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Khorsandi, L., Heidari-Moghadam, A., Younesi, E., Khodayar, M.-J., & Asadi-Fard, Y. (2024). Naringenin ameliorates cytotoxic effects of bisphenol A on mouse Sertoli cells by suppressing oxidative stress and modulating mitophagy: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 22(3), 219–228. https://doi.org/10.18502/ijrm.v22i3.16166
https://doi.org/10.18502/ijrm.v22i3.16166
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authors
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Layasadat Khorsandi
Layasadat Khorsandi
Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Abbas Heidari-Moghadam
Abbas Heidari-Moghadam
Department of Anatomical Sciences, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran.
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Elham Younesi
Elham Younesi
Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Mohammad-Javad Khodayar
Mohammad-Javad Khodayar
Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Yousef Asadi-Fard
Yousef Asadi-Fard
Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
Published Date
- May 12, 2024
Naringenin ameliorates cytotoxic effects of bisphenol A on mouse Sertoli cells by suppressing oxidative stress and modulating mitophagy: An experimental study
Abstract
Background: Bisphenol A (BPA), an endocrine-disrupting agent, is widely used as polycarbonate plastics for producing food containers. BPA exposure at environmentally relevant concentrations can cause reproductive disorders.
Objective: The effect of Naringenin (NG) on BPA-induced Sertoli cell toxicity and its mechanism was examined in the present study.
Materials and Methods: In this experimental-laboratory study, the mouse TM4 cells were treated to BPA (0.8 μm) or NG for 24 hr at concentrations of 10, 20, and 50 μg/ml. Cell viability, reactive oxygen species (ROS) production, malondialdehyde (MDA) content, antioxidant level, and mitochondrial membrane potential (MMP) were examined. The expression of mitophagy-related genes, including Parkin and PTEN-induced putative kinase 1 (Pink1), was also evaluated.
Results: BPA significantly lowered the viability of the Sertoli cells (p = 0.004). Pink1 and Parkin levels of the BPA group were significantly increased (p < 0.001), while the MMP was considerably decreased (p < 0.001). BPA raised MDA and ROS levels (p < 0.001) and reduced antioxidant biomarkers (p = 0.003). NG at the 20 and 50 μg/ml concentrations could significantly improve the viability and MMP of TM4 cells (p = 0.034). NG depending on concentration, could decrease Pink1 and Parkin at mRNA and protein levels compared to the BPA group (p = 0.024). NG enhanced antioxidant factors, while ROS and MDA levels were decreased in the BPA-exposed cells.
Conclusion: The beneficial impacts of NG on BPA-exposed Sertoli cells are related to the suppression of mitophagy and the reduction of oxidative stress.
Key words: Mitophagy, Naringenin, Sertoli cells, Bisphenol A, Reactive oxygen species, Pink1, Parkin.
References
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[14] Han X, Parker TL. Antiinflammatory activity of cinnamon (Cinnamomum zeylanicum) bark essential oil in a human skin disease model. Phytother Res 2017; 31: 1034–1038.
[15] Qiu M, Wei W, Zhang J, Wang H, Bai Y, Guo DA. A scientometric study to a critical review on promising anticancer and neuroprotective compounds: Citrus flavonoids. Antioxidants (Basel) 2023; 12: 669–692.
[16] Pengnet S, Prommaouan S, Sumarithum P, Malakul W. Naringin reverses high-cholesterol diet-induced vascular dysfunction and oxidative stress in rats via regulating LOX- 1 and NADPH oxidase subunit expression. Biomed Res Int 2019; 2019: 3708497.
[17] Li F, Zhan Z, Qian J, Cao C, Yao W, Wang N. Naringin attenuates rat myocardial ischemia/reperfusion injury via PI3K/Akt pathway-mediated inhibition of apoptosis, oxidative stress and autophagy. Exp Ther Med 2021; 22: 811–819.
[18] Hsueh TP, Sheen JM, Pang JH, Bi KW, Huang CC, Wu HT, et al. The anti-atherosclerotic effect of naringin is associated with reduced expressions of cell adhesion molecules and chemokines through NF-??B pathway. Molecules 2016; 21: 195–210.
[19] Mohamed EE, Ahmed OM, Abdel-Moneim A, Zoheir KMA, Elesawy BH, Al Askary A, et al. Protective effects of naringin-dextrin nanoformula against chemically induced hepatocellular carcinoma in Wistar rats: Roles of oxidative stress, inflammation, cell apoptosis, and proliferation. Pharmaceuticals (Basel) 2022; 15: 1558–1582.
[20] Alboghobeish S, Mahdavinia M, Zeidooni L, Samimi A, Oroojan AA, Alizadeh S, et al. Efficiency of naringin against reproductive toxicity and testicular damages induced by bisphenol A in rats. Iran J Basic Med Sci 2019; 22: 315– 325.
[21] Mehranfard N, Ghasemi M, Rajabian A, Ansari L. Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease. Heliyon 2023; 9: e22820.
[22] Elhemiely AA, Yahia R, Gad AM. Naringenin alleviate reproductive toxicity evoked by lead acetate via attenuation of sperm profile and biochemical alterations in male Wistar rat: Involvement of TGF??/AKT/mTOR pathway. J Biochem Mol Toxicol 2023; 37: e23335.
[23] Zhang Y, Han L, Yang H, Pang J, Li P, Zhang G, et al. Bisphenol A affects cell viability involved in autophagy and apoptosis in goat testis sertoli cell. Environ Toxicol Pharmacol 2017; 55: 137–147.
[24] Mostafa H-S, Abd El-Baset SA, Kattaia AA, Zidan RA, Al Sadek MM. Efficacy of naringenin against permethrininduced testicular toxicity in rats. Int J Exp Pathol 2016; 97: 37–49.
[25] Sengul E, Gelen V, Yildirim S, Cinar I, Aksu EH. Effects of naringin on oxidative stress, inflammation, some reproductive parameters, and apoptosis in acrylamideinduced testis toxicity in rat. Environ Toxicol 2023; 38: 798–808.
[26] Gassman NR. Induction of oxidative stress by bisphenol A and its pleiotropic effects. Environ Mol Mutagen 2017; 58: 60–71.
[27] Matic I, Strobbe D, Frison M, Campanella M. Controlled and impaired mitochondrial quality in neurons: Molecular physiology and prospective pharmacology. Pharmacol Res 2015; 99: 410–424.
[28] Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 2013; 20: 31–42.
[29] Anand SK, Sharma A, Singh N, Kakkar P. Activation of autophagic flux via LKB1/AMPK/mTOR axis against xenoestrogen Bisphenol-A exposure in primary rat hepatocytes. Food Chem Toxicol 2020; 141: 111314–111329.
[30] Morshed AKMH, Paul S, Hossain A, Basak T, Hossain MS, Hasan MM, et al. Baicalein as promising anticancer agent: A comprehensive analysis on molecular mechanisms and therapeutic perspectives. Cancers (Basel) 2023; 15: 2128– 2156.
[31] Li S, Zhang J, Liu C, Wang Q, Yan J, Hui L, et al. The role of mitophagy in regulating cell death. Oxid Med Cell Longev 2021; 2021: 6617256.
[32] Decker ST, Matias AA, Bannon ST, Madden JP, Alexandrou-Majaj N, Layec G. Effects of cigarette smoke on in situ mitochondrial substrate oxidation of slow- and fast-twitch skeletal muscles. Life Sci 2023; 315: 121376.
[33] Song Y, Ding W, Xiao Y, Lu KJ. The progress of mitophagy and related pathogenic mechanisms of the neurodegenerative diseases and tumor. Neurosci J 2015; 2015: 543758.
[34] Sun T, Ding W, Xu T, Ao X, Yu T, Li M, et al. Parkin regulates programmed necrosis and myocardial ischemia/reperfusion INGury by targeting cyclophilin-D. Antioxid Redox Signal 2019; 31: 1177–1193.
[35] Paech F, Mingard C, Grünig D, Abegg VF, Bouitbir J, Krähenbühl S. Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells. Toxicology 2018; 395: 34–44.
[36] Wang M, Luan S, Fan X, Wang J, Huang J, Gao X, et al. The emerging multifaceted role of PINK1 in cancer biology. Cancer Sci 2022; 113: 4037–4047.
[37] Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, et al. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis 2023; 14: 88–100.
[38] Wei Y, Sun L, Liu C, Li L. Naringin regulates endoplasmic reticulum stress and mitophagy through the ATF3/PINK1 signaling axis to alleviate pulmonary fibrosis. Naunyn Schmiedebergs Arch Pharmacol 2023; 396: 1155–1169.
[39] Praharaj PP, Naik PP, Panigrahi DP, Bhol CS, Mahapatra KK, Patra S, et al. Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: Its implication in cancer therapeutics. Cell Mol Life Sci 2019; 76: 1641–1652.
[40] Chen Y, Chen HN, Wang K, Zhang L, Huang Z, Liu J, et al. Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J Hepatol 2019; 70: 66–77.
[2] Asadi-Fard Y, Zohour Soleimani M, Khodayar MJ, Khorsandi L, Shirani M, Samimi A. Morin improves bisphenol-A-induced toxicity in the rat testicular mitochondria and sperms. JBRA Assist Reprod 2023; 27: 174–179.
[3] Khan S, Beigh S, Chaudhari BP, Sharma S, Aliul Hasan Abdi S, Ahmad S, et al. Mitochondrial dysfunction induced by bisphenol A is a factor of its hepatotoxicity in rats. Environ Toxicol 2016; 31: 1922–1934.
[4] Wang Ch, Qi S, Liu Ch, Yang A, Fu W, Quan C, et al. Mitochondrial dysfunction and Ca2+ overload in injured Sertoli cells exposed to bisphenol A. Environ Toxicol 2017; 32: 823–831.
[5] Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y. Mitochondrial reactive oxygen species and their contribution in chronic kidney disease progression through oxidative stress. Front Physiol 2021; 12: 627837.
[6] Kaur S, Saluja M, Bansal MP. Bisphenol A induced oxidative stress and apoptosis in mice testes: Modulation by selenium. Andrologia 2018; 50: e12834.
[7] Lemasters JJ. Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and micromitophagy (type 3). Redox Biol 2014; 2: 749–754.
[8] Koyano F, Yamano K, Kosako H, Tanaka K, Matsuda N. Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL. J Biol Chem 2019; 294: 10300–10314.
[9] Choi M-S, Park H-J, Oh J-H, Lee E-H, Park S-M, Yoon S. Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway. J Appl Toxicol 2014; 34: 628–636.
[10] Gao Y, Mruk DD, Cheng CY. Sertoli cells are the target of environmental toxicants in the testis- a mechanistic and therapeutic insight. Expert Opin Ther Targets 2015; 19: 1073–1090.
[11] Qi S, Fu W, Wang C, Liu C, Quan C, Kourouma A, et al. BPAinduced apoptosis of rat Sertoli cells through Fas/FasL and JNKs/p38 MAPK pathways. Reprod Toxicol 2014; 50: 108– 116.
[12] Feng Y, Wu J, Lei R, Zhang Y, Qiao M, Zhou J, et al. N-acetyl-L-cysteine ameliorates BPAF-induced porcine Sertoli cell apoptosis and cell cycle arrest via inhibiting the ROS level. Toxics 2023; 11: 923–937.
[13] Amjad S, Rahman MS, Pang MG. Role of antioxidants in alleviating bisphenol A toxicity. Biomolecules 2020; 10: 1105–1131.
[14] Han X, Parker TL. Antiinflammatory activity of cinnamon (Cinnamomum zeylanicum) bark essential oil in a human skin disease model. Phytother Res 2017; 31: 1034–1038.
[15] Qiu M, Wei W, Zhang J, Wang H, Bai Y, Guo DA. A scientometric study to a critical review on promising anticancer and neuroprotective compounds: Citrus flavonoids. Antioxidants (Basel) 2023; 12: 669–692.
[16] Pengnet S, Prommaouan S, Sumarithum P, Malakul W. Naringin reverses high-cholesterol diet-induced vascular dysfunction and oxidative stress in rats via regulating LOX- 1 and NADPH oxidase subunit expression. Biomed Res Int 2019; 2019: 3708497.
[17] Li F, Zhan Z, Qian J, Cao C, Yao W, Wang N. Naringin attenuates rat myocardial ischemia/reperfusion injury via PI3K/Akt pathway-mediated inhibition of apoptosis, oxidative stress and autophagy. Exp Ther Med 2021; 22: 811–819.
[18] Hsueh TP, Sheen JM, Pang JH, Bi KW, Huang CC, Wu HT, et al. The anti-atherosclerotic effect of naringin is associated with reduced expressions of cell adhesion molecules and chemokines through NF-??B pathway. Molecules 2016; 21: 195–210.
[19] Mohamed EE, Ahmed OM, Abdel-Moneim A, Zoheir KMA, Elesawy BH, Al Askary A, et al. Protective effects of naringin-dextrin nanoformula against chemically induced hepatocellular carcinoma in Wistar rats: Roles of oxidative stress, inflammation, cell apoptosis, and proliferation. Pharmaceuticals (Basel) 2022; 15: 1558–1582.
[20] Alboghobeish S, Mahdavinia M, Zeidooni L, Samimi A, Oroojan AA, Alizadeh S, et al. Efficiency of naringin against reproductive toxicity and testicular damages induced by bisphenol A in rats. Iran J Basic Med Sci 2019; 22: 315– 325.
[21] Mehranfard N, Ghasemi M, Rajabian A, Ansari L. Protective potential of naringenin and its nanoformulations in redox mechanisms of injury and disease. Heliyon 2023; 9: e22820.
[22] Elhemiely AA, Yahia R, Gad AM. Naringenin alleviate reproductive toxicity evoked by lead acetate via attenuation of sperm profile and biochemical alterations in male Wistar rat: Involvement of TGF??/AKT/mTOR pathway. J Biochem Mol Toxicol 2023; 37: e23335.
[23] Zhang Y, Han L, Yang H, Pang J, Li P, Zhang G, et al. Bisphenol A affects cell viability involved in autophagy and apoptosis in goat testis sertoli cell. Environ Toxicol Pharmacol 2017; 55: 137–147.
[24] Mostafa H-S, Abd El-Baset SA, Kattaia AA, Zidan RA, Al Sadek MM. Efficacy of naringenin against permethrininduced testicular toxicity in rats. Int J Exp Pathol 2016; 97: 37–49.
[25] Sengul E, Gelen V, Yildirim S, Cinar I, Aksu EH. Effects of naringin on oxidative stress, inflammation, some reproductive parameters, and apoptosis in acrylamideinduced testis toxicity in rat. Environ Toxicol 2023; 38: 798–808.
[26] Gassman NR. Induction of oxidative stress by bisphenol A and its pleiotropic effects. Environ Mol Mutagen 2017; 58: 60–71.
[27] Matic I, Strobbe D, Frison M, Campanella M. Controlled and impaired mitochondrial quality in neurons: Molecular physiology and prospective pharmacology. Pharmacol Res 2015; 99: 410–424.
[28] Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 2013; 20: 31–42.
[29] Anand SK, Sharma A, Singh N, Kakkar P. Activation of autophagic flux via LKB1/AMPK/mTOR axis against xenoestrogen Bisphenol-A exposure in primary rat hepatocytes. Food Chem Toxicol 2020; 141: 111314–111329.
[30] Morshed AKMH, Paul S, Hossain A, Basak T, Hossain MS, Hasan MM, et al. Baicalein as promising anticancer agent: A comprehensive analysis on molecular mechanisms and therapeutic perspectives. Cancers (Basel) 2023; 15: 2128– 2156.
[31] Li S, Zhang J, Liu C, Wang Q, Yan J, Hui L, et al. The role of mitophagy in regulating cell death. Oxid Med Cell Longev 2021; 2021: 6617256.
[32] Decker ST, Matias AA, Bannon ST, Madden JP, Alexandrou-Majaj N, Layec G. Effects of cigarette smoke on in situ mitochondrial substrate oxidation of slow- and fast-twitch skeletal muscles. Life Sci 2023; 315: 121376.
[33] Song Y, Ding W, Xiao Y, Lu KJ. The progress of mitophagy and related pathogenic mechanisms of the neurodegenerative diseases and tumor. Neurosci J 2015; 2015: 543758.
[34] Sun T, Ding W, Xu T, Ao X, Yu T, Li M, et al. Parkin regulates programmed necrosis and myocardial ischemia/reperfusion INGury by targeting cyclophilin-D. Antioxid Redox Signal 2019; 31: 1177–1193.
[35] Paech F, Mingard C, Grünig D, Abegg VF, Bouitbir J, Krähenbühl S. Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells. Toxicology 2018; 395: 34–44.
[36] Wang M, Luan S, Fan X, Wang J, Huang J, Gao X, et al. The emerging multifaceted role of PINK1 in cancer biology. Cancer Sci 2022; 113: 4037–4047.
[37] Li W, Jiang WS, Su YR, Tu KW, Zou L, Liao CR, et al. PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis 2023; 14: 88–100.
[38] Wei Y, Sun L, Liu C, Li L. Naringin regulates endoplasmic reticulum stress and mitophagy through the ATF3/PINK1 signaling axis to alleviate pulmonary fibrosis. Naunyn Schmiedebergs Arch Pharmacol 2023; 396: 1155–1169.
[39] Praharaj PP, Naik PP, Panigrahi DP, Bhol CS, Mahapatra KK, Patra S, et al. Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: Its implication in cancer therapeutics. Cell Mol Life Sci 2019; 76: 1641–1652.
[40] Chen Y, Chen HN, Wang K, Zhang L, Huang Z, Liu J, et al. Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J Hepatol 2019; 70: 66–77.