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Lycopene Alleviates Titanium Dioxide Nanoparticle-Induced Testicular Toxicity by Inhibiting Oxidative Stress and Apoptosis in Mice

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Abstract

Purpose

The research was carried out to investigate the possible ameliorative effect of lycopene on TiO2 NPs-induced male reproductive toxicity and explore the possible mechanism.

Methods

Ninety-six healthy male Institute of Cancer Research (ICR) mice were equally divided into eight groups (control group, 50 mg/kg TiO2 NPs group, 5 mg/kg LYC group, 20 mg/kg LYC group, 40 mg/kg LYC group, 50 mg/kg TiO2 NPs + 5 mg/kg LYC group, 50 mg/kg TiO2 NPs + 20 mg/kg LYC group, 50 mg/kg TiO2 NPs + 40 mg/kg LYC group), and the mice were treated by intragastric administration every day for 30 days in this research. Sperm parameters, testicular histopathology, oxidant and antioxidant enzymes, and cell apoptosis-related protein expression in the testicular tissue were analyzed.

Results

The results showed that TiO2 NPs exposure significantly decreased sperm count and motility, and TiO2 NPs also increased sperm malformation in the epididymis; these characteristics were improved when co-administration with LYC. Testicular histopathological lesions like disorder of germ cells arrange, detachment, atrophy, and vacuolization were observed after TiO2 NPs exposure, and these abnormalities were effectively ameliorated by co-administration with LYC. Oxidative stress was induced by TiO2 NPs exposure as evidenced by increased the level of MDA and decreased the activity of SOD as well as the level of anti-O2, and these alterations were effectively prevented by co-administration with LYC. LYC also alleviated TiO2 NPs-induced germ cell apoptosis by inhibiting mitochondrial apoptotic pathway, as shown by the upregulation of Bcl-2, the downregulation of Bax, Cleaved Caspase 3, and Cleaved Caspase 9.

Conclusion

LYC could ameliorate TiO2 NPs-induced testicular damage via inhibiting oxidative stress and apoptosis, which could be used to alleviate the testicular toxicity associated with TiO2 NPs intake.

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Data Availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

References

  1. Chen X, Mao SS (2007) Titanium dioxide nanomaterials: synthesis, properties, modifications, and applications. Chem Rev 107(7):2891–2959. https://doi.org/10.1021/cr0500535

    Article  CAS  PubMed  Google Scholar 

  2. Tsuji JS, Maynard AD, Howard PC, James JT, Lam CW, Warheit DB, Santamaria AB (2006) Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles. Toxicol Sci 89(1):42–50. https://doi.org/10.1093/toxsci/kfi339

    Article  CAS  PubMed  Google Scholar 

  3. Zahin N, Anwar R, Tewari D, Kabir MT, Sajid A, Mathew B, Abdel-Daim MM (2020) Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery. Environ Sci Pollut Res Int 27(16):19151–19168. https://doi.org/10.1007/s11356-019-05211-0

    Article  CAS  PubMed  Google Scholar 

  4. Oliveira WF, Arruda IRS, Silva GMM, Machado G, Coelho L, Correia MTS (2017) Functionalization of titanium dioxide nanotubes with biomolecules for biomedical applications. Mater Sci Eng C Mater Biol Appl 81:597–606. https://doi.org/10.1016/j.msec.2017.08.0

    Article  CAS  PubMed  Google Scholar 

  5. Shakeel M, Jabeen F, Shabbir S, Asghar MS, Khan MS, Chaudhry AS (2016) Toxicity of nano-titanium dioxide (TiO2-NP) through various routes of exposure: a review. Biol Trace Elem Res 172(1):1–36. https://doi.org/10.1007/s12011-015-0550-x

    Article  CAS  PubMed  Google Scholar 

  6. Hong F, Yu X, Wu N, Zhang YQ (2017) Progress of in vivo studies on the systemic toxicities induced by titanium dioxide nanoparticles. Toxicol Res (Camb) 6(2):115–133. https://doi.org/10.1039/c6tx00338a

    Article  CAS  Google Scholar 

  7. Shi H, Magaye R, Castranova V, Zhao J (2013) Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 10:15. https://doi.org/10.1186/1743-8977-10-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao L, Zhu Y, Chen Z, Xu H, Zhou J, Tang S, Jia G (2018) Cardiopulmonary effects induced by occupational exposure to titanium dioxide nanoparticles. Nanotoxicol 12(2):169–184. https://doi.org/10.1080/17435390.2018.1425502

    Article  CAS  Google Scholar 

  9. Wang R, Song B, Wu J, Zhang Y, Chen A, Shao L (2018) Potential adverse effects of nanoparticles on the reproductive system. Int J Nanomed 13:8487–8506. https://doi.org/10.2147/ijn.S170723

    Article  CAS  Google Scholar 

  10. Wu T, Tang M (2018) Review of the effects of manufactured nanoparticles on mammalian target organs. J Appl Toxicol 38(1):25–40. https://doi.org/10.1002/jat.3499

    Article  CAS  PubMed  Google Scholar 

  11. Hussein MMA, Gad E, Ahmed MM, Arisha AH, Mahdy HF, Swelum AA, Saadeldin IM (2019) Amelioration of titanium dioxide nanoparticle reprotoxicity by the antioxidants morin and rutin. Environ Sci Pollut Res Int 26(28):29074–29084. https://doi.org/10.1007/s11356-019-06091-0

    Article  CAS  PubMed  Google Scholar 

  12. Miura N, Ohtani K, Hasegawa T, Yoshioka H, Hwang GW (2019) Biphasic adverse effect of titanium nanoparticles on testicular function in mice. Sci Re 9(1):14373. https://doi.org/10.1038/s41598-019-50741-9

    Article  CAS  Google Scholar 

  13. Lauvås AJ, Skovmand A, Poulsen MS, Kyjovska ZO, Roursgaard M, Goericke-Pesch S, Hougaard KS (2019) Airway exposure to TiO2 nanoparticles and quartz and effects on sperm counts and testosterone levels in male mice. Reprod Toxicol 90:134–140. https://doi.org/10.1016/j.reprotox.2019.07.023

    Article  CAS  PubMed  Google Scholar 

  14. Hong F, Zhao X, Si W, Ze Y, Wang L, Zhou Y, Zhang J (2015) Decreased spermatogenesis led to alterations of testis-specific gene expression in male mice following nano-TiO2 exposure. J Hazard Mater 300:718–728. https://doi.org/10.1016/j.jhazmat.2015.08.010

    Article  CAS  PubMed  Google Scholar 

  15. Arslan NP, Keles ON, Gonul-Baltaci N (2021) Effect of Titanium Dioxide and Silver Nanoparticles on Mitochondrial Dynamics in Mouse Testis Tissue. Biol Trace Elem Res. https://doi.org/10.1007/s12011-021-02763-6

    Article  PubMed  Google Scholar 

  16. Hong F, Zhou Y (2020) Spermatogenic apoptosis and the involvement of the Nrf2 pathway in male mice following exposure to nano titanium dioxide. J Biomed Nanotechnol 16(3):373–381. https://doi.org/10.1166/jbn.2020.2895

    Article  CAS  PubMed  Google Scholar 

  17. Ye L, Hong F, Ze X, Li L, Zhou Y, Ze Y (2017) Toxic effects of TiO2 nanoparticles in primary cultured rat sertoli cells are mediated via a dysregulated Ca(2+) /PKC/p38 MAPK/NF-κB cascade. J Biomed Mater Res A 105(5):1374–1382. https://doi.org/10.1002/jbm.a.36021

    Article  CAS  PubMed  Google Scholar 

  18. Mao Z, Yao M, Xu B, Ji X, Jiang H, Han X, Xia Y (2017) Cytoskeletons of two reproductive germ cell lines response differently to titanium dioxide nanoparticles mediating vary reproductive toxicity. J Biomed Nanotechnol 13(4):409–416. https://doi.org/10.1166/jbn.2017.2360

    Article  CAS  PubMed  Google Scholar 

  19. Alaee S, Ilani M (2017) Effect of titanium dioxide nanoparticles on male and female reproductive systems. J Adv Med Sci App Technol 3(1):3. https://doi.org/10.18869/nrip.jamsat.3.1.3

    Article  Google Scholar 

  20. Mishra DP, Shaha C (2005) Estrogen-induced spermatogenic cell apoptosis occurs via the mitochondrial pathway: role of superoxide and nitric oxide. J Biol Chem 280(7):6181–6196. https://doi.org/10.1074/jbc.M405970200

    Article  CAS  PubMed  Google Scholar 

  21. Morgan AM, Ibrahim MA, Noshy PA (2017) Reproductive toxicity provoked by titanium dioxide nanoparticles and the ameliorative role of Tiron in adult male rats. Biochem Biophys Res Commun 486(2):595–600. https://doi.org/10.1016/j.bbrc.2017.03.098

    Article  CAS  PubMed  Google Scholar 

  22. Gao G, Ze Y, Zhao X, Sang X, Zheng L, Ze X (2013) Zhang X (2013) Titanium dioxide nanoparticle-induced testicular damage, spermatogenesis suppression, and gene expression alterations in male mice. J Hazard Mater 258–259:133–143. https://doi.org/10.1016/j.jhazmat.2013.04.046

    Article  CAS  PubMed  Google Scholar 

  23. Hong F, Zhao X, Chen M, Zhou Y, Ze Y, Wang L, Ye L (2016) TiO2 nanoparticles-induced apoptosis of primary cultured Sertoli cells of mice. J Biomed Mater Res A 104(1):124–135. https://doi.org/10.1002/jbm.a.35548

    Article  CAS  PubMed  Google Scholar 

  24. Durairajanayagam D, Agarwal A, Ong C, Prashast P (2014) Lycopene and male infertility. Asian J Androl 16(3):420–425. https://doi.org/10.4103/1008-682x.126384

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chen J, Song Y, Zhang L (2013) Effect of lycopene supplementation on oxidative stress: an exploratory systematic review and meta-analysis of randomized controlled trials. J Med Food 16(5):361–374. https://doi.org/10.1089/jmf.2012.2682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Matos HR, Capelozzi VL, Gomes OF, Mascio PD, Medeiros MH (2001) Lycopene inhibits DNA damage and liver necrosis in rats treated with ferric nitrilotriacetate. Arch Biochem Biophys 396(2):171–177. https://doi.org/10.1006/abbi.2001.2611

    Article  CAS  PubMed  Google Scholar 

  27. Aly H (2019) Testicular toxicity of gentamicin in adult rats: ameliorative effect of lycopene. Hum Exp Toxicol 38(11):1302–1313. https://doi.org/10.1177/0960327119864160

    Article  CAS  PubMed  Google Scholar 

  28. Li W, Jiang B, Cao X, Xie Y, Huang T (2017) Protective effect of lycopene on fluoride-induced ameloblasts apoptosis and dental fluorosis through oxidative stress-mediated Caspase pathways. Chem Biol Interact 261:27–34. https://doi.org/10.1016/j.cbi.2016.11.021

    Article  CAS  PubMed  Google Scholar 

  29. Palabiyik SS, Erkekoglu P, Zeybek ND, Kizilgun M, Baydar DE, Sahin G, Giray BK (2013) Protective effect of lycopene against ochratoxin A induced renal oxidative stress and apoptosis in rats. Exp Toxicol Pathol 65(6):853–861. https://doi.org/10.1016/j.etp.2012.12.004

    Article  CAS  PubMed  Google Scholar 

  30. Palozza P, Simone R, Catalano A, Boninsegna A, Böhm V, Fröhlich K, Ranelletti FO (2010) Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. J Nutr Biochem 21(1):34–46. https://doi.org/10.1016/j.jnutbio.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  31. Salem EA, Salem NA, Maarouf AM, Serefoglu EC, Hellstrom WJ (2012) Selenium and lycopene attenuate cisplatin-induced testicular toxicity associated with oxidative stress in Wistar rats. Urology 79(5):1184.e1181-1186. https://doi.org/10.1016/j.urology.2011.12.006

    Article  Google Scholar 

  32. Krishnamoorthy G, Selvakumar K, Venkataraman P, Elumalai P, Arunakaran J (2013) Lycopene supplementation prevents reactive oxygen species mediated apoptosis in Sertoli cells of adult albino rats exposed to polychlorinated biphenyls. Interdiscip Toxicol 6(2):83–92. https://doi.org/10.2478/intox-2013-0015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Altayeb ZM, El-Mahalaway AM, Salem MM (2017) Histological and immunohistochemical study of titanium dioxide nanoparticle effect on the rat renal cortex and the possible protective role of lycopene. J Egy Histol 40(1):80–93. https://doi.org/10.21608/EJH.2017.3700

    Article  Google Scholar 

  34. Lu T, Ling C, Hu M, Meng X, Deng Y, An H, Guo S (2020) Effect of nano-titanium dioxide on blood-testis barrier and MAPK signaling pathway in male mice. Biol Trace Elem Res. https://doi.org/10.1007/s12011-020-02404-4

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hussein MM, Ali HA, Saadeldin IM, Ahmed MM (2016) Querectin alleviates zinc oxide nanoreprotoxicity in male albino rats. J Biochem Mol Toxicol 30(10):489–496. https://doi.org/10.1002/jbt.21812

    Article  CAS  PubMed  Google Scholar 

  36. Agarwal A, Makker K, Sharma R (2008) Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol 59(1):2–11. https://doi.org/10.1111/j.1600-0897.2007.00559.x

    Article  CAS  PubMed  Google Scholar 

  37. Ghasemnejad-Berenji M, Ghazi-Khansari M, Yazdani I, Nobakht M, Abdollahi A, Ghasemnejad-Berenji H, Dehpour AR (2018) Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testicular torsion/detorsion in rats. Andrologia 50(2). https://doi.org/10.1111/and.12846

  38. Khorsandi L, Orazizadeh M, Moradi-Gharibvand N, Hemadi M, Mansouri E (2017) Beneficial effects of quercetin on titanium dioxide nanoparticles induced spermatogenesis defects in mice. Environ Sci Pollut Res Int 24(6):5595–5606. https://doi.org/10.1007/s11356-016-8325-2

    Article  CAS  PubMed  Google Scholar 

  39. Kong L, Hu W, Lu C, Cheng K, Tang M (2019) Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo-protective effects of vitamin C in male rats. Chemosphere 218:259–265. https://doi.org/10.1016/j.chemosphere.2018.11.128

    Article  CAS  PubMed  Google Scholar 

  40. Hong F, Si W, Zhao X, Wang L, Zhou Y, Chen M, Zhang J (2015) TiO2 nanoparticle exposure decreases spermatogenesis via biochemical dysfunctions in the testis of male mice. J Agric Food Chem 63(31):7084–7092. https://doi.org/10.1021/acs.jafc.5b02652

    Article  CAS  PubMed  Google Scholar 

  41. Narayana K, D’Souza UJ, Seetharama Rao KP (2002) Ribavirin-induced sperm shape abnormalities in Wistar rat. Mutat Res 513(1–2):193–196. https://doi.org/10.1016/s1383-5718(01)00308-4

    Article  CAS  PubMed  Google Scholar 

  42. Orazizadeh M, Khorsandi L, Absalan F, Hashemitabar M, Daneshi E (2014) Effect of beta-carotene on titanium oxide nanoparticles-induced testicular toxicity in mice. J Assist Reprod Genet 31(5):561–568. https://doi.org/10.1007/s10815-014-0184-5

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ghanbary F, Seydi E, Naserzadeh P, Salimi A (2018) Toxicity of nanotitanium dioxide (TiO2-NP) on human monocytes and their mitochondria. Environ Sci Pollut Res Int 25(7):6739–6750. https://doi.org/10.1007/s11356-017-0974-2

    Article  CAS  PubMed  Google Scholar 

  44. Geraets L, Oomen AG, Krystek P, Jacobsen NR, Wallin H, Laurentie M, Jong WH (2014) Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats. Part Fibre Toxicol 11:30. https://doi.org/10.1186/1743-8977-11-30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jafari A, Karimipour M, Khaksar MR, Ghasemnejad-Berenji M (2020) Protective effects of orally administered thymol against titanium dioxide nanoparticle-induced testicular damage. Environ Sci Pollut Res Int 27(2):2353–2360. https://doi.org/10.1007/s11356-019-06937-7

    Article  CAS  PubMed  Google Scholar 

  46. Kao SH, Chao HT, Chen HW, Hwang TIS, Liao TL, Wei YH (2008) Increase of oxidative stress in human sperm with lower motility. Fertil Steril 89(5):1183–1190. https://doi.org/10.1016/j.fertnstert.2007.05.029

    Article  CAS  PubMed  Google Scholar 

  47. Bahrami N, Mehrzadi S, Goudarzi M, Mansouri E, Fatemi I (2018) Lycopene abrogates di-(2-ethylhexyl) phthalate induced testicular injury by modulating oxidative, endocrine and inflammatory changes in mice. Life Sci 207:265–271. https://doi.org/10.1016/j.lfs.2018.06.009

    Article  CAS  PubMed  Google Scholar 

  48. Costa-Rodrigues J, Pinho O, Monteiro PRR (2018) Can lycopene be considered an effective protection against cardiovascular disease? Food Chem 245:1148–1153. https://doi.org/10.1016/j.foodchem.2017.11.055

    Article  CAS  PubMed  Google Scholar 

  49. Tian Y, Xiao Y, Wang B, Sun C, Tang K, Sun F (2018) Vitamin E and lycopene reduce coal burning fluorosis-induced spermatogenic cell apoptosis via oxidative stress-mediated JNK and ERK signaling pathways. Biosci Rep 38(4). https://doi.org/10.1042/bsr20171003

  50. Xu A, Wang J, Wang H, Sun Y, Hao T (2019) Protective effect of lycopene on testicular toxicity induced by Benzo[a]pyrene intake in rats. Toxicology 427:152301. https://doi.org/10.1016/j.tox.2019.152301

    Article  CAS  PubMed  Google Scholar 

  51. Ghobrial IM, Witzig TE, Adjei AA (2005) Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 55(3):178–194. https://doi.org/10.3322/canjclin.55.3.178

    Article  PubMed  Google Scholar 

  52. Xu F, Wang P, Yao Q, Shao B, Yu H, Yu K, Li Y (2019) Lycopene alleviates AFB(1)-induced immunosuppression by inhibiting oxidative stress and apoptosis in the spleen of mice. Food Funct 10(7):3868–3879. https://doi.org/10.1039/c8fo02300j

    Article  CAS  PubMed  Google Scholar 

  53. Kvansakul M, Caria S, Hinds MG (2017) The Bcl-2 family in host-virus interactions. Viruses 9(10). https://doi.org/10.3390/v9100290

  54. Würstle ML, Rehm M (2014) A systems biology analysis of apoptosome formation and apoptosis execution supports allosteric procaspase-9 activation. J Biol Chem 289(38):26277–26289. https://doi.org/10.1074/jbc.M114.590034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 21966027, 32060125), the Xinjiang Uygur Autonomous region Graduate Student Innovation Project (XJ2019G092), and the Open Sharing Fund for the Large-scale Instruments and Equipment of Shihezi University.

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Methodology and data curation: Xiaojia Meng, Li Li, and Hongmei An. Formal analysis and writing, and original draft preparation: Xiaojia Meng, Yaxin Deng, Chunmei Ling, Tianjiao Lu, Guanling Song, and Yan Wang. Funding acquisition, review, and editing: Guanling Song.

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Correspondence to Guanling Song or Yan Wang.

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The study protocols were approved by the Animal Experiments Ethical Committee of the First Affiliated Hospital of medical college of Shihezi University (Approval No. A2019-156–01).

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Xiaojia Meng and Li Li contributed equally to this work

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Meng, X., Li, L., An, H. et al. Lycopene Alleviates Titanium Dioxide Nanoparticle-Induced Testicular Toxicity by Inhibiting Oxidative Stress and Apoptosis in Mice. Biol Trace Elem Res 200, 2825–2837 (2022). https://doi.org/10.1007/s12011-021-02881-1

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