Hostname: page-component-586b7cd67f-2plfb Total loading time: 0 Render date: 2024-11-28T11:27:25.088Z Has data issue: false hasContentIssue false

Surgery-induced cryptorchidism induces apoptosis and autophagy of spermatogenic cells in mice

Published online by Cambridge University Press:  19 March 2019

Yi Zheng
Affiliation:
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi712100, China
Pengfei Zhang
Affiliation:
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi712100, China
Conghui Zhang
Affiliation:
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi712100, China
Wenxian Zeng*
Affiliation:
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi712100, China
*
Address for correspondence: Wenxian Zeng. College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. E-mail: [email protected]

Summary

Cryptorchidism, characterized by the presence of one (unilateral) or both (bilateral) undescended testes, is a common male urogenital defect. Cryptorchidism can lead to male infertility, testicular cancer being the most extreme clinical symptom, as well as psychological issues of the inflicted individual. Despite this, both knowledge about the aetiology of cryptorchidism and the mechanism for cryptorchidism-induced male infertility remain limited. In this present study, by using an artificial cryptorchid mouse model, we investigated the effects of surgery-induced cryptorchidism on spermatogenic cells and seminiferous epithelial cycles. We found that surgery-induced cryptorchidism led to a reduced testicular weight, aberrant seminiferous epithelial cycles and impaired spermatogenesis characterized by degenerating spermatogenic cells. We also observed multinucleated giant cells after surgery-induced cryptorchidism. Transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot assays demonstrated cryptorchidism-induced apoptosis of spermatogenic cells. Moreover, we identified the occurrence of autophagy in germ cells after surgery-induced cryptorchidism. Interestingly, apoptosis and autophagy were synchronous, suggestive of their synergetic roles in promoting germ cell death. Our results provide novel insights into the cryptorchidism-induced male infertility, thereby contributing to the development of male contraceptive strategies as well as treatment options for male infertility caused by cryptorchidism.

Type
Research Article
Copyright
© Cambridge University Press 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

These authors contributed equally to this work.

References

Absalan, F, Movahedin, M and Mowla, SJ (2010) Germ cell apoptosis induced by experimental cryptorchidism is mediated by molecular pathways in mouse testis. Andrologia 42, 512.Google Scholar
Allan, DJ, Harmon, BV and Roberts, SA (1992) Spermatogonial apoptosis has three morphologically recognizable phases and shows no circadian rhythm during normal spermatogenesis in the rat. Cell Proliferat 25, 241250.Google Scholar
Barqawi, A, Trummer, H and Meacham, R (2004) Effect of prolonged cryptorchidism on germ cell apoptosis and testicular sperm count. Asian J Androl 6, 4751.Google Scholar
Boise, LH, Gonzalez-Garcia, M, Postema, CE, Ding, L, Lindsten, T, Turka, LA, Mao, X, Nunez, G and Thompson, CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597608.Google Scholar
Chaki, SP, Misro, MM, Ghosh, D, Gautam, DK and Srinivas, M (2005) Apoptosis and cell removal in the cryptorchid rat testis. Apoptosis 10, 395405.Google Scholar
Chen, Y and Klionsky, DJ (2011) The regulation of autophagy-unanswered questions. J Cell Sci 124, 161170.Google Scholar
Chowdhury, AK and Steinberger, E (1970) Early changes in the germinal epithelium of rat testes following exposure to heat. J Reprod Fertil 22, 205212.Google Scholar
Clegg, EJ (1963) Studies on artificial cryptorchidism: degenerative and regenerative changes in the germinal epithelium of the rat testis. J Endocrinol 27, 241251.Google Scholar
Coto-Montes, A, Boga, JA, Rosales-Corral, S, Fuentes-Broto, L, Tan, DX and Reiter, RJ (2012) Role of melatonin in the regulation of autophagy and mitophagy: a review. Mol Cell Endocrinol 361, 1223.Google Scholar
de Kretser, DM (1997) Male infertility. Lancet 349, 787790.Google Scholar
Deretic, V (2006) Autophagy as an immune defense mechanism. Curr Opin Immunol 18, 375382.Google Scholar
Eisenberg-Lerner, A, Bialik, S, Simon, HU and Kimchi, A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16, 966975.Google Scholar
Elmore, S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35, 495516.Google Scholar
Evers, JL (2002) Female subfertility. Lancet 360, 151159.Google Scholar
Fan, Q, Huang, ZM, Boucher, M, Shang, X, Zuo, L, Brinks, H, Lau, WB, Zhang, J, Chuprun, JK and Gao, E (2013) Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model. PLoS One 8, e73537.Google Scholar
Gnoth, C, Godehardt, E, Frank-Herrmann, P, Friol, K, Tigges, J and Freundl, G (2005) Definition and prevalence of subfertility and infertility. Hum Reprod 20, 11441147.Google Scholar
Gozuacik, D and Kimchi, A (2007) Autophagy and cell death. Curr Topics Dev Biol 78, 217245.Google Scholar
Gump, JM and Thorburn, A (2011) Autophagy and apoptosis: what is the connection? Trends Cell Biol 21, 387392.Google Scholar
Henriksen, K, Hakovirta, H and Parvinen, M (1995) In-situ quantification of stage-specific apoptosis in the rat seminiferous epithelium: effects of short-term experimental cryptorchidism. Int J Androl 18, 256262.Google Scholar
Hikim, AP, Lue, Y, Yamamoto, CM, Vera, Y, Rodriguez, S, Yen, PH, Soeng, K, Wang, C and Swerdloff, RS (2003) Key apoptotic pathways for heat-induced programmed germ cell death in the testis. Endocrinology 144, 31673175.Google Scholar
Ivell, R (2007) Lifestyle effect and the biology of the human scrotum. Reprod Biol Endocrinol 5, 15.Google Scholar
Jung, KY, Yon, JM, Lin, C, Jung, AY, Lee, JG, Baek, IJ, Lee, BJ, Yun, YW and Nam, SY (2015) Phospholipid hydroperoxide glutathione peroxidase is involved in the maintenance of male fertility under cryptorchidism in mice. Reprod Toxicol 57, 7380.Google Scholar
Kabeya, Y, Mizushima, N, Ueno, T, Yamamoto, A, Kirisako, T, Noda, T, Kominami, E, Ohsumi, Y and Yoshimori, T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 57205728.Google Scholar
Kaur, S and Bansal, MP (2015) Protective role of dietary-supplemented selenium and vitamin E in heat-induced apoptosis and oxidative stress in mice testes. Andrologia 47, 11091119.Google Scholar
Kerr, JB, Rich, KA and de Kretser, DM (1979) Effects of experimental cryptorchidism on the ultrastructure and function of the Sertoli cell and peritubular tissue of the rat testis. Biol Reprod 21, 823838.Google Scholar
Kheradmand, A, Dezfoulian, O and Tarrahi, MJ (2011) Ghrelin attenuates heat-induced degenerative effects in the rat testis. Regul Pept 167, 97104.Google Scholar
Kliosnky, D et al. (2016) Guidelines for the use and interpretation of assays for monitoring autophagy 3rd edn. Autophagy 12, 1222.Google Scholar
Kocak, I, Dundar, M, Hekimgil, M and Okyay, P (2002) Assessment of germ cell apoptosis in cryptorchid rats. Asian J Androl 4, 183186.Google Scholar
Kumar, N and Singh, AK (2015) Trends of male factor infertility, an important cause of infertility: a review of the literature. J Hum Reprod Sci 8, 191196.Google Scholar
Kumar, V, Misro, MM and Datta, K (2012) Simultaneous accumulation of hyaluronan binding protein 1 (HABP1/p32/gC1qR) and apoptotic induction of germ cells in cryptorchid testis. J Androl 33, 114121.Google Scholar
Lee, PA, Bellinger, MF, Songer, NJ, O’Leary, L, Fishbough, R and LaPorte, R (1993) An epidemiologic study of paternity after cryptorchidism: initial results. Eur J Pediatr 152(Suppl 2), S25S27.Google Scholar
Lin, C, Shin, DG, Park, SG, Chu, SB, Gwon, LW, Lee, JG, Yon, JM, Baek, IJ and Nam, SY (2015) Curcumin dose-dependently improves spermatogenic disorders induced by scrotal heat stress in mice. Food Function 6, 37703777.Google Scholar
Liu, F, Huang, H, Xu, ZL, Qian, XJ and Qiu, WY (2012) Germ cell removal after induction of cryptorchidism in adult rats. Tissue Cell 44, 281287.Google Scholar
Liu, Z, Chen, P, Gao, H, Gu, Y, Yang, J, Peng, H, Xu, X, Wang, H, Yang, M, Liu, X, Fan, L, Chen, S, Zhou, J, Sun, Y, Ruan, K, Cheng, S, Komatsu, M, White, E, Li, L, Ji, H, Finley, D and Hu, R (2014) Ubiquitylation of autophagy receptor optineurin by HACE1 activates selective autophagy for tumor suppression. Cancer Cell 26, 106120.Google Scholar
Lue, YH, Hikim, AP, Swerdloff, RS, Im, P, Taing, KS, Bui, T, Leung, A and Wang, C (1999) Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of intratesticular testosterone on stage specificity. Endocrinology 140, 17091717.Google Scholar
Maiuri, MC, Zalckvar, E, Kimchi, A and Kroemer, G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8, 741752.Google Scholar
Nakatogawa, H, Suzuki, K, Kamada, Y and Ohsumi, Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nature Rev Mol Cell Biol 10, 458467.Google Scholar
Nantel, F, Monaco, L, Foulkes, NS, Masquilier, D, LeMeur, M, Henriksen, K, Dierich, A, Parvinen, M and Sassone-Corsi, P (1996) Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 380, 159162.Google Scholar
Ogi, S, Tanji, N, Yokoyama, M, Takeuchi, M and Terada, N (1998) Involvement of Fas in the apoptosis of mouse germ cells induced by experimental cryptorchidism. Urol Res 26, 1721.Google Scholar
Ohsumi, Y (2014) Historical landmarks of autophagy research. Cell Res 24, 923.Google Scholar
Oltvai, ZN, Milliman, CL and Korsmeyer, SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609619.Google Scholar
Peterson, JS, Timmons, AK, Mondragon, AA and McCall, K (2015) The end of the beginning: cell death in the germline. Curr Topics Dev Biol 114, 93119.Google Scholar
Pettersson, A, Richiardi, L, Nordenskjold, A, Kaijser, M and Akre, O (2007) Age at surgery for undescended testis and risk of testicular cancer. New Engl J Med 356, 18351841.Google Scholar
Schulz, RW and Miura, T (2002) Spermatogenesis and its endocrine regulation. Fish Physiol Biochem 26, 4356.Google Scholar
Sharlip, ID, Jarow, JP, Belker, AM, Lipshultz, LI, Sigman, M, Thomas, AJ, Schlegel, PN, Howards, SS, Nehra, A, Damewood, MD, Overstreet, JW and Sadovsky, R (2002) Best practice policies for male infertility. Fertil Steril 77, 873882.Google Scholar
Shikone, T, Billig, H and Hsueh, AJ (1994) Experimentally induced cryptorchidism increases apoptosis in rat testis. Biol Reprod 51, 865872.Google Scholar
Song, BS, Yoon, SB, Kim, JS, Sim, BW, Kim, YH, Cha, JJ, Choi, SA, Min, HK, Lee, Y, Huh, JW, Lee, SR, Kim, SH, Koo, DB, Choo, YK, Kim, HM, Kim, SU and Chang, KT (2012) Induction of autophagy promotes preattachment development of bovine embryos by reducing endoplasmic reticulum stress. Biol Reprod 87, 8, 111.Google Scholar
Xi, M, Cheng, L, Wan, YP and Hua, W (2015) [Incidence of depression and its related factors in cryptorchidism patients after surgical treatment]. Zhonghua nan ke xue [in Chinese] 21, 5760.Google Scholar
Xu, YR, Dong, HS and Yang, WX (2016) Regulators in the apoptotic pathway during spermatogenesis: killers or guards? Gene 582, 97111.Google Scholar
Yang, E, Zha, J, Jockel, J, Boise, LH, Thompson, CB and Korsmeyer, SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285291.Google Scholar
Yin, Y, DeWolf, WC and Morgentaler, A (1998) Experimental cryptorchidism induces testicular germ cell apoptosis by p53-dependent and-independent pathways in mice. Biol Reprod 58, 492496.Google Scholar
Yin, Y, Hawkins, KL, DeWolf, WC and Morgentaler, A (1997) Heat stress causes testicular germ cell apoptosis in adult mice. J Androl 18, 159165.Google Scholar
Zhang, MQ, Jiang, M, Bi, Y, Zhu, H, Zhou, ZM and Sha, JH. (2012) Autophagy and apoptosis act as partners to induce germ cell death after heat stress in mice. PLoS One 7, e41412.Google Scholar