK, Kerek E, Prenner EJ, Thévenod F (2017) Initial autophagic protection switches to disruption of autophagic flux by lysosomal instability during cadmium stress accrual in renal NRK-52E cells. Arch Toxicol. 91(10):3225-3245. https://doi.org/10.1007/s00204-017-1942-9
[46] Mizushima N, Yoshimori, T (2007) How to interpret LC3 immunoblotting. Autophagy. 3(6):542–545. https://doi.org/10.4161/auto.4600
[47] Gump JM, Thorburn A (2011) Autophagy and apoptosis: what is the connection? Trends Cell Biol. 21(7):387-92. https://doi.org/10.1016/j.tcb.2011.03.007
[48] Gao M, Li C, Xu M, Liu Y, Cong M, Liu S (2018) LncRNA MT1DP Aggravates Cadmium-Induced Oxidative Stress by Repressing the Function of Nrf2 and is Dependent on Interaction with miR-365. Adv Sci (Weinh). 5(7):1800087. https://doi.org/10.1002/advs.201800087
[49] Yokouchi M, Hiramatsu N, Hayakawa K, Kasai A, Takano Y, Yao J, Kitamura M (2007) Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response. Cell Death Differ 14(8):1467–1474. https://doi.org/10.1038/sj.cdd.4402154
[50] Xu C, Wu F, Mao C, Wang X, Zheng T, Bu L, Mou X, Zhou Y, Yuan G, Wang S, Xiao Y (2016) Excess iodine promotes apoptosis of thyroid follicular epithelial cells by inducing autophagy suppression and is associated with Hashimoto thyroiditis disease. J Autoimmun. 75:50-57. https://doi.org/10.1016/j.jaut.2016.07.008
Downloads
Published
How to Cite
License
Copyright (c) 2026 Mustafa Alimoğulları, Uygar Sacik, Ebru Alimogullari, Bahar Kartal
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
