{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:57:06Z","timestamp":1791863826000,"version":"4.3.4"},"reference-count":110,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Consejo Nacional de Humanidades Ciencias y Tecnologias (CONAHCYT)","award":["997006"],"award-info":[{"award-number":["997006"]}]},{"name":"Consejo Nacional de Humanidades Ciencias y Tecnologias (CONAHCYT)","award":["777856"],"award-info":[{"award-number":["777856"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spermatogenesis is a very complex process with an intricate transcriptional regulation. The transition from the diploid to the haploid state requires the involvement of specialized genes in meiosis, among other specific functions for the formation of the spermatozoon. The transcription factor cAMP-response element modulator (CREM) is a key modulator that triggers the differentiation of the germ cell into the spermatozoon through the modification of gene expression. CREM has multiple repressor and activator isoforms whose expression is tissue-cell-type specific and tightly regulated by various factors at the transcriptional, post-transcriptional and post-translational level. The activator isoform CREM\u03c4 controls the expression of several relevant genes in post-meiotic stages of spermatogenesis. In addition, exposure to xenobiotics negatively affects CREM\u03c4 expression, which is linked to male infertility. On the other hand, antioxidants could have a positive effect on CREM\u03c4 expression and improve sperm parameters in idiopathically infertile men. Therefore, CREM expression could be used as a biomarker to detect and even counteract male infertility. This review examines the importance of CREM as a transcription factor for sperm production and its relevance in male fertility, infertility and the response to environmental xenobiotics that may affect CREM\u03c4 expression and the downstream regulation that alters male fertility. Also, some health disorders in which CREM expression is altered are discussed.<\/jats:p>","DOI":"10.3390\/ijms241612558","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:26:39Z","timestamp":1691497599000},"page":"12558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1229-4232","authenticated-orcid":false,"given":"Diego Eduardo","family":"S\u00e1nchez-Jasso","sequence":"first","affiliation":[{"name":"Departamento de Gen\u00e9tica y Biolog\u00eda Molecular, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-4931","authenticated-orcid":false,"given":"Sergio Federico","family":"L\u00f3pez-Guzm\u00e1n","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica y Biolog\u00eda Molecular, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0463-9357","authenticated-orcid":false,"given":"Rosa Maria","family":"Berm\u00fadez-Cruz","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica y Biolog\u00eda Molecular, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-5751","authenticated-orcid":false,"given":"Norma","family":"Oviedo","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Immunolog\u00eda e Infectolog\u00eda, Centro M\u00e9dico Nacional La Raza, Instituto Mexicano del Seguro Social (IMSS), Mexico City 02990, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1101\/gad.9.16.2007","article-title":"Targeted disruption of the pituitary glycoprotein hormone alpha-subunit produces hypogonadal and hypothyroid mice","volume":"9","author":"Kendall","year":"1995","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/humrep\/13.suppl_1.1","article-title":"Spermatogenesis","volume":"13","author":"Loveland","year":"1998","journal-title":"Hum. Reprod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"T51","DOI":"10.1530\/JME-22-0067","article-title":"Cellular and molecular basis for the action of retinoic acid in spermatogenesis","volume":"69","author":"Griswold","year":"2022","journal-title":"J. Mol. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12201","DOI":"10.1073\/pnas.1635054100","article-title":"A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets","volume":"100","author":"Schultz","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1095\/biolreprod.103.026880","article-title":"The murine testicular transcriptome: Characterizing gene expression in the testis during the progression of spermatogenesis","volume":"71","author":"Shima","year":"2004","journal-title":"Biol. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/355080a0","article-title":"Developmental switch of CREM function during spermatogenesis: From antagonist to activator","volume":"355","author":"Foulkes","year":"1992","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0303-7207(01)00696-7","article-title":"The expanding family of CREB\/CREM transcription factors that are involved with spermatogenesis","volume":"187","author":"Don","year":"2002","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/362264a0","article-title":"Pituitary hormone FSH directs the CREM functional switch during spermatogenesis","volume":"362","author":"Foulkes","year":"1993","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/0092-8674(91)90503-Q","article-title":"CREM gene: Use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription","volume":"64","author":"Foulkes","year":"1991","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1046\/j.1365-2605.2001.00277.x","article-title":"cAMP response element modulator (CREM): An essential factor for spermatogenesis in primates?","volume":"24","author":"Behr","year":"2001","journal-title":"Int. J. Androl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0968-0004(99)01414-0","article-title":"Signaling routes to CREM and CREB: Plasticity in transcriptional activation","volume":"24","author":"Fimia","year":"1999","journal-title":"Trends. Biochem. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/18237","article-title":"CBP-independent activation of CREM and CREB by the LIM-only protein ACT","volume":"398","author":"Fimia","year":"1999","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0303-7207(01)00463-4","article-title":"Transcriptional cascades during spermatogenesis: Pivotal role of CREM and ACT","volume":"179","author":"Fimia","year":"2001","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1126\/science.1077265","article-title":"CREM-dependent transcription in male germ cells controlled by a kinesin","volume":"298","author":"Macho","year":"2002","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10620","DOI":"10.1073\/pnas.0401947101","article-title":"Abnormal sperm in mice with targeted deletion of the act (activator of cAMP-responsive element modulator in testis) gene","volume":"101","author":"Kotaja","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/14647270500463400","article-title":"Regulation of gene expression in post-meiotic male germ cells: CREM-signalling pathways and male fertility","volume":"9","author":"Hogeveen","year":"2006","journal-title":"Hum. Fertil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10673","DOI":"10.1073\/pnas.92.23.10673","article-title":"Pituitary follicle-stimulating hormone (FSH) induces CREM gene expression in Sertoli cells: Involvement in long-term desensitization of the FSH receptor","volume":"92","author":"Monaco","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0303-7207(94)90290-9","article-title":"The key role of CREM in the cAMP signaling pathway in the testis","volume":"100","author":"Delmas","year":"1994","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1002\/j.1460-2075.1992.tb05195.x","article-title":"Multiple mRNA isoforms of the transcription activator protein CREB: Generation by alternative splicing and specific expression in primary spermatocytes","volume":"11","author":"Ruppert","year":"1992","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12423","DOI":"10.1073\/pnas.91.26.12423","article-title":"An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription","volume":"91","author":"Walker","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1210\/endo.141.11.7758","article-title":"Novel cyclic adenosine 3\u2032,5\u2032-monophosphate (cAMP) response element modulator theta isoforms expressed by two newly identified cAMP-responsive promoters active in the testis","volume":"141","author":"Daniel","year":"2000","journal-title":"Endocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/molehr\/8.11.965","article-title":"Novel leader exons of the cyclic adenosine 3\u2032,5\u2032-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates","volume":"8","author":"Gellersen","year":"2002","journal-title":"Mol. Hum. Reprod."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1080\/01485010701569866","article-title":"Crem activator isoforms in normal and impaired human spermatogenesis analyzed by real time RT-PCR","volume":"53","author":"Fiszer","year":"2007","journal-title":"Arch. Androl."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Guan, Y., Liang, G., Martin, G.B., and Guan, L.L. (2017). Functional changes in mRNA expression and alternative pre-mRNA splicing associated with the effects of nutrition on apoptosis and spermatogenesis in the adult testis. BMC Genom., 18.","DOI":"10.1186\/s12864-016-3385-8"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1095\/biolreprod.115.134684","article-title":"TauCstF-64 Mediates Correct mRNA Polyadenylation and Splicing of Activator and Repressor Isoforms of the Cyclic AMP-Responsive Element Modulator (CREM) in Mouse Testis","volume":"94","author":"Grozdanov","year":"2016","journal-title":"Biol. Reprod."},{"key":"ref_26","unstructured":"Gene [Internet] (2023, June 27). Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gene\/1390."},{"key":"ref_27","unstructured":"Gene [Internet] (2023, June 27). Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gene\/12916."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.devcel.2018.07.025","article-title":"A Comprehensive Roadmap of Murine Spermatogenesis Defined by Single-Cell RNA-Seq","volume":"46","author":"Green","year":"2018","journal-title":"Dev. Cell."},{"key":"ref_29","first-page":"3722","article-title":"Cyclic adenosine 3\u2032,5\u2032-monophosphate-responsive element modulator gene expression in germ cells of normo- and oligoazoospermic men","volume":"83","author":"Peri","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1016\/j.theriogenology.2011.10.043","article-title":"Detection of the activator cAMP responsive element modulator (CREM) isoform ortholog proteins in porcine spermatids and sperm","volume":"77","author":"Noda","year":"2012","journal-title":"Theriogenology"},{"key":"ref_31","first-page":"736","article-title":"Dynamic Expression and Chromatin Incorporation of ACT and CREM Transcription Factors in Testis Tissues of Infertile Men","volume":"23","author":"Jazireian","year":"2021","journal-title":"Cell J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1369\/00221554211032008","article-title":"Expression of Transcription Factor CREM in Human Tissues","volume":"69","author":"Kaprio","year":"2021","journal-title":"J. Histochem. Cytochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1210\/endo.139.7.6111","article-title":"Genetic rescue of follicle-stimulating hormone beta-deficient mice","volume":"139","author":"Kumar","year":"1998","journal-title":"Endocrinology."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1073\/pnas.95.23.13612","article-title":"Impairing follicle-stimulating hormone (FSH) signaling in vivo: Targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance","volume":"95","author":"Dierich","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12958-020-00686-w","article-title":"FSH regulates RA signaling to commit spermatogonia into differentiation pathway and meiosis","volume":"19","author":"Khanehzad","year":"2021","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12958-022-00971-w","article-title":"Follicle-stimulating hormone signaling in Sertoli cells: A licence to the early stages of spermatogenesis","volume":"20","author":"Wang","year":"2022","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18532","DOI":"10.1038\/s41598-021-97961-6","article-title":"DAPL1 is a novel regulator of testosterone production in Leydig cells of mouse testis","volume":"11","author":"Chen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"689624","DOI":"10.3389\/fcell.2021.689624","article-title":"Epigenetics of Male Infertility: The Role of DNA Methylation","volume":"9","author":"Rotondo","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/aja.2010.160","article-title":"Analysis of the methylation pattern of six gene promoters in sperm of men with abnormal protamination","volume":"13","author":"Nanassy","year":"2011","journal-title":"Asian J. Androl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.fertnstert.2011.03.096","article-title":"Abnormal methylation of the promoter of CREM is broadly associated with male factor infertility and poor sperm quality but is improved in sperm selected by density gradient centrifugation","volume":"95","author":"Nanassy","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43684","DOI":"10.1007\/s11356-021-13459-8","article-title":"The effect of SiNPs on DNA methylation of genome in mouse spermatocytes","volume":"28","author":"Sang","year":"2021","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9858","DOI":"10.1093\/nar\/gkt746","article-title":"DAZAP1 regulates the splicing of Crem, Crisp2 and Pot1a transcripts","volume":"41","author":"Chen","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1074\/jbc.M109.066845","article-title":"Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-regulated gene expression and spermatogenesis","volume":"285","author":"Liu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.bbrc.2005.05.157","article-title":"TSSK5, a novel member of the testis-specific serine\/threonine kinase family, phosphorylates CREB at Ser-133, and stimulates the CRE\/CREB responsive pathway","volume":"333","author":"Chen","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1080\/09168451.2016.1146067","article-title":"Phosphorylated testis-specific serine\/threonine kinase 4 may phosphorylate Crem at Ser-117","volume":"80","author":"Fu","year":"2016","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4327","DOI":"10.1093\/nar\/gky240","article-title":"The arginine methyltransferase CARM1 represses p300\u2022ACT\u2022CREM\u03c4 activity and is required for spermiogenesis","volume":"46","author":"Bao","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1016\/j.febslet.2010.05.016","article-title":"Sperm associated antigen 8 (SPAG8), a novel regulator of activator of CREM in testis during spermatogenesis","volume":"584","author":"Wu","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"31739","DOI":"10.1074\/jbc.M505971200","article-title":"Microtubule-independent and protein kinase A-mediated function of kinesin KIF17b controls the intracellular transport of activator of CREM in testis (ACT)","volume":"280","author":"Kotaja","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1083\/jcb.201009043","article-title":"TDRD5 is required for retrotransposon silencing, chromatoid body assembly, and spermiogenesis in mice","volume":"192","author":"Yabuta","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1093\/nar\/gkp1220","article-title":"Functional cooperation between CREM and GCNF directs gene expression in haploid male germ cells","volume":"38","author":"Rajkovic","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/1477-7827-7-133","article-title":"Fhl5\/Act, a CREM-binding transcriptional activator required for normal sperm maturation and morphology, is not essential for testicular gene expression","volume":"7","author":"Lardenois","year":"2009","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/380162a0","article-title":"Severe impairment of spermatogenesis in mice lacking the CREM gene","volume":"380","author":"Blendy","year":"1996","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/380159a0","article-title":"Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice","volume":"380","author":"Nantel","year":"1996","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Martianov, I., Choukrallah, M.A., Krebs, A., Ye, T., Legras, S., Rijkers, E., Van Ijcken, W., Jost, B., Sassone-Corsi, P., and Davidson, I. (2010). Cell-specific occupancy of an extended repertoire of CREM and CREB binding loci in male germ cells. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-530"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kosir, R., Juvan, P., Perse, M., Budefeld, T., Majdic, G., Fink, M., Sassone-Corsi, P., and Rozman, D. (2012). Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031798"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7871","DOI":"10.1128\/MCB.00990-07","article-title":"In vivo analysis of developmentally and evolutionarily dynamic protein-DNA interactions regulating transcription of the Pgk2 gene during mammalian spermatogenesis","volume":"27","author":"Yoshioka","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"686","DOI":"10.2164\/jandrol.106.000596","article-title":"Stage-specific expression of the Atce1\/Tisp40alpha isoform of CREB3L4 in mouse spermatids","volume":"27","author":"Azzi","year":"2006","journal-title":"J. Androl."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"15073","DOI":"10.1074\/jbc.M602051200","article-title":"Transcription factors, cAMP-responsive element modulator (CREM) and Tisp40, act in concert in postmeiotic transcriptional regulation","volume":"281","author":"Nagamori","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.arcmed.2018.06.004","article-title":"Human CATSPER1 Promoter Is Regulated by CREB1 and CREM\u03c4 Transcriptional Factors In Vitro","volume":"49","author":"Oviedo","year":"2018","journal-title":"Arch. Med. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1002\/2211-5463.13518","article-title":"Characterization of the promoter region of the murine Catsper2 gene","volume":"12","author":"Oviedo","year":"2022","journal-title":"FEBS Open Bio"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20040974","article-title":"cAMP-response element modulator-tau activates a distinct promoter element for the expression of the phospholipid hydroperoxide\/sperm nucleus glutathione peroxidase gene","volume":"383","author":"Tramer","year":"2004","journal-title":"Biochem. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1095\/biolreprod.109.078915","article-title":"Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity","volume":"82","author":"Ghanayem","year":"2010","journal-title":"Biol. Reprod."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/molehr\/gal006","article-title":"Sequencing and haplotype analysis of the activator of CREM in the testis (ACT) gene in populations of fertile and infertile males","volume":"12","author":"Christensen","year":"2006","journal-title":"Mol. Hum. Reprod."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1095\/biolreprod.114.120527","article-title":"CREM variants rs4934540 and rs2295415 conferred susceptibility to nonobstructive azoospermia risk in the Chinese population","volume":"91","author":"He","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_65","first-page":"e14558","article-title":"Determining the expression levels of CSF-1 and OCT4, CREM-1, and protamine in testicular biopsies of adult Klinefelter patients: Their possible correlation with spermatogenesis","volume":"54","author":"Lunenfeld","year":"2022","journal-title":"Andrologia"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1007\/s10815-021-02157-6","article-title":"Sperm DNA integrity status is associated with DNA methylation signatures of imprinted genes and non-imprinted genes","volume":"38","author":"Song","year":"2021","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Dvorakova-Hortova, K., Sidlova, A., Ded, L., Hladovcova, D., Vieweg, M., Weidner, W., Steger, K., Stopka, P., and Paradowska-Dogan, A. (2014). Toxoplasma gondii decreases the reproductive fitness in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096770"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/jncimonographs\/lgi006","article-title":"Mechanisms of toxic damage to spermatogenesis","volume":"34","author":"Boekelheide","year":"2005","journal-title":"J. Natl. Cancer. Inst. Monogr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1093\/humupd\/dmx022","article-title":"Temporal trends in sperm count: A systematic review and meta-regression analysis","volume":"23","author":"Levine","year":"2017","journal-title":"Hum. Reprod. Update"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/andr.12149","article-title":"Decline in sperm count and motility in young adult men from 2003 to 2013: Observations from a U.S. Sperm Bank","volume":"4","author":"Centola","year":"2017","journal-title":"Andrology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1093\/toxsci\/kfx182","article-title":"1,2-Dichloroethane Induces Reproductive Toxicity Mediated by the CREM\/CREB Signaling Pathway in Male NIH Swiss Mice","volume":"160","author":"Zhang","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1177\/0748233718754471","article-title":"Abnormal spermatogenesis following sodium fluoride exposure is associated with the downregulation of CREM and ACT in the mouse testis","volume":"34","author":"Wang","year":"2018","journal-title":"Toxicol. Ind. Health"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ecoenv.2019.03.103","article-title":"Low dose carbendazim disrupts mouse spermatogenesis might Be through estrogen receptor related histone and DNA methylation","volume":"176","author":"Liu","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s00128-011-0428-3","article-title":"Cistanches herba induces testis cytotoxicity in male mice","volume":"88","author":"Kim","year":"2012","journal-title":"Bull. Environ. Contam. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Nagahori, K., Qu, N., Kuramasu, M., Ogawa, Y., Kiyoshima, D., Suyama, K., Hayashi, S., Sakabe, K., Yoshimoto, T., and Itoh, M. (2022). Changes in Expression of Specific mRNA Transcripts after Single- or Re-Irradiation in Mouse Testes. Genes, 13.","DOI":"10.3390\/genes13010151"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fendo.2014.00056","article-title":"Roles of reactive oxygen species in the spermatogenesis regulation","volume":"5","author":"Guerriero","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_77","unstructured":"Lee, S.J., and S\u014fn-ju, Y. (1966). Korean Folk Medicine, Seoul National University Press."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.nut.2005.02.012","article-title":"Induction of apoptosis by the aqueous extract of Rubus coreanum in HT-29 human colon cancer cells","volume":"21","author":"Kim","year":"2005","journal-title":"Nutrition"},{"key":"ref_79","unstructured":"Bensky, D., and Barolet, R. (1990). Chinese Herbal Medicine Formulas and Strategies, Vol. 7\u20138, Eastland Press."},{"key":"ref_80","first-page":"366","article-title":"Hydrolyzable tannins from the fruits of Rubus coreanum","volume":"27","author":"Pang","year":"1996","journal-title":"Korean J. Pharmacogn."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF02975185","article-title":"A triterpene glucosyl ester from the roots of Rubus crataegifolius","volume":"24","author":"Kim","year":"2001","journal-title":"Arch. Pharmacal Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.2174\/0929867043365143","article-title":"Therapeutic Constituents and Actions of Rubus Species","volume":"11","author":"Patel","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.jep.2007.08.025","article-title":"Effects of Rubus coreanus on sperm parameters and cAMP-responsive element modulator (CREM) expression in rat testes","volume":"114","author":"Oh","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.reprotox.2007.05.007","article-title":"Yukmijihwang-tang protects against cyclophosphamide-induced reproductive toxicity","volume":"24","author":"Oh","year":"2007","journal-title":"Reprod. Toxicol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e362","DOI":"10.1016\/j.fertnstert.2019.07.1037","article-title":"Efficacy of antioxidant supplementation on conventional and advanced sperm function tests in patients with idiopathic male infertility","volume":"112","author":"Arafa","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00210-016-1223-9","article-title":"Lutein modulates transcription dysregulation of adhesion molecules and spermatogenesis transcription factors induced by testicular ischemia reperfusion injury: It could be SAFE","volume":"389","author":"Renno","year":"2016","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.theriogenology.2021.12.032","article-title":"Dietary folic acid supplementation improves semen quality and spermatogenesis through altering autophagy and histone methylation in the testis of aged broiler breeder roosters","volume":"181","author":"Ye","year":"2022","journal-title":"Theriogenology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Agarwal, A., Panner Selvam, M.K., Samanta, L., Vij, S.C., Parekh, N., Sabanegh, E., Tadros, N.N., Arafa, M., and Sharma, R. (2019). Effect of Antioxidant Supplementation on the Sperm Proteome of Idiopathic Infertile Men. Antioxidants, 8.","DOI":"10.3390\/antiox8100488"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/jnr.21469","article-title":"Inducible cAMP early repressor (ICER)-evoked delayed neuronal death in the organotypic hippocampal culture","volume":"86","author":"Mioduszewska","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6459","DOI":"10.1523\/JNEUROSCI.0412-08.2008","article-title":"Inducible cAMP early repressor acts as a negative regulator for kindling epileptogenesis and long-term fear memory","volume":"28","author":"Kojima","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.neuroscience.2007.10.064","article-title":"The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER) in epileptogenesis","volume":"152","author":"Porter","year":"2008","journal-title":"Neuroscience"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"9328","DOI":"10.1074\/jbc.M705110200","article-title":"Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor","volume":"283","author":"Hu","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"ra9","DOI":"10.1126\/scisignal.1162396","article-title":"BDNF selectively regulates GABAA receptor transcription by activation of the JAK\/STAT pathway","volume":"1","author":"Lund","year":"2008","journal-title":"Sci. Signal."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.2337\/db10-1743","article-title":"Impaired expression of the inducible cAMP early repressor accounts for sustained adipose CREB activity in obesity","volume":"60","author":"Favre","year":"2011","journal-title":"Diabetes"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4161\/adip.20000","article-title":"Evidence for tuning adipocytes ICER levels for obesity care","volume":"1","author":"Brajkovic","year":"2012","journal-title":"Adipocyte"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/sj.emboj.7601008","article-title":"ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis","volume":"25","author":"Abderrahmani","year":"2006","journal-title":"EMBO J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1007\/s00125-011-2165-x","article-title":"Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets","volume":"54","author":"Favre","year":"2011","journal-title":"Diabetologia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10318","DOI":"10.1074\/jbc.M112.445692","article-title":"Inducible cAMP early repressor regulates the Period 1 gene of the hepatic and adrenal clocks","volume":"288","author":"Zmrzljak","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1161\/ATVBAHA.107.145011","article-title":"Inducible cAMP early repressor inhibits growth of vascular smooth muscle cell","volume":"27","author":"Ohtsubo","year":"2007","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.4049\/jimmunol.0802976","article-title":"The cyclic AMP response element modulator {alpha} suppresses CD86 expression and APC function","volume":"182","author":"Ahlmann","year":"2009","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"16606","DOI":"10.1073\/pnas.1210129109","article-title":"cAMP response element modulator \u03b1 controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus","volume":"109","author":"Hedrich","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1074\/jbc.M110.166785","article-title":"Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus","volume":"286","author":"Juang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13148-016-0294-2","article-title":"Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5\u2032-monophosphate response element modulator alpha in systemic lupus erythematosus","volume":"8","author":"Zhang","year":"2016","journal-title":"Clin. Epigenet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4715","DOI":"10.1074\/jbc.M111.323261","article-title":"cAMP-responsive element modulator \u03b1 (CREM\u03b1) suppresses IL-17F protein expression in T lymphocytes from patients with systemic lupus erythematosus (SLE)","volume":"287","author":"Hedrich","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jmcb\/mjs004","article-title":"CREM\u03b1 overexpression decreases IL-2 production, induces a T(H)17 phenotype and accelerates autoimmunity","volume":"4","author":"Lippe","year":"2012","journal-title":"J. Mol. Cell. Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: Making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"W109","DOI":"10.1093\/nar\/gkv345","article-title":"The ReproGenomics Viewer: An integrative cross-species toolbox for the reproductive science community","volume":"43","author":"Darde","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1093\/bioinformatics\/btz047","article-title":"The ReproGenomics Viewer: A multi-omics and cross-species resource compatible with single-cell studies for the reproductive science community","volume":"35","author":"Darde","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:27:53Z","timestamp":1760128073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/16\/12558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":110,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241612558"],"URL":"https:\/\/doi.org\/10.3390\/ijms241612558","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,8]]}}}