Chronic stress is a crucial public issue that occurs when a person is repetitively stimulated by various stressors. Previous researches have reported that chronic stress induces spermatogenesis dysfunction in the reproductive system, but its molecular mechanisms remain unclear. The nectin protein family, including nectin-1 to nectin-4, is Ca(2+)-independent immunoglobulin-like cell adhesion molecules, that are widely expressed in the hippocampus, testicular tissue, epithelial cells and other sites. Nectin-3 contributes to the sperm development at the late stage, and the abnormal expression of nectin-3 impairs spermatogenesis. Some recent studies have demonstrated that stress induces a decrease in nectin-3 expression in the hippocampus via corticotropin-releasing hormone (CRH) to corticotropin-releasing hormone receptor 1 (CRHR1) pathway. Here, we tested whether chronic stress also caused a reduction in nectin-3 expression in the testis. We established a chronic social defeat stress paradigm, which provides naturalistic and complex chronic stress inmale C57BL/6 mice. After 25 days of chronic social defeat stress, the mice showed weight loss, thymic atrophy and some other typical symptoms of chronic stress (e.g.anxiety-like behavior and social avoidance behavior). We found gonad atrophy, testicular histological structure changes and semen quality reductions in the stressed mice. The stressed male mice significantly spent more time to impregnate the female mice than the control male mice. Moreover, nectin-3 protein levels in stressed mice were significantly decreased in the testes compared with those in control mice. In addition, we found that the CRHR1 expression level was increased in the testes of stressed mice. Therefore, we demonstrated a decreased level of nectin-3 expression and an increase in CRHR1 expression in the testis after exposure to chronic stress, which may provide a potential therapeutic target for the spermatogenesis dysfunction induced by chronic stress.

Department of Urology and Nephrology The 3rd Affiliated Hospital Chongqing Medical University Chongqing China

Zobrazit více v PubMed

ALMEIDA SA, PETENUSCI SO, FRANCI JA, ROSA E SILVA AA, CARVALHO TL. Chronic immobilization-induced stress increases plasma testosterone and delays testicular maturation in pubertal rats. Andrologia. 2000;32:7–11. doi: 10.1111/j.1439-0272.2000.tb02858.x. PubMed DOI

BERTON O, McCLUNG CA, DILEONE RJ, KRISHNAN V, RENTHAL W, RUSSO SJ, GRAHAM D, TSANKOVA NM, BOLANOS CA, RIOS M, MONTEGGIA LM, SELF DW, NESTLER EJ. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–868. doi: 10.1126/science.1120972. PubMed DOI

CHARMANDARI E, TSIGOS C, CHROUSOS G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259–284. doi: 10.1146/annurev.physiol.67.040403.120816. PubMed DOI

CHROUSOS GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–381. doi: 10.1038/nrendo.2009.106. PubMed DOI

CHROUSOS GP, GOLD PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992;267:1244–1252. doi: 10.1001/jama.267.9.1244. PubMed DOI

FABBRI A, TINAJERO JC, DUFAU ML. Corticotropin-releasing factor is produced by rat Leydig cells and has a major local antireproductive role in the testis. Endocrinology. 1990;127:1541–1543. doi: 10.1210/endo-127-3-1541. PubMed DOI

FENSTER L, KATZ DF, WYROBEK AJ, PIEPER C, REMPEL DM, OMAN D, SWAN SH. Effects of psychological stress on human semen quality. J Androl. 1997;18:194–202. doi: 10.1097/00005392-199811000-00100. PubMed DOI

GHIZZONI L, MASTORAKOS G, VOTTERO A, BARRECA A, FURLINI M, CESARONE A, FERRARI B, CHROUSOS GP, BERNASCONI S. Corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulosa-lutein cells in a CRH and interleukin-1 receptor-mediated fashion. Endocrinology. 1997;138:4806–4811. doi: 10.1210/endo.138.11.5474. PubMed DOI

GOLDEN SA, COVINGTON HE, 3RD, BERTON O, RUSSO SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–1191. doi: 10.1038/nprot.2011.361. PubMed DOI PMC

GOLLENBERG AL, LIU F, BRAZIL C, DROBNIS EZ, GUZICK D, OVERSTREET JW, REDMON JB, SPARKS A, WANG C, SWAN SH. Semen quality in fertile men in relation to psychosocial stress. Fertil Steril. 2010;93:1104–1111. doi: 10.1016/j.fertnstert.2008.12.018. PubMed DOI

HOU G, XIONG W, WANG M, CHEN X, YUAN TF. Chronic stress influences sexual motivation and causes damage to testicular cells in male rats. J Sex Med. 2014;11:653–663. doi: 10.1111/jsm.12416. PubMed DOI

HUANG K, LUI WY. Nectins and nectin-like molecules (Necls): Recent findings and their role and regulation in spermatogenesis. Semin Cell Dev Biol. 2016;59:54–61. doi: 10.1016/j.semcdb.2016.01.034. PubMed DOI

ILGIN S, KILIC G, BAYSAL M, KILIC V, KORKUT B, UCARCAN S, ATLI O. Citalopram induces reproductive toxicity in male rats. Birth Defects Res. 2017;109:475–485. doi: 10.1002/bdr2.1010. PubMed DOI

INAGAKI M, IRIE K, ISHIZAKI H, TANAKA-OKAMOTO M, MIYOSHI J, TAKAI Y. Role of cell adhesion molecule nectin-3 in spermatid development. Genes Cells. 2006;11:1125–1132. doi: 10.1111/j.1365-2443.2006.01006.x. PubMed DOI

IRIE K, SHIMIZU K, SAKISAKA T, IKEDA W, TAKAI Y. Roles and modes of action of nectins in cell-cell adhesion. Semin Cell Dev Biol. 2004;15:643–656. doi: 10.1016/S1084-9521(04)00088-6. PubMed DOI

JANEVIC T, KAHN LG, LANDSBERGIS P, CIRILLO PM, COHN BA, LIU X, FACTOR-LITVAK P. Effects of work and life stress on semen quality. Fertil Steril. 2014;102:530–538. doi: 10.1016/j.fertnstert.2014.04.021. PubMed DOI PMC

KALANTARIDOU SN, ZOUMAKIS E, MAKRIGIANNAKIS A, LAVASIDIS LG, VREKOUSSIS T, CHROUSOS GP. Corticotropin-releasing hormone, stress and human reproduction: an update. J Reprod Immunol. 2010;85:33–39. doi: 10.1016/j.jri.2010.02.005. PubMed DOI

KOPERA IA, BILINSKA B, CHENG CY, MRUK DD. Sertoli-germ cell junctions in the testis: a review of recent data. Philos Trans R Soc Lond B Biol Sci. 2010;365:1593–1605. doi: 10.1098/rstb.2009.0251. PubMed DOI PMC

LIU W, WANG X, MEI Z, GONG J, GAO X, ZHAO Y, MA J, XIE F, QIAN L. Chronic stress promotes the progression of pressure overload-induced cardiac dysfunction through inducing more apoptosis and fibrosis. Physiol Res. 2015;64:325–334. doi: 10.33549/physiolres.932778. PubMed DOI

NESTLER EJ, HYMAN SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–1169. doi: 10.1038/nn.2647. PubMed DOI PMC

NICOLAIDES NC, KYRATZI E, LAMPROKOSTOPOULOU A, CHROUSOS GP, CHARMANDARI E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22:6–19. doi: 10.1159/000362736. PubMed DOI

PARHIZKAR S, YUSOFF MJ, DOLLAH MA. Effect of Phaleria macrocarpa on Sperm Characteristics in Adult Rats. Adv Pharm Bull. 2013;3:345–352. PubMed PMC

RIBEIRO CT, de SOUZA DB, COSTA WS, SAMPAIO FJB, PEREIRA-SAMPAIO MA. Immediate and late effects of chronic stress in the testes of prepubertal and adult rats. Asian J Androl. 2018;20:385–390. doi: 10.4103/aja.aja_68_17. PubMed DOI PMC

RYGULA R, ABUMARIA N, FLUGGE G, HIEMKE C, FUCHS E, RUTHER E, HAVEMANN-REINECKE U. Citalopram counteracts depressive-like symptoms evoked by chronic social stress in rats. Behav Pharmacol. 2006;17:19–29. doi: 10.1097/01.fbp.0000186631.53851.71. PubMed DOI

SAKI G, RAHIM F, ALIZADEH K. Effect of forced swimming stress on count, motility and fertilization capacity of the sperm in adult rats. J Hum Reprod Sci. 2009;2:72–75. doi: 10.4103/0974-1208.57226. PubMed DOI PMC

SCHMIDT MV, SCHARF SH, STERLEMANN V, GANEA K, LIEBL C, HOLSBOER F, MULLER MB. High susceptibility to chronic social stress is associated with a depression-like phenotype. Psychoneuroendocrinology. 2010;35:635–643. doi: 10.1016/j.psyneuen.2009.10.002. PubMed DOI

TAO J, LIN M, SHA J, TAN G, SOONG TW, LI S. Separate locations of urocortin and its receptors in mouse testis: function in male reproduction and the relevant mechanisms. Cell Physiol Biochem. 2007;19:303–312. doi: 10.1159/000100649. PubMed DOI

TOYAMA Y, SUZUKI-TOYOTA F, MAEKAWA M, ITO C, TOSHIMORI K. Disruption of ectoplasmic specializations between Sertoli cells and maturing spermatids by anti-nectin-2 and anti-nectin-3 antibodies. Asian J Androl. 2008;10:577–584. doi: 10.1111/j.1745-7262.2008.00357.x. PubMed DOI

WANG B, ZHOU J, ZHUANG YY, WANG LL, PU JX, HUANG YH, XIA F, LV JX. The Non-Peptide Vasopressin V1b Receptor Antagonist, SSR149415, Ameliorates Spermatogenesis Function in a Mouse Model of Chronic Social Defeat Stress. J Cell Biochem. 2017a;118:3891–3898. doi: 10.1002/jcb.26040. PubMed DOI

WANG FF, WANG Q, CHEN Y, LIN Q, GAO HB, ZHANG P. Chronic stress induces ageing-associated degeneration in rat Leydig cells. Asian J Androl. 2012;14:643–648. doi: 10.1038/aja.2011.183. PubMed DOI PMC

WANG XD, CHEN Y, WOLF M, WAGNER KV, LIEBL C, SCHARF SH, HARBICH D, MAYER B, WURST W, HOLSBOER F, DEUSSING JM, BARAM TZ, MULLER MB, SCHMIDT MV. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol Dis. 2011;42:300–310. doi: 10.1016/j.nbd.2011.01.020. PubMed DOI PMC

WANG XD, SU YA, WAGNER KV, AVRABOS C, SCHARF SH, HARTMANN J, WOLF M, LIEBL C, KUHNE C, WURST W, HOLSBOER F, EDER M, DEUSSING JM, MULLER MB, SCHMIDT MV. Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci. 2013;16:706–713. doi: 10.1038/nn.3395. PubMed DOI

WANG XX, LI JT, XIE XM, GU Y, SI TM, SCHMIDT MV, WANG XD. Nectin-3 modulates the structural plasticity of dentate granule cells and long-term memory. Transl Psychiatry. 2017b;7:e1228. doi: 10.1038/tp.2017.196. PubMed DOI PMC