Detrimental effects of cerium oxide nanoparticles on testis, sperm parameters quality, and in vitro fertilization in mice: An experimental study


Background: Cerium oxide nanoparticles (CeO2 NPs) as an important nanomaterial have a wide range of applications in many fields and human beings’ exposure to this nanomaterial is unavoidable. The effects of CeO2 NPs on the male reproductive system are controversial.

Objective: To determine the effects of the administration of CeO2 NPs on the testis tissue, sperm parameters, and in vitro fertilization (IVF) in mice.

Materials and Methods: Twenty-four male mice were divided into three groups (n = 8/each): one control and two experimental groups receiving CeO2 NPs at doses of 50 and 100 mg/kg body weight, respectively, for 35 days. At the end of the experiment, the diameter of seminiferous tubules (SNTs), epithelial height of SNTs, spermiogenesis index in testes, sperm parameters (count, motility, viability, and morphology), sperm chromatin condensation, DNA integrity, and IVF assays were analyzed.

Results: Histological results showed that the tubular diameter, the epithelial height of the SNTs, and the spermiogenesis index were significantly decreased in the experimental groups receiving CeO2 NPs. All sperm parameters in the experimental groups were significantly reduced and, additionally, the percentages of immature sperms and sperms with DNA damage were significantly increased in groups treated with CeO2 NPs compared to the control. Furthermore, the rates of IVF and in vitro embryo development were decreased.

Conclusion: Collectively, the current study showed that oral administration of CeO2 NPs in mice had detrimental effects on the male reproductive system through inducing testicular tissue alterations, decreasing sperm parameters quality, and also diminishing the IVF rate and in vitro embryonic development.

Key words: Cerium oxide, Testis, Sperm, Fertilization, Mice.

[1] Park EJ, Cho WS, Jeong J, Yi Jh, Choi K, Kim Y, et al. Induction of inflammatory responses in mice treated with cerium oxide nanoparticles by intratracheal instillation. J Health Sci 2010; 56: 387–396.

[2] Bottero JY, Rose J, Wiesner MR. Nanotechnologies: Tools for sustainability in a new wave of water treatment processes. Integr Environ Assess Manag 2006; 2: 391– 395.

[3] Vance ME, Kuiken T, Vejerano EP, McGinnis SP, Hochella Jr MF, Rejeski D, et al. Nanotechnology in the real world: Redeveloping the nanomaterial consumer products inventory. Beilstein J Nanotechnol 2015; 6: 1769–1780.

[4] Sarkar A, Fatima I, Mohammad Sajid Jamal Q, Sayeed U, Khan KA, Akhtar S, et al. Nanoparticles as a carrier system for drug delivery across blood brain barrier. Curr Drug Metab 2017; 18: 129–137.

[5] Das J, Choi YJ, Yasuda H, Han JW, Park C, Song H, et al. Efficient delivery of C/EBP beta gene into human mesenchymal stem cells via polyethyleniminecoated gold nanoparticles enhances adipogenic differentiation. Sci Rep 2016; 6: 33784. 1–17.

[6] Soni D, Gandhi D, Tarale P, Bafana A, Pandey R, Sivanesan S. Oxidative stress and genotoxicity of zinc oxide nanoparticles to Pseudomonas species, human promyelocytic leukemic (HL-60), and blood cells. Biol Trace Elem Res 2017; 178: 218–227.

[7] Nyoka M, Choonara YE, Kumar P, Kondiah PP, Pillay VJN. Synthesis of cerium oxide nanoparticles using various methods: Implications for biomedical applications. Nanomaterials (Basel) 2020; 10: 242. 1– 21.

[8] Cassee FR, van Balen EC, Singh C, Green D, Muijser H, Weinstein J, et al. Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Crit Rev Toxicol 2011; 41: 213–229.

[9] Blanchard V, Blanchet P. Color stability for wood products during use: Effects of inorganic nanoparticles. Bio Resourses 2011; 6: 1219–1229.

[10] Park B, Donaldson K, Duffin R, Tran L, Kelly F, Mudway I, et al. Hazard and risk assessment of a nanoparticulate cerium oxide-based diesel fuel additive - A case study. Inhal Toxicol 2008; 20: 547–566.

[11] Courbiere B, Auffan M, Rollais R, Tassistro V, Bonnefoy A, Botta A, et al. Ultrastructural interactions and genotoxicity assay of cerium dioxide nanoparticles on mouse oocytes. Int J Mol Sci 2013; 14: 21613–21628.

[12] Celardo I, Pedersen JZ, Traversa E, Ghibelli L. Pharmacological potential of cerium oxide nanoparticles. Nanoscale 2011; 3: 1411–1420.

[13] Hirst SM, Karakoti A, Singh S, Self W, Tyler R, Seal S, et al. Bio−distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice. Environ Toxicol 2013; 28: 107–118.

[14] Vafaei-Pour Z, Shokrzadeh M, Jahani M, Shaki F. Embryo-protective effects of cerium oxide nanoparticles against gestational diabetes in mice. Iran J Pharm Res 2018; 17: 964–975.

[15] Hirst SM, Karakoti AS, Tyler RD, Sriranganathan N, Seal S, Reilly CM. Anti−inflammatory properties of cerium oxide nanoparticles. Small 2009; 5: 2848–2856.

[16] Nemmar A, Al-Salam S, Beegam S, Yuvaraju P, Ali BH. The acute pulmonary and thrombotic effects of cerium oxide nanoparticles after intratracheal instillation in mice. Int J Nanomedicine 2017; 12: 2913–2922.

[17] Qin F, Shen T, Li J, Qian J, Zhang J, Zhou G, et al. SF-1 mediates reproductive toxicity induced by cerium oxide nanoparticles in male mice. J Nanobiotechnology 2019; 17: 41. 1–13.

[18] Hamzeh M, Hosseinimehr SJ, Karimpour A, Mohammadi HR, Khalatbary AR, Talebpour Amiri F. Cerium oxide nanoparticles protect cyclophosphamide-induced testicular toxicity in mice. Int J Prev Med 2019; 10: 5.

[19] Falchi L, Galleri G, Dore GM, Zedda MT, Pau S, Bogliolo L, et al. Effect of exposure to CeO2 nanoparticles on ram spermatozoa during storage at 4°C for 96 hours. Reprod Biol Endocrinol 2018; 16: 19. 1–10.

[20] Qin F, Shen T, Cao H, Qian J, Zou D, Ye M, et al. CeO2 NPs relieve radiofrequency radiation, improve testosterone synthesis, and clock gene expression in Leydig cells by enhancing antioxidation. Int J Nanomedicine 2019; 14: 4601–4611.

[21] Hess RA, Chen P. Computer tracking of germ cells in the cycle of the seminiferous epithelium and prediction of changes in cycle duration in animals commonly used in reproductive biology and toxicology. J Androl 1992; 13: 185–190.

[22] Narayana K, Prashanthi N, Nayanatara A, Bairy LK, D’Souza UJ. An organophosphate insecticide methyl parathion (o-o-dimethyl o-4-nitrophenyl phosphorothioate) induces cytotoxic damage and tubular atrophy in the testis despite elevated testosterone level in the rat. J Toxicol Sci 2006; 31: 177–189.

[23] Karimipour M, Dibayi Z, Ahmadi A, Javanmard MZ, Hosseinalipour E. The protective effect of vitamin C on phenylhydrazine-induced hemolytic anemia on sperm quality and in-vitro embryo development in mice. Int J Reprod Biomed 2018; 16: 791–800.

[24] Wyrobek AJ, Gordon LA, Burkhart JG, Francis MW, Kapp Jr RW, Letz G, et al. An evaluation of the mouse sperm morphology test and other sperm tests in nonhuman mammals: A report of the US Environmental Protection Agency gene-tox program. Mutation Research 1983; 115: 1–72.

[25] Zahmatkesh E, Najafi G, Nejati V. Protective effect of royal jelly on in vitro fertilization (IVF) in male mice treated with oxymetholone. Cell J 2015; 17: 569–575.

[26] Karimipour M, Javanmard MZ, Ahmadi A, Jafari A. Oral administration of titanium dioxide nanoparticle through ovarian tissue alterations impairs mice embryonic development. Int J Reprod Biomed 2018; 16: 397–404.

[27] Robayo I, Montenegro V, Valdes C, Cox JF. CASA assessment of kinematic parameters of ram spermatozoa and their relationship to migration efficiency in ruminant cervical mucus. Reprod Domest Anim 2008; 43: 393–399.

[28] Nemati A, Farhadi A, Jalili C, Gholami M. The effect of cerium oxide during pregnancy on the development of the testicular tissue of newborn NMRI mice. Biol Trace Elem Res 2020; 195: 196–204.

[29] Perrin J, Tassistro V, Auffan M, Liu W, Botta A, Sari- Minodier I, et al. Cerium dioxide nanoparticles induce DNA damage in human spermatozoa. Hum Reprod 2014; 29: 8–9.

[30] Falchi L, Bogliolo L, Galleri G, Ariu F, Zedda MT, Pinna A, et al. Cerium dioxide nanoparticles did not alter the functional and morphologic characteristics of ram sperm during short-term exposure. Theriogenology 2016; 85: 1274–1281. e3.

[31] Kobyliak NM, Falalyeyeva TM, Kuryk OG, Beregova TV, Bodnar PM, Zholobak NM, et al. Antioxidative effects of cerium dioxide nanoparticles ameliorate age-related male infertility: Optimistic results in rats and the review of clinical clues for integrative concept of men health and fertility. EPMA J 2015; 6: 12. 1–22.

[32] Geraets L, Oomen AG, Schroeter JD, Coleman VA, Cassee FR. Tissue distribution of inhaled micro-and nano-sized cerium oxide particles in rats: Results from a 28-day exposure study. Toxicol Sci 2012; 127: 463–473.

[33] Talebi AR, Sarcheshmeh AA, Khalili MA, Tabibnejad N. Effects of ethanol consumption on chromatin condensation and DNA integrity of epididymal spermatozoa in rat. Alcohol 2011; 45: 403–409.

[34] Artimani T, Amiri I, Soleimani Asl S, Saidijam M, Hasanvand D, Afshar S. Amelioration of diabetes−induced testicular and sperm damage in rats by cerium oxide nanoparticle treatment. Andrologia 2018; 50: e13089.

[35] Preaubert L, Courbiere B, Achard V, Tassistro V, Greco F, Orsiere T, et al. Cerium dioxide nanoparticles affect in vitro fertilization in mice. Nanotoxicology 2016; 10: 111–117.

[36] Ramos AC, H Dos Santos A, Silveira KM, Kiss AC, Mesquita SFP, Gerardin DC, et al. Maternal treatment with fluoxetine promotes testicular alteration in male rat pups. Reprod Fertil Dev 2015; 28: 1206–1213.

[37] Hooley RP, Paterson M, Brown P, Kerr K, Saunders PT. Intra-testicular injection of adenoviral constructs results in Sertoli cellspecific gene expression and disruption of the seminiferous epithelium. Reproduction 2009; 137: 361–370.