Inhibition of Testosterone Synthesis Induced by Oral TiO NPs is Associated with ROS-MAPK(ERK1/2)-StAR Signaling Pathway in SD Rat

Overview

Journal Toxicol Res (Camb)

Publisher Oxford University Press

Date 2021 Sep 6

PMID 34484685

Citations 8

Authors

Shanji Liu

Yizhou Tang

Bolu Chen

Yu Zhao

Zoraida P Aguilar

Xueying Tao

Hengyi Xu

Affiliations

Soon will be listed here.

Abstract

Titanium dioxide nanoparticles (TiO NPs) have been widely used in food, medical, and other fields; their reproductive toxicity has been reported in numerous studies. However, the relevant toxicity mechanism still requires further exploration. In this paper, the effect of oral exposure to 500 mg/kg TiO NPs (anatase and rutile) in adult male SD rats was studied over 3 and 7 days. Results showed that the total sperm count and testosterone level of 7 days of exposure in serum decreased in the experimental group. Testicular tissue lesions, such as disappearance of Leydig cells, disorder of arrangement of spermatogenic cells in the lumen of convoluted seminiferous tubules, and disorder of arrangement of germ cells, were observed. Meanwhile, the expression of steroidogenic acute regulatory (StAR; the key factors of testosterone synthesis), MAPK (ERK1/2), and phosphorylated ERK1/2 in testes of SD rats after exposure to TiO NPs for 7 days decreased, while the malondialdehyde content increased and superoxide dismutase activity decreased in serum. The present study showed that TiO NPs could cause reproductive toxicity. Notably, anatase is more toxic than rutile. In addition, exposure to 500 mg/kg TiO NPs for 7 days inhibited testosterone synthesis in male rat, which may be related to the reactive oxygen species (ROS)-MAPK (ERK1/2)-StAR signal pathway. Warning that the use of TiO NPs should be regulated.

Citing Articles

Efficacy of Chlorogenic Acid in Treating Tripterygium Glycoside-Induced Asthenozoospermia in Rats and Its Possible Mechanisms.

Chen L, Bello-Onaghise G, Chen M, Li S, Zhang Y, Wang H Vet Sci. 2025; 12(1).

PMID: 39852941 PMC: 11768533. DOI: 10.3390/vetsci12010066.

Examining the Relationship Between Polystyrene Microplastics and Male Fertility: Insights From an In Vivo Study and In Vitro Sertoli Cell Culture.

Jeon B, Ko Y, Cha J, Kim C, Seo M, Lee S J Korean Med Sci. 2024; 39(38):e259.

PMID: 39376189 PMC: 11458380. DOI: 10.3346/jkms.2024.39.e259.

Exposure to Titanium Dioxide Nanoparticles Leads to Specific Disorders of Spermatid Elongation via Multiple Metabolic Pathways in Testes.

Cheng X, Jiang T, Huang Q, Ji L, Li J, Kong X ACS Omega. 2024; 9(22):23613-23623.

PMID: 38854533 PMC: 11154731. DOI: 10.1021/acsomega.4c01140.

Single-cell transcriptome profiling implicates the psychological stress-induced disruption of spermatogenesis.

Li R, Du Y, Li K, Xiong X, Zhang L, Guo C Mol Ther Nucleic Acids. 2024; 35(1):102158.

PMID: 38439912 PMC: 10910125. DOI: 10.1016/j.omtn.2024.102158.

Influence of titanium dioxide nanoparticles and/or cadmium chloride oral exposure on testicular morphology, oxidative stress, and apoptosis in rats: Ameliorative role of co-enzyme Q10.

Behairy A, Hashem M, Abo-El-Sooud K, Soliman A, Mouneir S, El-Metwally A Heliyon. 2024; 10(1):e24049.

PMID: 38268588 PMC: 10806338. DOI: 10.1016/j.heliyon.2024.e24049.

References

Luo D, Yang G, Liu J, Yang Y, Dong Q . Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J Androl. 2010; 13(2):287-91. PMC: 3739182. DOI: 10.1038/aja.2010.111. View

De Matteis V, Cascione M, Brunetti V, Toma C, Rinaldi R . Toxicity assessment of anatase and rutile titanium dioxide nanoparticles: The role of degradation in different pH conditions and light exposure. Toxicol In Vitro. 2016; 37:201-210. DOI: 10.1016/j.tiv.2016.09.010. View

Shakeel M, Jabeen F, Shabbir S, Asghar M, Khan M, Chaudhry A . Toxicity of Nano-Titanium Dioxide (TiO2-NP) Through Various Routes of Exposure: a Review. Biol Trace Elem Res. 2015; 172(1):1-36. DOI: 10.1007/s12011-015-0550-x. View

Hong F, Wang L . Nanosized titanium dioxide-induced premature ovarian failure is associated with abnormalities in serum parameters in female mice. Int J Nanomedicine. 2018; 13:2543-2549. PMC: 5927354. DOI: 10.2147/IJN.S151215. View

Sharafutdinova L, Fedorova A, Bashkatov S, Sinelnikov K, Valiullin V . Structural and Functional Analysis of the Spermatogenic Epithelium in Rats Exposed to Titanium Dioxide Nanoparticles. Bull Exp Biol Med. 2018; 166(2):279-282. DOI: 10.1007/s10517-018-4332-2. View

Uboldi C, Urban P, Gilliland D, Bajak E, Valsami-Jones E, Ponti J . Role of the crystalline form of titanium dioxide nanoparticles: Rutile, and not anatase, induces toxic effects in Balb/3T3 mouse fibroblasts. Toxicol In Vitro. 2015; 31:137-45. DOI: 10.1016/j.tiv.2015.11.005. View

Agarwal A, Mulgund A, Hamada A, Chyatte M . A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015; 13:37. PMC: 4424520. DOI: 10.1186/s12958-015-0032-1. View

Wang H, Wang Q, Zhao X, Liu P, Meng X, Yu T . Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes. Arch Toxicol. 2009; 84(1):53-61. DOI: 10.1007/s00204-009-0479-y. View

SLAUNWHITE Jr W, Burgett M . In vitro testosterone synthesis by rat testicular tissue. Steroids. 1965; 6(6):721-35. DOI: 10.1016/0039-128x(65)90096-6. View

10.

Weir A, Westerhoff P, Fabricius L, Hristovski K, von Goetz N . Titanium dioxide nanoparticles in food and personal care products. Environ Sci Technol. 2012; 46(4):2242-50. PMC: 3288463. DOI: 10.1021/es204168d. View

11.

Seger R, KREBS E . The MAPK signaling cascade. FASEB J. 1995; 9(9):726-35. View

12.

Hall P, Osawa S, Mrotek J . The influence of calmodulin on steroid synthesis in leydig cells from rat testis. Endocrinology. 1981; 109(5):1677-82. DOI: 10.1210/endo-109-5-1677. View

13.

Dohle G, Smit M, Weber R . Androgens and male fertility. World J Urol. 2003; 21(5):341-5. DOI: 10.1007/s00345-003-0365-9. View

14.

Elnagar A, Ibrahim A, Soliman A . Histopathological Effects of Titanium Dioxide Nanoparticles and The Possible Protective Role of N-Acetylcysteine on The Testes of Male Albino Rats. Int J Fertil Steril. 2018; 12(3):249-256. PMC: 6018179. DOI: 10.22074/ijfs.2018.5389. View

15.

Gao G, Ze Y, Zhao X, Sang X, Zheng L, Ze X . Titanium dioxide nanoparticle-induced testicular damage, spermatogenesis suppression, and gene expression alterations in male mice. J Hazard Mater. 2013; 258-259:133-43. DOI: 10.1016/j.jhazmat.2013.04.046. View

16.

Matzkin M, Yamashita S, Ascoli M . The ERK1/2 pathway regulates testosterone synthesis by coordinately regulating the expression of steroidogenic genes in Leydig cells. Mol Cell Endocrinol. 2013; 370(1-2):130-7. PMC: 3631444. DOI: 10.1016/j.mce.2013.02.017. View

17.

Castillo A, Orlando U, Helfenberger K, Poderoso C, Podesta E . The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis. Mol Cell Endocrinol. 2014; 408:73-9. DOI: 10.1016/j.mce.2014.12.011. View

18.

Son Y, Cheong Y, Kim N, Chung H, Kang D, Pae H . Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How Can ROS Activate MAPK Pathways?. J Signal Transduct. 2011; 2011:792639. PMC: 3100083. DOI: 10.1155/2011/792639. View

19.

Martinat N, Crepieux P, Reiter E, Guillou F . Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. Reprod Nutr Dev. 2005; 45(1):101-8. DOI: 10.1051/rnd:2005007. View

20.

Wang C, Li P, Xuan J, Zhu C, Liu J, Shan L . Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation. Cell Physiol Biochem. 2017; 42(2):729-742. DOI: 10.1159/000477890. View