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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Research Article

In vitro Pretreatment with Zinc Alleviates the Adverse Effects of Tetrahydrocannabinol on Cultured Mouse Sertoli Cells: Role of Anti-apoptotic and Antioxidant Activities

Author(s): Kimia Ahmadi, Fatemeh Asgharzadeh, Shadi Mohammadpour-Asl, Fatemeh Ayari, Fatemeh Rahbar, Morteza Motazakker, Shiva Roshan-Milani and Amin Abdollahzade Fard*

Volume 23, Issue 13, 2023

Published on: 15 June, 2023

Page: [1611 - 1620] Pages: 10

DOI: 10.2174/1871530323666230322092046

Price: $65

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Abstract

Background: Global rise in cannabis abuse during reproductive years has placed a large number of men at risk for the adverse consequences of δ-9-tetrahydrocannabinol (THC), the primary active component of cannabis. It has been reported that THC affects male fertility and causes testicular cell dysfunction and apoptosis. This study aimed to investigate the possible protective role of zinc pretreatment against the toxic effects of THC in cultured mouse Sertoli cells and the underlying mechanism.

Methods: The Mus Musculus Sertoli cell line (TM4) was cultured, exposed to THC alone (470 μM, 24 h), co-administered with zinc (8 μM, 48 h), and investigated in three groups: control, THC, and THC + zinc. The MTT was performed to evaluate cell viability. TUNEL assay was also applied for the detection of cell apoptosis and a western blot was performed for measuring protein expression levels of Caspase3, Pro-caspase3, SOD, and PDGF-A.

Results: THC significantly decreased cell viability (p < 0.001) and expression levels of SOD, PDGF-A, and pro-caspase3 proteins (p < 0.05 for all), whereas increased Sertoli cells apoptosis (p < 0.001) and expression level of cleaved caspase3 protein (p < 0.001). Pretreatment with zinc reversed THC-induced apoptotic and oxidative effects and reduced cleaved caspase3/pro-caspase3 ratio but could not reverse THC-induced reduction of PDGF-A expression level in TM4 cells.

Conclusion: The present data suggest that THC induces Sertoli cell damage through a multitarget mechanism. Zinc was reported to protect against THC-induced Sertoli cell damage due to its antiapoptotic and antioxidant activities, indicating its clinical importance against THC-induced testicular toxicity among addicted men.

Keywords: Apoptosis, caspase 3, PDGF-A, sertoli cell, SOD, tetrahydrocannabinol, zinc.

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[1]
Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: Endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 1998; 21(12): 521-8.
[http://dx.doi.org/10.1016/S0166-2236(98)01283-1] [PMID: 9881850]
[2]
Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005; 310(5746): 329-32.
[http://dx.doi.org/10.1126/science.1115740] [PMID: 16224028]
[3]
Iversen LL. The science of marijuana. Oxford University Press 2001; p. 273.
[4]
Juknat A, Kozela E, Kaushansky N, Mechoulam R, Vogel Z. Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol-studies in BV-2 microglia and encephalitogenic T cells. J Basic Clin Physiol Pharmacol 2016; 27(3): 289-96.
[http://dx.doi.org/10.1515/jbcpp-2015-0071] [PMID: 26540221]
[5]
Venderová K. Růžička, E.; Voříšek, V.; Višňovský, P. Survey on cannabis use in Parkinson’s disease: Subjective improvement of motor symptoms. Mov Disord 2004; 19(9): 1102-6.
[http://dx.doi.org/10.1002/mds.20111] [PMID: 15372606]
[6]
Fiz J, Durán M, Capellà D, Carbonell J, Farré M. Cannabis use in patients with fibromyalgia: Effect on symptoms relief and health-related quality of life. PLoS One 2011; 6(4): e18440.
[http://dx.doi.org/10.1371/journal.pone.0018440] [PMID: 21533029]
[7]
Mendelson JH, Kuehnle J, Ellingboe J, Babor TF. Plasma testosterone levels before, during and after chronic marihuana smoking. N Engl J Med 1974; 291(20): 1051-5.
[http://dx.doi.org/10.1056/NEJM197411142912003] [PMID: 4415097]
[8]
Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med 1974; 290(16): 872-4.
[http://dx.doi.org/10.1056/NEJM197404182901602] [PMID: 4816961]
[9]
Coggins WJ, Swenson EW, Dawson WW, et al. Health status of chronic heavy cannabis users. Ann N Y Acad Sci 1976; 282(1 Chronic Canna): 148-61.
[http://dx.doi.org/10.1111/j.1749-6632.1976.tb49894.x] [PMID: 1071375]
[10]
Lacerda LD, Kowarski A, Johanson AJ, Athanasiou R, Migeon CJ. Integrated concentration and circadian variation of plasma testosterone in normal men. J Clin Endocrinol Metab 1973; 37(3): 366-71.
[http://dx.doi.org/10.1210/jcem-37-3-366] [PMID: 4799032]
[11]
Hembree WC, Zeidenberg P, Nahas GG. Marihuana’s effects on human gonadal function Marihuana. Springer 1976; pp. 521-32.
[12]
Mandal TK, Das NS. Effect of δ-9-tetrahydrocannabinol on altered antioxidative enzyme defense mechanisms and lipid peroxidation in mice testes. Eur J Pharmacol 2009; 607(1-3): 178-87.
[http://dx.doi.org/10.1016/j.ejphar.2009.01.025] [PMID: 19326570]
[13]
Goldstein H, Harclerode J, Nyquist SE. Effects of chronic administration of delta-9-tetrahydrocannabinol and cannabidiol on rat testicular esterase isozymes. Life Sci 1977; 20(6): 951-4.
[http://dx.doi.org/10.1016/0024-3205(77)90280-6] [PMID: 850463]
[14]
Dalterio S, Bartke A. Perinatal exposure to cannabinoids alters male reproductive function in mice. Science 1979; 205(4413): 1420-2.
[http://dx.doi.org/10.1126/science.472762] [PMID: 472762]
[15]
Dixit VP, Sharma VN, Lohiya NK. The effect of chronically administered cannabis extract on the testicular function of mice. Eur J Pharmacol 1974; 26(1): 111-4.
[http://dx.doi.org/10.1016/0014-2999(74)90081-8] [PMID: 4831978]
[16]
Merari A, Barak A, Plaves M. Effects of? 1(2)-tetrahydrocannabinol on copulation in the male rat. Psychopharmacology 1973; 28(3): 243-6.
[http://dx.doi.org/10.1007/BF00429304] [PMID: 4690999]
[17]
Ahmadi K, Roshan-Milani S, Asgharzadeh F, Pourjabali M, Fard AA. In vitro and in vivo pretreatment with selenium mitigates tetrahydrocannabinol-induced testicular cell apoptosis: The role of AKT and p53 pathways. Biol Trace Elem Res 2021; 199(6): 2278-87.
[http://dx.doi.org/10.1007/s12011-020-02322-5] [PMID: 32815089]
[18]
Nahas GG, Frick HC, Lattimer JK, Latour C, Harvey D. Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa. Hum Psychopharmacol 2002; 17(2): 103-13.
[http://dx.doi.org/10.1002/hup.369] [PMID: 12404700]
[19]
Fonseca BM, Correia-da-Silva G, Teixeira NA. Cannabinoid-induced cell death in endometrial cancer cells: Involvement of TRPV1 receptors in apoptosis. J Physiol Biochem 2018; 74(2): 261-72.
[http://dx.doi.org/10.1007/s13105-018-0611-7] [PMID: 29441458]
[20]
Patsos HA, Greenhough A, Hicks DJ, et al. The endogenous cannabinoid, anandamide, induces COX-2-dependent cell death in apoptosis-resistant colon cancer cells. Int J Oncol 2010; 37(1): 187-93.
[PMID: 20514410]
[21]
Almada M, Costa L, Fonseca BM, Amaral C, Teixeira N, Correia-da-Silva G. The synthetic cannabinoid WIN-55,212 induced-apoptosis in cytotrophoblasts cells by a mechanism dependent on CB1 receptor. Toxicology 2017; 385: 67-73.
[http://dx.doi.org/10.1016/j.tox.2017.04.013] [PMID: 28495606]
[22]
Gómez R, Conde J, Scotece M, et al. Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes. J Orthop Res 2014; 32(9): 1137-46.
[http://dx.doi.org/10.1002/jor.22660] [PMID: 24902823]
[23]
Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10−/− mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 2012; 258(2): 256-67.
[http://dx.doi.org/10.1016/j.taap.2011.11.005] [PMID: 22119709]
[24]
Maccarrone M, Cecconi S, Rossi G, Battista N, Pauselli R, Finazzi-Agrò A. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Endocrinology 2003; 144(1): 20-8.
[http://dx.doi.org/10.1210/en.2002-220544] [PMID: 12488326]
[25]
Rossi G, Gasperi V, Paro R, Barsacchi D, Cecconi S, Maccarrone M. Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Endocrinology 2007; 148(3): 1431-9.
[http://dx.doi.org/10.1210/en.2006-0969] [PMID: 17110429]
[26]
Campbell VA. Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacology 2001; 40(5): 702-9.
[http://dx.doi.org/10.1016/S0028-3908(00)00210-0] [PMID: 11311898]
[27]
Kiraz Y, Adan A, Kartal Yandim M, Baran Y. Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol 2016; 37(7): 8471-86.
[http://dx.doi.org/10.1007/s13277-016-5035-9] [PMID: 27059734]
[28]
Basciani S, Mariani S, Spera G, Gnessi L. Role of platelet-derived growth factors in the testis. Endocr Rev 2010; 31(6): 916-39.
[http://dx.doi.org/10.1210/er.2010-0004] [PMID: 20650860]
[29]
Hoch RV, Soriano P. Roles of PDGF in animal development 2003.
[http://dx.doi.org/10.1242/dev.00721]
[30]
Kheradmand F, Hashemnia SMR, Valizadeh N, Roshan-Milani S. The effects of imatinib mesylate on cellular viability, platelet derived growth factor and stem cell factor in mouse testicular normal leydig cells. J Reprod Infertil 2016; 17(2): 82-7.
[PMID: 27141462]
[31]
Nurmio M, Kallio J, Toppari J, Jahnukainen K. Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis. Reprod Toxicol 2008; 25(4): 442-6.
[http://dx.doi.org/10.1016/j.reprotox.2008.03.004] [PMID: 18472395]
[32]
Reigstad LJ, Varhaug JE, Lillehaug JR. Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. FEBS J 2005; 272(22): 5723-41.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04989.x] [PMID: 16279938]
[33]
Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: A clinical approach. BJU Int 2005; 95(4): 503-7.
[http://dx.doi.org/10.1111/j.1464-410X.2005.05328.x] [PMID: 15705068]
[34]
Takeshima T, Usui K, Mori K, et al. Oxidative stress and male infertility. Reprod Med Biol 2021; 20(1): 41-52.
[http://dx.doi.org/10.1002/rmb2.12353] [PMID: 33488282]
[35]
Torres-Arce E, Vizmanos B, Babio N, Márquez-Sandoval F, Salas-Huetos A. Dietary antioxidants in the treatment of male infertility: Counteracting oxidative stress. Biology 2021; 10(3): 241.
[http://dx.doi.org/10.3390/biology10030241] [PMID: 33804600]
[36]
Zhaku V, Agarwal A, Beadini S, Henkel R, Finelli R, Beadini N. Male Infertility, Oxidative Stress and Antioxidants. Vitamin E in Health and Disease-Interactions, Diseases and Health Aspects. IntechOpen, London; England 2021.
[37]
Khoobbakht Z, Roostaei-Ali Mehr M, Mohammadi M, Mohammadghasemi F, Sohani MM. Supplementation of various zinc sources modify sexual development and testicular IGF family gene expression in pre-pubertal male Japanese quail. Res Vet Sci 2020; 130: 87-92.
[http://dx.doi.org/10.1016/j.rvsc.2020.03.004] [PMID: 32155471]
[38]
Pourhassanali N, Roshan-Milani S, Kheradmand F, Motazakker M, Bagheri M, Saboory E. Zinc attenuates ethanol-induced Sertoli cell toxicity and apoptosis through caspase-3 mediated pathways. Reprod Toxicol 2016; 61: 97-103.
[http://dx.doi.org/10.1016/j.reprotox.2016.03.041] [PMID: 27033740]
[39]
Türk S, Mändar R, Mahlapuu R, Viitak A, Punab M, Kullisaar T. Male infertility: Decreased levels of selenium, zinc and antioxidants. J Trace Elem Med Biol 2014; 28(2): 179-85.
[http://dx.doi.org/10.1016/j.jtemb.2013.12.005] [PMID: 24462254]
[40]
Prasad AS. Zinc: An antioxidant and anti-inflammatory agent: Role of zinc in degenerative disorders of aging. J Trace Elem Med Biol 2014; 28(4): 364-71.
[http://dx.doi.org/10.1016/j.jtemb.2014.07.019] [PMID: 25200490]
[41]
Prasad AS. Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Front Nutr 2014; 1: 14.
[http://dx.doi.org/10.3389/fnut.2014.00014] [PMID: 25988117]
[42]
Yu ZP, Le GW, Shi YH. Effect of zinc sulphate and zinc methionine on growth, plasma growth hormone concentration, growth hormone receptor and insulin-like growth factor-I gene expression in mice. Clin Exp Pharmacol Physiol 2005; 32(4): 273-8.
[http://dx.doi.org/10.1111/j.1440-1681.2005.04183.x] [PMID: 15810991]
[43]
Asgharzadeh F, Roshan-Milani S, Fard AA, et al. The protective effect of zinc on morphine-induced testicular toxicity via p53 and Akt pathways: An in vitro and in vivo approach. J Trace Elem Med Biol 2021; 67: 126776.
[http://dx.doi.org/10.1016/j.jtemb.2021.126776] [PMID: 33984544]
[44]
Soltanineghad M, Roshan-Milani S, Saboory E, et al. Opioid-mediated Sertoli cells apoptosis is involved in testicular homeostasis and/or reproductive dysfunction. Bratisl Med J 2019; 120(4): 277-83.
[http://dx.doi.org/10.4149/BLL_2019_041] [PMID: 31023050]
[45]
Hashemnia SMR, Atari-Hajipirloo S. Roshan- Milani, S.; Valizadeh, N.; Mahabadi, S.; Kheradmand, F. Imatinib alters cell viability but not growth factors levels in TM4 Sertoli cells. Int J Reprod Biomed 2016; 14(9): 577-82.
[http://dx.doi.org/10.29252/ijrm.14.9.577] [PMID: 27738659]
[46]
Pourheydar B, Soleimani Asl S, Azimzadeh M, Rezaei Moghadam A, Marzban A, Mehdizadeh M. Neuroprotective effects of bone marrow mesenchymal stem cells on bilateral common carotid arteries occlusion model of cerebral ischemia in rat. Behav Neurol 2016; 2016: 1-10.
[http://dx.doi.org/10.1155/2016/2964712] [PMID: 27847404]
[47]
Brubacher JR, Chan H, Erdelyi S, et al. Cannabis use as a risk factor for causing motor vehicle crashes: A prospective study. Addiction 2019; 114(9): 1616-26.
[http://dx.doi.org/10.1111/add.14663] [PMID: 31106494]
[48]
Battistella G, Fornari E, Thomas A, et al. Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving. PLoS One 2013; 8(1): e52545.
[http://dx.doi.org/10.1371/journal.pone.0052545] [PMID: 23300977]
[49]
Desrosiers NA, Himes SK, Scheidweiler KB, Concheiro-Guisan M, Gorelick DA, Huestis MA. Phase I and II cannabinoid disposition in blood and plasma of occasional and frequent smokers following controlled smoked cannabis. Clin Chem 2014; 60(4): 631-43.
[http://dx.doi.org/10.1373/clinchem.2013.216507] [PMID: 24563491]
[50]
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 1992; 16(5): 276-82.
[http://dx.doi.org/10.1093/jat/16.5.276] [PMID: 1338215]
[51]
Bronson M, Latour C, Nahas GG. Distribution and disposition of delta-9-tetrahydrocannabinol (THC) in different tissues of the rat. The cannabinoids: Chemical, pharmacologic, and therapeutic aspects. Elsevier 1984; pp. 309-17.
[52]
Hembree W, Nahas G, Zeidenberg P, Huang H. Changes in human spermatozoa associated with high dose marihuana smoking. Marihuana Biological Effects. Elsevier, Amsterdam; Netherlands 1978; pp. 429-39.
[53]
Huang H, Nahas G, Hembree WC. Morphological-changes of spermatozoa during marihuana induced depression of human spermatogenesis. Feder proc 1978; 37(3): 739-9.
[54]
Chai F, Truong-Tran AQ, Ho LH, Zalewski PD. Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review. Immunol Cell Biol 1999; 77(3): 272-8.
[http://dx.doi.org/10.1046/j.1440-1711.1999.00825.x] [PMID: 10361260]
[55]
Zalewski PD, Forbes IJ, Giannakis C. Physiological role for zinc in prevention of apoptosis (gene-directed death). Biochem Int 1991; 24(6): 1093-101.
[PMID: 1781788]
[56]
El-Habashi AA, Mousa MA, El-Eraky WI, Ahmed WKKHH, Moad NA. Possible mechanisms for the toxic effects of marijuana smoke on the reproductive axis of male albino rats. J Appl Pharm Sci 2013; 3(4): S59-67.
[57]
Galve-Roperh I, Sánchez C, Cortés ML, del Pulgar TG, Izquierdo M, Guzmán M. Anti-tumoral action of cannabinoids: Involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 2000; 6(3): 313-9.
[http://dx.doi.org/10.1038/73171] [PMID: 10700234]
[58]
Sun W, Ni Z, Li R, et al. Flurochloridone induces Sertoli cell apoptosis through ROS-dependent mitochondrial pathway. Ecotoxicol Environ Saf 2021; 216: 112183.
[http://dx.doi.org/10.1016/j.ecoenv.2021.112183] [PMID: 33812209]
[59]
Osadchuk LVO, Danilenko ADD, Osadchuk AVO. An influence of zinc on male infertility. Urologiia 2021; 5_2021(5): 84-93.
[http://dx.doi.org/10.18565/urology.2021.5.84-93] [PMID: 34743439]
[60]
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): 1010-8.
[http://dx.doi.org/10.1139/apnm-2018-0070] [PMID: 29726717]
[61]
Mruk DD, Silvestrini B, Mo M, Cheng CY. Antioxidant superoxide dismutase-a review: its function, regulation in the testis, and role in male fertility. Contraception 2002; 65(4): 305-11.
[http://dx.doi.org/10.1016/S0010-7824(01)00320-1] [PMID: 12020784]
[62]
Solinas M, Massi P, Cinquina V, et al. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PLoS One 2013; 8(10): e76918.
[http://dx.doi.org/10.1371/journal.pone.0076918] [PMID: 24204703]
[63]
Rajesh M, Mukhopadhyay P, Haskó G, Pacher P. Cannabinoid CB1 receptor inhibition decreases vascular smooth muscle migration and proliferation. Biochem Biophys Res Commun 2008; 377(4): 1248-52.
[http://dx.doi.org/10.1016/j.bbrc.2008.10.159] [PMID: 18996082]
[64]
Barres BA, Schmid R, Sendnter M, Raff MC. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 1993; 118(1): 283-95.
[http://dx.doi.org/10.1242/dev.118.1.283] [PMID: 8375338]
[65]
Flores AI, Mallon BS, Matsui T, et al. Akt-mediated survival of oligodendrocytes induced by neuregulins. J Neurosci 2000; 20(20): 7622-30.
[http://dx.doi.org/10.1523/JNEUROSCI.20-20-07622.2000] [PMID: 11027222]
[66]
Adedara IA, Abiola MA, Adegbosin AN, Odunewu AA, Farombi EO. Impact of binary waterborne mixtures of nickel and zinc on hypothalamic-pituitary-testicular axis in rats. Chemosphere 2019; 237: 124501.
[http://dx.doi.org/10.1016/j.chemosphere.2019.124501] [PMID: 31398612]
[67]
Lei KY, Abbasi A, Prasad AS. Function of pituitary-gonadal axis in zinc-deficient rats. Am J Physiol 1976; 230(6): 1730-2.
[http://dx.doi.org/10.1152/ajplegacy.1976.230.6.1730] [PMID: 779495]
[68]
Root AW, Duckett G, Sweetland M, Reiter EO. Effects of zinc deficiency upon pituitary function in sexually mature and immature male rats. J Nutr 1979; 109(6): 958-64.
[http://dx.doi.org/10.1093/jn/109.6.958] [PMID: 376793]

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