{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T09:23:19Z","timestamp":1782379399064,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"National Key Research and Development Project of China","doi-asserted-by":"publisher","award":["2018YFC1004201"],"award-info":[{"award-number":["2018YFC1004201"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>As a typical environmental endocrine disrupting chemical (EDC), di-(2-ethylhexyl) phthalate (DEHP) is thought to be related to reproductive disorders, especially in males. Growing evidence suggests that various EDCs may result in an impaired telomere structure and function, which is associated with male infertility. However, the adverse effect of DEHP on telomeres in male reproductive cells has rarely been studied, and the related mechanisms remain unclear. In this study, we tested the effects of mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, on telomere dysfunction in mouse spermatogonia-derived cells (GC-1) and the potential role of TERT and c-Myc in MEHP-induced spermatogenic cell damage. Results showed that MEHP induced cell viability inhibition, G0\/G1 phase cell cycle arrest, and apoptosis in GC-1 cells in a dose-dependent manner. Shortened telomeres, reduced telomerase activity, and decreased expression of TERT, c-Myc, and upstream transcription factors of c-Myc were also observed in the MEHP-treated cells. In conclusion, it can be concluded that TERT-mediated telomere dysfunction may contribute to MEHP-induced G0\/G1 phase cell cycle arrest and apoptosis in GC-1 cells through the impairment of c-Myc and its upstream transcription factors.<\/jats:p>","DOI":"10.3390\/toxics11050448","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T01:57:51Z","timestamp":1683683871000},"page":"448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Telomere Structure and Function Disorder Mediates Cell Cycle Dysregulation and Apoptosis via c-Myc and Its Upstream Transcription Factors in a Mouse Spermatogonia-Derived (GC-1) Cell Line"],"prefix":"10.3390","volume":"11","author":[{"given":"Fangji","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7689-9601","authenticated-orcid":false,"given":"Ziyuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121005","DOI":"10.1016\/j.lfs.2022.121005","article-title":"N6-methyladenosine modification on Hmbox1 is related to telomere dysfunction in DEHP-induced male reproductive injury","volume":"309","author":"Zhu","year":"2022","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151412","DOI":"10.1016\/j.scitotenv.2021.151412","article-title":"Phthalate esters in seawater and sediment of the northern South China Sea: Occurrence, distribution, and ecological risks","volume":"811","author":"Cao","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jhazmat.2014.06.055","article-title":"A comprehensive assessment of human exposure to phthalates from environmental media and food in Tianjin, China","volume":"279","author":"Ji","year":"2014","journal-title":"J. Hazard. Mater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.envint.2015.07.005","article-title":"Phthalate exposure and reproductive parameters in young men from the general Swedish population","volume":"85","author":"Axelsson","year":"2015","journal-title":"Environ. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"140673","DOI":"10.1016\/j.scitotenv.2020.140673","article-title":"Phthalate exposure and semen quality in infertile male population from Tianjin, China: Associations and potential mediation by reproductive hormones","volume":"744","author":"Wang","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77047","DOI":"10.1007\/s11356-022-21134-9","article-title":"The inhibition of CFTR in the descended testis of SD rats with unilateral cryptorchidism induced by di-(2-ethylhexyl) phthalate (DEHP)","volume":"29","author":"Tang","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"137216","DOI":"10.1016\/j.chemosphere.2022.137216","article-title":"Di-2-ethylhexyl phthalate (DEHP) exposure induces sperm quality and functional defects in mice","volume":"312","author":"XueXia","year":"2023","journal-title":"Chemosphere"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Coluzzi, E., Leone, S., and Sgura, A. (2019). Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest. Cells, 8.","DOI":"10.3390\/cells8010019"},{"key":"ref_9","first-page":"1097","article-title":"Content of seminal plasma plasticizer in the patients with idiopathic asthenozoospermia and its impact on male fertility","volume":"25","author":"Mao","year":"2019","journal-title":"Zhonghua Nan Ke Xue"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1039\/C8TX00045J","article-title":"Genotoxic, histologic, immunohistochemical, morphometric and hormonal effects of di-(2-ethylhexyl)-phthalate (DEHP) on reproductive systems in pre-pubertal male rats","volume":"7","author":"Karabulut","year":"2018","journal-title":"Toxicol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10114","DOI":"10.1073\/pnas.89.21.10114","article-title":"Telomere length predicts replicative capacity of human fibroblasts","volume":"89","author":"Allsopp","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.biochi.2007.09.006","article-title":"Telomere dysfunction and stem cell ageing","volume":"90","author":"Ju","year":"2008","journal-title":"Biochimie"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14723","DOI":"10.1073\/pnas.95.25.14723","article-title":"Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization","volume":"95","author":"Counter","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1101\/gad.13.18.2388","article-title":"Telomere shortening and apoptosis in telomerase-inhibited human tumor cells","volume":"13","author":"Zhang","year":"1999","journal-title":"Genes Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3826","DOI":"10.1073\/pnas.071043198","article-title":"Switch from Myc\/Max to Mad1\/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells","volume":"98","author":"Xu","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","first-page":"5917","article-title":"Estrogen activates telomerase","volume":"59","author":"Kyo","year":"1999","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1101\/gad.271783.115","article-title":"High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells","volume":"29","author":"Pech","year":"2015","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1289\/ehp.0901831","article-title":"Annual ambient black carbon associated with shorter telomeres in elderly men: Veterans Affairs Normative Aging Study","volume":"118","author":"McCracken","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s00204-016-1725-8","article-title":"Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure","volume":"91","author":"Ziegler","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15786","DOI":"10.1038\/s41598-020-72546-x","article-title":"Long-term exposure to \u201clow-dose\u201d bisphenol A decreases mitochondrial DNA copy number, and accelerates telomere shortening in human CD8 + T cells","volume":"10","author":"Tran","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1016\/j.envpol.2018.09.090","article-title":"Impact of prenatal heavy metal exposure on newborn leucocyte telomere length: A birth-cohort study","volume":"243","author":"Wai","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00412-015-0555-4","article-title":"Telomere homeostasis in mammalian germ cells: A review","volume":"125","year":"2016","journal-title":"Chromosoma"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.envpol.2017.12.099","article-title":"TERT regulates telomere-related senescence and apoptosis through DNA damage response in male germ cells exposed to BPDE in vitro and to B[a]P in vivo","volume":"235","author":"Ling","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106307","DOI":"10.1016\/j.envint.2020.106307","article-title":"BDE-209 and DBDPE induce male reproductive toxicity through telomere-related cell senescence and apoptosis in SD rat","volume":"146","author":"Li","year":"2021","journal-title":"Environ. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"124308","DOI":"10.1016\/j.jhazmat.2020.124308","article-title":"Sperm mtDNA copy number, telomere length, and seminal spermatogenic cells in relation to ambient air pollution: Results of a cross-sectional study in Jing-Jin-Ji region of China","volume":"406","author":"Zhou","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_26","first-page":"96","article-title":"Effect of fluoride on expression of telomerase reverse transcriptase expression and proliferating cell nuclear antigen in germ cells of rats\u2019 testes","volume":"25","author":"Jiang","year":"2007","journal-title":"Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/6010","article-title":"Direct activation of TERT transcription by c-MYC","volume":"21","author":"Wu","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S1383-5742(99)00091-5","article-title":"Telomeres, telomerase, and myc. An update","volume":"462","author":"Cerni","year":"2000","journal-title":"Mutat. Res."},{"key":"ref_29","first-page":"742","article-title":"In vitro metabolism of mono-2-ethylhexyl phthalate by microsomal enzymes. Similarity to omega- and (omega-1) oxidation of fatty acids","volume":"12","author":"Albro","year":"1984","journal-title":"Drug Metab. Dispos."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1007\/s00204-015-1619-1","article-title":"Hepatic and intestinal glucuronidation of mono(2-ethylhexyl) phthalate, an active metabolite of di(2-ethylhexyl) phthalate, in humans, dogs, rats, and mice: An in vitro analysis using microsomal fractions","volume":"90","author":"Hanioka","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0300-483X(01)00567-4","article-title":"Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague-Dawley rats","volume":"171","author":"Park","year":"2002","journal-title":"Toxicology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s40572-018-0174-3","article-title":"Impact of Di-2-Ethylhexyl Phthalate Metabolites on Male Reproductive Function: A Systematic Review of Human Evidence","volume":"5","author":"Hoyer","year":"2018","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6040","DOI":"10.1111\/mec.16150","article-title":"How telomere dynamics are influenced by the balance between mitochondrial efficiency, reactive oxygen species production and DNA damage","volume":"31","author":"Metcalfe","year":"2022","journal-title":"Mol. Ecol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87007","DOI":"10.1289\/EHP4492","article-title":"Prenatal Exposure to Phthalates and Newborn Telomere Length: A Birth Cohort Study in Wuhan, China","volume":"127","author":"Song","year":"2019","journal-title":"Environ. Health Perspect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ebiom.2016.02.027","article-title":"Urinary Phthalates and Leukocyte Telomere Length: An Analysis of NHANES 1999-2002","volume":"6","author":"Scinicariello","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1079966","DOI":"10.3389\/fendo.2022.1079966","article-title":"Sperm telomere length as a novel biomarker of male infertility and embryonic development: A systematic review and meta-analysis","volume":"13","author":"Yuan","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.envint.2016.08.001","article-title":"Shorter sperm telomere length in association with exposure to polycyclic aromatic hydrocarbons: Results from the MARHCS cohort study in Chongqing, China and in vivo animal experiments","volume":"95","author":"Ling","year":"2016","journal-title":"Environ. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.envpol.2016.10.026","article-title":"Polycyclic aromatic hydrocarbons exposure decreased sperm mitochondrial DNA copy number: A cross-sectional study (MARHCS) in Chongqing, China","volume":"220","author":"Ling","year":"2017","journal-title":"Environ. Pollut."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1095\/biolreprod56.5.1120","article-title":"Telomerase activity in female and male rat germ cells undergoing meiosis and in early embryos","volume":"56","author":"Eisenhauer","year":"1997","journal-title":"Biol. Reprod."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/mrd.22962","article-title":"Regionally distinct patterns of STAT3 phosphorylation in the seminiferous epithelia of mouse testes","volume":"85","author":"Nagasawa","year":"2018","journal-title":"Mol. Reprod. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1210\/en.2017-00844","article-title":"GnRH Receptor Expression and Reproductive Function Depend on JUN in GnRH Receptor\u2013Expressing Cells","volume":"159","author":"Jonak","year":"2018","journal-title":"Endocrinology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28355","DOI":"10.1038\/srep28355","article-title":"CTCF contributes in a critical way to spermatogenesis and male fertility","volume":"6","author":"Lilienthal","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jsbmb.2018.11.007","article-title":"Endocrine disruption through membrane estrogen receptors and novel pathways leading to rapid toxicological and epigenetic effects","volume":"187","author":"Rosenfeld","year":"2019","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e979103","DOI":"10.4161\/21565562.2014.979103","article-title":"Disruption of estrogen receptor signaling and similar pathways in the efferent ductules and initial segment of the epididymis","volume":"4","author":"Hess","year":"2014","journal-title":"Spermatogenesis"}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/11\/5\/448\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:31:48Z","timestamp":1760124708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/11\/5\/448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,10]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["toxics11050448"],"URL":"https:\/\/doi.org\/10.3390\/toxics11050448","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,10]]}}}