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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Dysregulation of lncRNA and circRNA Expression in Mouse Testes after Exposure to Triptolide

Author(s): Suping Xiong, Yanting Li, Yang Xiang, Na Peng, Chunmiao Shen, Yanqiu Cai, Dandan Song, Peng Zhang, Xiaolong Wang, Xuihui Zeng and Xiaoning Zhang*

Volume 20, Issue 8, 2019

Page: [665 - 673] Pages: 9

DOI: 10.2174/1389200220666190729130020

open access plus

Abstract

Background: Triptolide has been shown to exert various pharmacological effects on systemic autoimmune diseases and cancers. However, its severe toxicity, especially reproductive toxicity, prevents its widespread clinical use for people with fertility needs. Noncoding RNAs including lncRNAs and circRNAs are novel regulatory molecules that mediate a wide variety of physiological activities; they are crucial for spermatogenesis and their dysregulation might cause male infertility. However, whether they are involved in triptolide-induced reproductive toxicity is completely unknown.

Methods: After exposure of mice to triptolide, the total RNAs were used to investigate lncRNA/circRNA/mRNA expression profiles by strand-specific RNA sequencing at the transcriptome level to help uncover RNA-related mechanisms in triptolide-induced toxicity.

Results: Triptolide significantly decreased testicular weight, damaged testis and sperm morphology, and reduced sperm motility and density. Remarkable deformities in sperm head and tail were also found in triptolide-exposed mice. At the transcriptome level, the triptolide-treated mice exhibited aberrant expression profiles of lncRNAs/circRNAs/mRNAs. Gene Ontology and pathway analyses revealed that the functions of the differentially expressed lncRNA targets, circRNA cognate genes, and mRNAs were closely linked to many processes involved in spermatogenesis. In addition, some lncRNAs/circRNAs were greatly upregulated or inducibly expressed, implying their potential value as candidate markers for triptolide-induced male reproductive toxicity.

Conclusion: This study provides a preliminary database of triptolide-induced transcriptome, promotes understanding of the reproductive toxicity of triptolide, and highlights the need for research on increasing the medical efficacy of triptolide and decreasing its toxicity.

Keywords: Triptolide, lncRNA, circRNA, RNA sequencing, spermatogenesis, male infertility.

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[1]
Wang, X.; Zu, Y.; Huang, L.; Yu, J.; Zhao, H.; Wen, C.; Chen, Z.; Xu, Z. Treatment of rheumatoid arthritis with combination of methotrexate and Tripterygium wilfordii: A meta-analysis. Life Sci., 2017, 171, 45-50.
[http://dx.doi.org/10.1016/j.lfs.2017.01.004] [PMID: 28088452]
[2]
Li, C.; Sun, X.; Cao, Y.; Xu, W.; Zhang, W.; Dong, Z. Case report: Remarkable remission of SAPHO syndrome in response to Tripterygium wilfordii hook f treatment. Medicine , 2017, 96(47)e8903
[http://dx.doi.org/10.1097/MD.0000000000008903] [PMID: 29382023]
[3]
Kim, S.T.; Kim, S.Y.; Lee, J.; Kim, K.; Park, S.H.; Park, Y.S.; Lim, H.Y.; Kang, W.K.; Park, J.O. Triptolide as a novel agent in pancreatic cancer: The validation using patient derived pancreatic tumor cell line. BMC Cancer, 2018, 18(1), 1103.
[http://dx.doi.org/10.1186/s12885-018-4995-0] [PMID: 30419860]
[4]
Yang, Y.; Zhang, L.J.; Bai, X.G.; Xu, H.J.; Jin, Z.L.; Ding, M. Synergistic antitumour effects of triptolide plus gemcitabine in bladder cancer. Biomed. Pharmacother., 2018, 106, 1307-1316.
[http://dx.doi.org/10.1016/j.biopha.2018.07.083] [PMID: 30119201]
[5]
Yan, P.; Sun, X. Triptolide: A new star for treating human malignancies. J. Cancer Res. Ther., 2018, 14(Suppl.), S271-S275.
[http://dx.doi.org/10.4103/0973-1482.235340] [PMID: 29970675]
[6]
Song, W.; Liu, M.; Wu, J.; Zhai, H.; Chen, Y.; Peng, Z. Preclinical pharmacokinetics of triptolide: A potential antitumor drug. Curr. Drug Metab., 2019, 20(2), 147-154.
[http://dx.doi.org/10.2174/1389200219666180816141506] [PMID: 30112986]
[7]
Xi, C.; Peng, S.; Wu, Z.; Zhou, Q.; Zhou, J. Toxicity of triptolide and the molecular mechanisms involved. Biomed. Pharmacother., 2017, 90, 531-541.
[http://dx.doi.org/10.1016/j.biopha.2017.04.003] [PMID: 28402922]
[8]
Singla, N.; Challana, S. Reproductive toxicity of triptolide in male house rat, Rattus rattus. ScientificWorldJournal, 2014, 2014879405
[http://dx.doi.org/10.1155/2014/879405] [PMID: 25374942]
[9]
Singla, N.; Kaur, G.; Babbar, B.K.; Sandhu, B.S. Potential of triptolide in reproductive management of the house rat, Rattus rattus. Integr. Zool., 2013, 8(3), 260-276.
[http://dx.doi.org/10.1111/1749-4877.12013] [PMID: 24020465]
[10]
Lue, Y.; Sinha Hikim, A.P.; Wang, C.; Leung, A.; Baravarian, S.; Reutrakul, V.; Sangsawan, R.; Chaichana, S.; Swerdloff, R.S. Triptolide: A potential male contraceptive. J. Androl., 1998, 19(4), 479-486.
[PMID: 9733151]
[11]
Luk, A.C.; Gao, H.; Xiao, S.; Liao, J.; Wang, D.; Tu, J.; Rennert, O.M.; Chan, W.Y.; Lee, T.L. GermlncRNA: A unique catalogue of long non-coding RNAs and associated regulations in male germ cell development. Database , 2015, 2015bav044
[http://dx.doi.org/10.1093/database/bav044] [PMID: 25982314]
[12]
Necsulea, A.; Soumillon, M.; Warnefors, M.; Liechti, A.; Daish, T.; Zeller, U.; Baker, J.C.; Grützner, F.; Kaessmann, H. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature, 2014, 505(7485), 635-640.
[http://dx.doi.org/10.1038/nature12943] [PMID: 24463510]
[13]
Liang, M.; Li, W.; Tian, H.; Hu, T.; Wang, L.; Lin, Y.; Li, Y.; Huang, H.; Sun, F. Sequential expression of long noncoding RNA as mRNA gene expression in specific stages of mouse spermatogenesis. Sci. Rep., 2014, 4, 5966.
[http://dx.doi.org/10.1038/srep05966] [PMID: 25097017]
[14]
Zhang, C.; Gao, L.; Xu, E.Y. LncRNA, a new component of expanding RNA-protein regulatory network important for animal sperm development. Semin. Cell Dev. Biol., 2016, 59, 110-117.
[http://dx.doi.org/10.1016/j.semcdb.2016.06.013] [PMID: 27345292]
[15]
Wen, K.; Yang, L.; Xiong, T.; Di, C.; Ma, D.; Wu, M.; Xue, Z.; Zhang, X.; Long, L.; Zhang, W.; Zhang, J.; Bi, X.; Dai, J.; Zhang, Q.; Lu, Z.J.; Gao, G. Critical roles of long noncoding RNAs in Drosophila spermatogenesis. Genome Res., 2016, 26(9), 1233-1244.
[http://dx.doi.org/10.1101/gr.199547.115] [PMID: 27516619]
[16]
Tani, H.; Onuma, Y.; Ito, Y.; Torimura, M. Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells. PLoS One, 2014, 9(8)e106282
[http://dx.doi.org/10.1371/journal.pone.0106282] [PMID: 25171338]
[17]
Huang, Q.; Liu, Y.; Dong, S. Emerging roles of long non-coding RNAs in the toxicology of environmental chemicals. J. Appl. Toxicol., 2018, 38(7), 934-943.
[http://dx.doi.org/10.1002/jat.3595] [PMID: 29388697]
[18]
Jeck, W.R.; Sharpless, N.E. Detecting and characterizing circular RNAs. Nat. Biotechnol., 2014, 32(5), 453-461.
[http://dx.doi.org/10.1038/nbt.2890] [PMID: 24811520]
[19]
Dong, W.W.; Li, H.M.; Qing, X.R.; Huang, D.H.; Li, H.G. Identification and characterization of human testis derived circular RNAs and their existence in seminal plasma. Sci. Rep., 2016, 6, 39080.
[http://dx.doi.org/10.1038/srep39080] [PMID: 27958373]
[20]
Sai, L.; Li, L.; Hu, C.; Qu, B.; Guo, Q.; Jia, Q.; Zhang, Y.; Bo, C.; Li, X.; Shao, H.; Ng, J.C.; Peng, C. Identification of circular RNAs and their alterations involved in developing male Xenopus laevis chronically exposed to atrazine. Chemosphere, 2018, 200, 295-301.
[http://dx.doi.org/10.1016/j.chemosphere.2018.02.140] [PMID: 29494910]
[21]
Gao, Y.; Wu, M.; Fan, Y.; Li, S.; Lai, Z.; Huang, Y.; Lan, X.; Lei, C.; Chen, H.; Dang, R. Identification and characterization of circular RNAs in Qinchuan cattle testis. R. Soc. Open Sci., 2018, 5(7)180413
[http://dx.doi.org/10.1098/rsos.180413] [PMID: 30109096]
[22]
Zhang, X.; Gao, F.; Fu, J.; Zhang, P.; Wang, Y.; Zeng, X. Systematic identification and characterization of long non-coding RNAs in mouse mature sperm. PLoS One, 2017, 12(3)e0173402
[http://dx.doi.org/10.1371/journal.pone.0173402] [PMID: 28291811]
[23]
Qian, S.Z. Tripterygium wilfordii, a Chinese herb effective in male fertility regulation. Contraception, 1987, 36(3), 335-345.
[http://dx.doi.org/10.1016/0010-7824(87)90104-1] [PMID: 3315438]
[24]
Huynh, P.N.; Hikim, A.P.; Wang, C.; Stefonovic, K.; Lue, Y.H.; Leung, A.; Atienza, V.; Baravarian, S.; Reutrakul, V.; Swerdloff, R.S. Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats. J. Androl., 2000, 21(5), 689-699.
[PMID: 10975416]
[25]
Hikim, A.P.; Lue, Y.H.; Wang, C.; Reutrakul, V.; Sangsuwan, R.; Swerdloff, R.S. Posttesticular antifertility action of triptolide in the male rat: Evidence for severe impairment of cauda epididymal sperm ultrastructure. J. Androl., 2000, 21(3), 431-437.
[PMID: 10819451]
[26]
Wang, Z.P.; Gu, Z.P.; Cao, L.; Xu, Y.; You, G.D.; Mao, B.Y.; Qian, S.Z. Effects of tripchlorolide on the epididymides and testes of rats. Asian J. Androl., 1999, 1(3), 121-125.
[PMID: 11250778]
[27]
Roberts, T.C.; Morris, K.V.; Weinberg, M.S. Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs. Epigenetics, 2014, 9(1), 13-20.
[http://dx.doi.org/10.4161/epi.26700] [PMID: 24149621]
[28]
Yang, Q.; Wu, J.; Zhao, J.; Xu, T.; Zhao, Z.; Song, X.; Han, P. Circular RNA expression profiles during the differentiation of mouse neural stem cells. BMC Syst. Biol., 2018, 12(Suppl. 8), 128.
[http://dx.doi.org/10.1186/s12918-018-0651-1] [PMID: 30577840]
[29]
Spiller, C.M.; Feng, C.W.; Jackson, A.; Gillis, A.J.; Rolland, A.D.; Looijenga, L.H.; Koopman, P.; Bowles, J. Endogenous nodal signaling regulates germ cell potency during mammalian testis development. Development, 2012, 139(22), 4123-4132.
[http://dx.doi.org/10.1242/dev.083006] [PMID: 23034635]
[30]
Fleming, J.C.; Tartaglini, E.; Kawatsuji, R.; Yao, D.; Fujiwara, Y.; Bednarski, J.J.; Fleming, M.D.; Neufeld, E.J. Male infertility and thiamine-dependent erythroid hypoplasia in mice lacking thiamine transporter Slc19a2. Mol. Genet. Metab., 2003, 80(1-2), 234-241.
[http://dx.doi.org/10.1016/S1096-7192(03)00141-0] [PMID: 14567973]
[31]
Jamsai, D.; O’Connor, A.E.; O’Donnell, L.; Lo, J.C.; O’Bryan, M.K. Uncoupling of transcription and translation of Fanconi anemia (FANC) complex proteins during spermatogenesis. Spermatogenesis, 2014, 5(1)e979061
[http://dx.doi.org/10.4161/21565562.2014.979061] [PMID: 26413409]
[32]
Sujit, K.M.; Sarkar, S.; Singh, V.; Pandey, R.; Agrawal, N.K.; Trivedi, S.; Singh, K.; Gupta, G.; Rajender, S. Genome-wide differential methylation analyses identifies methylation signatures of male infertility. Hum. Reprod., 2018, 33(12), 2256-2267.
[http://dx.doi.org/10.1093/humrep/dey319] [PMID: 30358834]
[33]
Rathke, C.; Baarends, W.M.; Awe, S.; Renkawitz-Pohl, R. Chromatin dynamics during spermiogenesis. Biochim. Biophys. Acta, 2014, 1839(3), 155-168.
[http://dx.doi.org/10.1016/j.bbagrm.2013.08.004] [PMID: 24091090]
[34]
Honda, S.; Hirose, S. Stage-specific enhanced expression of mitochondrial fusion and fission factors during spermatogenesis in rat testis. Biochem. Biophys. Res. Commun., 2003, 311(2), 424-432.
[http://dx.doi.org/10.1016/j.bbrc.2003.10.008] [PMID: 14592431]
[35]
Moreno, R.D.; Palomino, J.; Schatten, G. Assembly of spermatid acrosome depends on microtubule organization during mammalian spermiogenesis. Dev. Biol., 2006, 293(1), 218-227.
[http://dx.doi.org/10.1016/j.ydbio.2006.02.001] [PMID: 16540102]
[36]
Correa, L.M.; Thomas, A.; Meyers, S.A. The macaque sperm actin cytoskeleton reorganizes in response to osmotic stress and contributes to morphological defects and decreased motility. Biol. Reprod., 2007, 77(6), 942-953.
[http://dx.doi.org/10.1095/biolreprod.107.060533] [PMID: 17823088]
[37]
Gao, Y.; Mruk, D.D.; Lui, W.Y.; Lee, W.M.; Cheng, C.Y. F5-peptide induces aspermatogenesis by disrupting organization of actin- and microtubule-based cytoskeletons in the testis. Oncotarget, 2016, 7(39), 64203-64220.
[http://dx.doi.org/10.18632/oncotarget.11887] [PMID: 27611949]
[38]
Wang, X.; Zhao, F.; Lv, Z.M.; Shi, W.Q.; Zhang, L.Y.; Yan, M. Triptolide disrupts the actin-based Sertoli-germ cells adherens junctions by inhibiting Rho GTPases expression. Toxicol. Appl. Pharmacol., 2016, 310, 32-40.
[http://dx.doi.org/10.1016/j.taap.2016.08.017] [PMID: 27554044]
[39]
Johnson, G.D.; Sendler, E.; Lalancette, C.; Hauser, R.; Diamond, M.P.; Krawetz, S.A. Cleavage of rRNA ensures translational cessation in sperm at fertilization. Mol. Hum. Reprod., 2011, 17(12), 721-726.
[http://dx.doi.org/10.1093/molehr/gar054] [PMID: 21831882]
[40]
Vispé, S.; DeVries, L.; Créancier, L.; Besse, J.; Bréand, S.; Hobson, D.J.; Svejstrup, J.Q.; Annereau, J.P.; Cussac, D.; Dumontet, C.; Guilbaud, N.; Barret, J.M.; Bailly, C. Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. Mol. Cancer Ther., 2009, 8(10), 2780-2790.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0549] [PMID: 19808979]
[41]
Urdinguio, R.G.; Bayón, G.F.; Dmitrijeva, M.; Toraño, E.G.; Bravo, C.; Fraga, M.F.; Bassas, L.; Larriba, S.; Fernández, A.F. Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility. Hum. Reprod., 2015, 30(5), 1014-1028.
[http://dx.doi.org/10.1093/humrep/dev053] [PMID: 25753583]
[42]
Marchal, R.; Chicheportiche, A.; Dutrillaux, B.; Bernardino-Sgherri, J. DNA methylation in mouse gametogenesis. Cytogenet. Genome Res., 2004, 105(2-4), 316-324.
[http://dx.doi.org/10.1159/000078204] [PMID: 15237219]
[43]
Elhamamsy, A.R. Role of DNA methylation in imprinting disorders: An updated review. J. Assist. Reprod. Genet., 2017, 34(5), 549-562.
[http://dx.doi.org/10.1007/s10815-017-0895-5] [PMID: 28281142]
[44]
Zhang, D.; Trudeau, V.L. Integration of membrane and nuclear estrogen receptor signaling. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 2006, 144(3), 306-315.
[http://dx.doi.org/10.1016/j.cbpa.2006.01.025] [PMID: 16516516]
[45]
Zhang, J.; Liu, L.; Mu, X.; Jiang, Z.; Zhang, L. Effect of triptolide on estradiol release from cultured rat granulosa cells. Endocr. J., 2012, 59(6), 473-481.
[http://dx.doi.org/10.1507/endocrj.EJ11-0407] [PMID: 22447140]
[46]
Zhang, J.; Jiang, Z.; Mu, X.; Wen, J.; Su, Y.; Zhang, L. Effect of triptolide on progesterone production from cultured rat granulosa cells. Arzneimittelforschung, 2012, 62(6), 301-306.
[http://dx.doi.org/10.1055/s-0032-1309041] [PMID: 22592319]
[47]
Adham, I.M.; Nayernia, K.; Burkhardt-Göttges, E.; Topaloglu, O.; Dixkens, C.; Holstein, A.F.; Engel, W. Teratozoospermia in mice lacking the transition protein 2 (Tnp2). Mol. Hum. Reprod., 2001, 7(6), 513-520.
[http://dx.doi.org/10.1093/molehr/7.6.513] [PMID: 11385107]
[48]
Shirley, C.R.; Hayashi, S.; Mounsey, S.; Yanagimachi, R.; Meistrich, M.L. Abnormalities and reduced reproductive potential of sperm from Tnp1- and Tnp2-null double mutant mice. Biol. Reprod., 2004, 71(4), 1220-1229.
[http://dx.doi.org/10.1095/biolreprod.104.029363] [PMID: 15189834]
[49]
Takeda, N.; Yoshinaga, K.; Furushima, K.; Takamune, K.; Li, Z.; Abe, S.; Aizawa, S.; Yamamura, K. Viable offspring obtained from Prm1-deficient sperm in mice. Sci. Rep., 2016, 6, 27409.
[http://dx.doi.org/10.1038/srep27409] [PMID: 27250771]
[50]
Cho, C.; Willis, W.D.; Goulding, E.H.; Jung-Ha, H.; Choi, Y.C.; Hecht, N.B.; Eddy, E.M. Haploinsufficiency of protamine-1 or -2 causes infertility in mice. Nat. Genet., 2001, 28(1), 82-86.
[http://dx.doi.org/10.1038/ng0501-82] [PMID: 11326282]

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