Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Effects of Myo-inositol Alone and in Combination with Seleno-Lmethionine on Cadmium-Induced Testicular Damage in Mice

Author(s): Salvatore Benvenga, Antonio Micali*, Giovanni Pallio, Roberto Vita, Consuelo Malta, Domenico Puzzolo, Natasha Irrera, Francesco Squadrito, Domenica Altavilla and Letteria Minutoli

Volume 12, Issue 4, 2019

Page: [311 - 323] Pages: 13

DOI: 10.2174/1874467212666190620143303

Price: $65


Background: Cadmium (Cd) impairs gametogenesis and damages the blood-testis barrier.

Objective: As the primary mechanism of Cd-induced damage is oxidative stress, the effects of two natural antioxidants, myo-inositol (MI) and seleno-L-methionine (Se), were evaluated in mice testes.

Methods: Eighty-four male C57 BL/6J mice were divided into twelve groups: 0.9% NaCl (vehicle; 1 ml/kg/day i.p.); Se (0.2 mg/kg/day per os); Se (0.4 mg/kg/day per os); MI (360 mg/kg/day per os); MI plus Se (0.2 mg/kg/day); MI plus Se (0.4 mg/kg/day); CdCl2 (2 mg/kg/day i.p.) plus vehicle; CdCl2 plus MI; CdCl2 plus Se (0.2 mg/kg/day); CdCl2 plus Se (0.4 mg/kg/day); CdCl2 plus MI plus Se (0.2 mg/kg/day); and CdCl2 plus MI plus Se (0.4 mg/kg/day). After 14 days, testes were processed for biochemical, structural and immunohistochemical analyses.

Results: CdCl2 increased iNOS and TNF-α expression and Malondialdehyde (MDA) levels, lowered glutathione (GSH) and testosterone, induced testicular lesions, and almost eliminated claudin-11 immunoreactivity. Se administration at 0.2 or 0.4 mg/kg significantly reduced iNOS and TNF-α expression, maintained GSH, MDA and testosterone levels, structural changes and low claudin-11 immunoreactivity. MI alone or associated with Se at 0.2 or 0.4 mg/kg significantly reduced iNOS and TNF-α expression and MDA levels, increased GSH and testosterone levels, ameliorated structural organization and increased claudin-11 patches number.

Conclusion: We demonstrated a protective effect of MI, a minor role of Se and an evident positive role of the association between MI and Se on Cd-induced damages of the testis. MI alone or associated with Se might protect testes in subjects exposed to toxicants, at least to those with behavior similar to Cd.

Keywords: Endocrine disruptors, cadmium, myo-inositol, seleno-L-methionine, testis, spermatogenesis.

Graphical Abstract
Thévenod, F.; Lee, W.K. Toxicology of cadmium and its damage to mammalian organs. Met. Ions Life Sci., 2013, 11, 415-490.
[] [PMID: 23430781]
Marettová, E.; Maretta, M.; Legáth, J. Changes in the peritubular tissue of rat testis after cadmium treatment. Biol. Trace Elem. Res., 2010, 134(3), 288-295.
[] [PMID: 19669115]
de Souza Predes, F.; Diamante, M.A.; Dolder, H. Testis response to low doses of cadmium in Wistar rats. Int. J. Exp. Pathol., 2010, 91(2), 125-131.
[] [PMID: 20015210]
Yari, A.; Asadi, M.H.; Bahadoran, H.; Dashtnavard, H.; Imani, H.; Naghii, M.R. Cadmium toxicity in spermatogenesis and protective effects of L-carnitine in adult male rats. Biol. Trace Elem. Res., 2010, 137(2), 216-225.
[] [PMID: 20012383]
Minutoli, L.; Micali, A.; Pisani, A.; Puzzolo, D.; Bitto, A.; Rinaldi, M.; Pizzino, G.; Irrera, N.; Galfo, F.; Arena, S.; Pallio, G.; Mecchio, A.; Germanà, A.; Bruschetta, D.; Laurà, R.; Magno, C.; Marini, H.; Squadrito, F.; Altavilla, D. Flavocoxid protects against cadmium-induced disruption of the blood-testis barrier and improves testicular damage and germ cell impairment in mice. Toxicol. Sci., 2015, 148(1), 311-329.
[] [PMID: 26424772]
Acharya, U.R.; Mishra, M.; Patro, J.; Panda, M.K. Effect of vitamins C and E on spermatogenesis in mice exposed to cadmium. Reprod. Toxicol., 2008, 25(1), 84-88.
[] [PMID: 18065194]
Siu, E.R.; Wong, E.W.; Mruk, D.D.; Sze, K.L.; Porto, C.S.; Cheng, C.Y. An occludin-focal adhesion kinase protein complex at the blood-testis barrier: a study using the cadmium model. Endocrinology, 2009, 150(7), 3336-3344.
[] [PMID: 19213829]
Bu, T.; Mi, Y.; Zeng, W.; Zhang, C. Protective effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat. Rec. (Hoboken), 2011, 294(3), 520-526.
[] [PMID: 21337715]
Li, R.; Luo, X.; Li, L.; Peng, Q.; Yang, Y.; Zhao, L.; Ma, M.; Hou, Z. The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Biol. Trace Elem. Res., 2016, 170(1), 152-164.
[] [PMID: 26224376]
Rani, A.; Kumar, A.; Lal, A.; Pant, M. Cellular mechanisms of cadmium-induced toxicity: a review. Int. J. Environ. Health Res., 2014, 24(4), 378-399.
[] [PMID: 24117228]
El-Maraghy, S.A.; Nassar, N.N. Modulatory effects of lipoic acid and selenium against cadmium-induced biochemical alterations in testicular steroidogenesis. J. Biochem. Mol. Toxicol., 2011, 25(1), 15-25.
[] [PMID: 20957662]
Abarikwu, S.O.; Iserhienrhien, B.O.; Badejo, T.A. Rutin- and selenium-attenuated cadmium-induced testicular pathophysiology in rats. Hum. Exp. Toxicol., 2013, 32(4), 395-406.
[] [PMID: 23424207]
Koyuturk, M.; Yanardag, R.; Bolkent, S.; Tunali, S. Influence of combined antioxidants against cadmium induced testicular damage. Environ. Toxicol. Pharmacol., 2006, 21(3), 235-240.
[] [PMID: 21783663]
Ren, X.M.; Wang, G.G.; Xu, D.Q.; Luo, K.; Liu, Y.X.; Zhong, Y.H.; Cai, Y.Q. The protection of selenium on cadmium-induced inhibition of spermatogenesis via activating testosterone synthesis in mice. Food Chem. Toxicol., 2012, 50(10), 3521-3529.
[] [PMID: 22828241]
Chau, J.F.; Lee, M.K.; Law, J.W.; Chung, S.K.; Chung, S.S. Sodium/myo-inositol cotransporter-1 is essential for the development and function of the peripheral nerves. FASEB J., 2005, 19(13), 1887-1889.
[] [PMID: 16174787]
Dai, Z.; Chung, S.K.; Miao, D.; Lau, K.S.; Chan, A.W.; Kung, A.W. Sodium/myo-inositol cotransporter 1 and myo-inositol are essential for osteogenesis and bone formation. J. Bone Miner. Res., 2011, 26(3), 582-590.
[] [PMID: 20818642]
Condorelli, R.A.; La Vignera, S.; Bellanca, S.; Vicari, E.; Calogero, A.E. Myoinositol: does it improve sperm mitochondrial function and sperm motility? Urology, 2012, 79(6), 1290-1295.
[] [PMID: 22656408]
Croze, M.L.; Soulage, C.O. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie, 2013, 95(10), 1811-1827.
[] [PMID: 23764390]
Windhorst, S.; Blechner, C.; Lin, H.Y.; Elling, C.; Nalaskowski, M.; Kirchberger, T.; Guse, A.H.; Mayr, G.W. Ins(1,4,5)P3 3-kinase-A overexpression induces cytoskeletal reorganization via a kinase-independent mechanism. Biochem. J., 2008, 414(3), 407-417.
[] [PMID: 18498254]
Calogero, A.E.; Gullo, G.; La Vignera, S.; Condorelli, R.A.; Vaiarelli, A. Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo-controlled study. Andrology, 2015, 3(3), 491-495.
[] [PMID: 25854593]
Jiang, W.D.; Wu, P.; Kuang, S.Y.; Liu, Y.; Jiang, J.; Hu, K.; Li, S.H.; Tang, L.; Feng, L.; Zhou, X.Q. Myo-inositol prevents copper-induced oxidative damage and changes in antioxidant capacity in various organs and the enterocytes of juvenile Jian carp (Cyprinus carpio var. Jian). Aquat. Toxicol., 2011, 105(3-4), 543-551.
[] [PMID: 21924699]
Arafa, M.H.; Mohammad, N.S.; Atteia, H.H. Fenugreek seed powder mitigates cadmium-induced testicular damage and hepatotoxicity in male rats. Exp. Toxicol. Pathol., 2014, 66(7), 293-300.
[] [PMID: 24813645]
Stammler, A.; Lüftner, B.U.; Kliesch, S.; Weidner, W.; Bergmann, M.; Middendorff, R.; Konrad, L. Highly conserved testicular localization of claudin-11 in normal and impaired spermatogenesis. PLoS One, 2016, 11(8)e0160349
[] [PMID: 27486954]
Ji, Y.L.; Wang, Z.; Wang, H.; Zhang, C.; Zhang, Y.; Zhao, M.; Chen, Y.H.; Meng, X.H.; Xu, D.X. Ascorbic acid protects against cadmium-induced endoplasmic reticulum stress and germ cell apoptosis in testes. Reprod. Toxicol., 2012, 34(3), 357-363.
[] [PMID: 22569276]
Chakraborty, S.; Gang, S.; Sengupta, M. Functional status of testicular macrophages in an immunopriviledged niche in cadmium intoxicated murine testes. Am. J. Reprod. Immunol., 2014, 72(1), 14-21.
[] [PMID: 24629031]
Kline, A.E.; Massucci, J.L.; Ma, X.; Zafonte, R.D.; Dixon, C.E. Bromocriptine reduces lipid peroxidation and enhances spatial learning and hippocampal neuron survival in a rodent model of focal brain trauma. J. Neurotrauma, 2004, 21(12), 1712-1722.
[] [PMID: 15684763]
Johnsen, S.G. Testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones, 1970, 1(1), 2-25.
[PMID: 5527187]
Mizuno, K.; Hayashi, Y.; Kojima, Y.; Kurokawa, S.; Sasaki, S.; Kohri, K. Influence for testicular development and histological peculiarity in the testes of flutamide-induced cryptorchid rat model. Int. J. Urol., 2007, 14(1), 67-72.
[] [PMID: 17199863]
Minutoli, L.; Antonuccio, P.; Romeo, C.; Nicòtina, P.A.; Bitto, A.; Arena, S.; Polito, F.; Altavilla, D.; Turiaco, N.; Cutrupi, A.; Zuccarello, B.; Squadrito, F. Evidence for a role of mitogen-activated protein kinase 3/mitogen-activated protein kinase in the development of testicular ischemia-reperfusion injury. Biol. Reprod., 2005, 73(4), 730-736.
[] [PMID: 15944243]
Chang, Y.F.; Lee-Chang, J.S.; Panneerdoss, S.; MacLean, J.A., II; Rao, M.K. Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis. Biotechniques, 2011, 51(5), 341-342, 344.
[] [PMID: 22054547]
Cheng, C.Y.; Mruk, D.D. The blood-testis barrier and its implications for male contraception. Pharmacol. Rev., 2012, 64(1), 16-64.
[] [PMID: 22039149]
Li, N.; Wang, T.; Han, D. Structural, cellular and molecular aspects of immune privilege in the testis. Front. Immunol., 2012, 3, 152.
[] [PMID: 22701457]
Chen, Q.; Deng, T.; Han, D. Testicular immunoregulation and spermatogenesis. Semin. Cell Dev. Biol., 2016, 59, 157-165.
[] [PMID: 26805443]
Su, L.; Mruk, D.D.; Lee, W.M.; Cheng, C.Y. Drug transporters and blood--testis barrier function. J. Endocrinol., 2011, 209(3), 337-351.
[] [PMID: 21471187]
Jenardhanan, P.; Panneerselvam, M.; Mathur, P.P. Effect of environmental contaminants on spermatogenesis. Semin. Cell Dev. Biol., 2016, 59, 126-140.
[] [PMID: 27060550]
Iavicoli, I.; Fontana, L.; Bergamaschi, A. The effects of metals as endocrine disruptors. J. Toxicol. Environ. Health B Crit. Rev., 2009, 12(3), 206-223.
[] [PMID: 19466673]
Cheng, C.Y.; Wong, E.W.; Lie, P.P.; Li, M.W.; Su, L.; Siu, E.R.; Yan, H.H.; Mannu, J.; Mathur, P.P.; Bonanomi, M.; Silvestrini, B.; Mruk, D.D. Environmental toxicants and male reproductive function. Spermatogenesis, 2011, 1(1), 2-13.
[] [PMID: 21866273]
Liu, Q.; Xu, C.; Ji, G.; Liu, H.; Mo, Y.; Tollerud, D.J.; Gu, A.; Zhang, Q. Sublethal effects of zinc oxide nanoparticles on male reproductive cells. Toxicol. In Vitro, 2016, 35, 131-138.
[] [PMID: 27247145]
Ramos-Treviño, J.; Bassol-Mayagoitia, S.; Ruiz-Flores, P.; Espino-Silva, P.K.; Saucedo-Cárdenas, O.; Villa-Cedillo, S.A.; Nava-Hernández, M.P. In vitro evaluation of damage by heavy metals in tight and gap junctions of Sertoli cells. DNA Cell Biol., 2017, 36(10), 829-836.
[] [PMID: 28829631]
Squadrito, F.; Micali, A.; Rinaldi, M.; Irrera, N.; Marini, H.; Puzzolo, D.; Pisani, A.; Lorenzini, C.; Valenti, A.; Laurà, R.; Germanà, A.; Bitto, A.; Pizzino, G.; Pallio, G.; Altavilla, D.; Minutoli, L. Polydeoxyribonucleotide, an adenosine-A2A receptor agonist, preserves blood testis barrier from cadmium-induced injury. Front. Pharmacol., 2017, 7, 537.
[] [PMID: 28119612]
Minutoli, L.; Puzzolo, D.; Rinaldi, M.; Irrera, N.; Marini, H.; Arcoraci, V.; Bitto, A.; Crea, G.; Pisani, A.; Squadrito, F.; Trichilo, V.; Bruschetta, D.; Micali, A.; Altavilla, D. ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid. Med. Cell. Longev., 2016.20162183026
[] [PMID: 27127546]
Roy, J.; Galano, J.M.; Durand, T.; Le Guennec, J.Y.; Lee, J.C. Physiological role of reactive oxygen species as promoters of natural defenses. FASEB J., 2017, 31(9), 3729-3745.
[] [PMID: 28592639]
Walczak-Jedrzejowska, R.; Wolski, J.K.; Slowikowska-Hilczer, J. The role of oxidative stress and antioxidants in male fertility. Cent. European J. Urol., 2013, 66(1), 60-67.
[] [PMID: 24578993]
Chouhan, S.; Yadav, S.K.; Prakash, J.; Westfall, S.; Ghosh, A.; Agarwal, N.K.; Singh, S.P. Increase in the expression of inducible nitric oxide synthase on exposure to bisphenol A: a possible cause for decline in steroidogenesis in male mice. Environ. Toxicol. Pharmacol., 2015, 39(1), 405-416.
[] [PMID: 25569322]
Lee, J.; Lim, K.T. Inhibitory effect of plant-originated glycoprotein (27 kDa) on expression of matrix metalloproteinase-9 in cadmium chloride-induced BNL CL.2 cells. J. Trace Elem. Med. Biol., 2011, 25(4), 239-246.
[] [PMID: 21924884]
Olszowski, T.; Baranowska-Bosiacka, I.; Gutowska, I.; Chlubek, D. Pro-inflammatory properties of cadmium. Acta Biochim. Pol., 2012, 59(4), 475-482.
[] [PMID: 23240106]
Pogue, A.I.; Li, Y.Y.; Cui, J.G.; Zhao, Y.; Kruck, T.P.; Percy, M.E.; Tarr, M.A.; Lukiw, W.J. Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells. J. Inorg. Biochem., 2009, 103(11), 1591-1595.
[] [PMID: 19540598]
Fouad, A.A.; Jresat, I. Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats. Fundam. Clin. Pharmacol., 2013, 27(2), 152-160.
[] [PMID: 21819444]
Zheng, J.L.; Yuan, S.S.; Wu, C.W.; Lv, Z.M. Acute exposure to waterborne cadmium induced oxidative stress and immunotoxicity in the brain, ovary and liver of zebrafish (Danio rerio). Aquat. Toxicol., 2016, 180, 36-44.
[] [PMID: 27642707]
Duntas, L.H.; Benvenga, S. Selenium: An element for life. Endocrine, 2015, 48(3), 756-775.
[] [PMID: 25519493]
Oldereid, N.B.; Thomassen, Y.; Purvis, K. Selenium in human male reproductive organs. Hum. Reprod., 1998, 13(8), 2172-2176.
[] [PMID: 9756291]
Minutoli, L.; Antonuccio, P.; Irrera, N.; Rinaldi, M.; Bitto, A.; Marini, H.; Pizzino, G.; Romeo, C.; Pisani, A.; Santoro, G.; Puzzolo, D.; Magno, C.; Squadrito, F.; Micali, A.; Altavilla, D. NLRP3 Inflammasome Involvement in the Organ Damage and Impaired Spermatogenesis Induced by Testicular Ischemia and Reperfusion in Mice. J. Pharmacol. Exp. Ther., 2015, 355(3), 370-380.
[] [PMID: 26407722]
Jiang, W-D.; Feng, L.; Liu, Y.; Jiang, J.; Zhou, X-Q. Myo-inositol prevents oxidative damage, inhibits oxygen radical generation and increases antioxidant enzyme activities of juvenile Jian carp (Cyprinus carpio var. Jian). Aquacult. Res., 2009, 40, 1770-1776.
Muraoka, S.; Miura, T. Inhibition of xanthine oxidase by phytic acid and its antioxidative action. Life Sci., 2004, 74(13), 1691-1700.
[] [PMID: 14738912]
Chihara, M.; Otsuka, S.; Ichii, O.; Hashimoto, Y.; Kon, Y. Molecular dynamics of the blood-testis barrier components during murine spermatogenesis. Mol. Reprod. Dev., 2010, 77(7), 630-639.
[] [PMID: 20578065]
Li, N.; Mruk, D.D.; Lee, W.M.; Wong, C.K.; Cheng, C.Y. Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis? Semin. Cell Dev. Biol., 2016, 59, 141-156.
[] [PMID: 26779951]
Yu, W.; Yaping, L.; Mingjun, W.; Jie, H.; Xiaogang, L.; Gang, L. BEX4 upregulation alters Sertoli cell growth properties and protein expression profiles: An explanation for cadmium-induced testicular Sertoli cell injury. J. Biochem. Mol. Toxicol., 2017, 31(7)e21908
[] [PMID: 28295929]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy