{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:31:54Z","timestamp":1787578314857,"version":"build-2736575974"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":224,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG1 CA189955"],"award-info":[{"award-number":["UG1 CA189955"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U10 CA180886"],"award-info":[{"award-number":["U10 CA180886"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U10 CA098543"],"award-info":[{"award-number":["U10 CA098543"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA175216"],"award-info":[{"award-number":["R01 CA175216"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The impacts of chemotherapy exposure on adolescent male osteosarcoma survivors as adults were investigated using a number of physiological parameters, with a focus on chemotherapy, reproduction, and sperm. The Children\u2019s Oncology Group (COG) clinical sites (protocol ALTE16C1) of previously collected and stored sperm samples were obtained for this analysis. The epigenetic DNA methylation alterations in sperm were assessed in 176 control adult male patients\u2019 sperm, and 183 chemotherapy-exposed osteosarcoma survivors\u2019 adult male sperm were provided by COG sites. The current study used a weighted gene co-expression network analysis computational approach that was adopted for use as a weighted epigenetic site correlation network analysis. This analysis identified correlation coefficients between differential DNA methylation regions and other DNA methylation sites with physiological and chemotherapy parameters. Module\u2013trait relationships in the data were determined for epigenetic modules, which highly correlated with sperm parameters, reproductive hormones, and several chemotherapies (e.g. cisplatin). Gene associations of these epigenetic sites were identified and correlated to chemotherapy-associated genes and pathways, as well as reproductive parameters. Observations demonstrate dramatic impacts of adolescent chemotherapy on later adult life sperm epigenetics. Clearly, epigenetics has the potential to mediate the actions of chemotherapy on later life physiology and may potentially impact future generations through epigenetic transgenerational inheritance mechanisms, but this needs further investigation.<\/jats:p>","DOI":"10.1093\/eep\/dvag029","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:54:23Z","timestamp":1786625663000},"source":"Crossref","is-referenced-by-count":0,"title":["Weighted epigenetic site correlation network analysis of chemotherapy impacts on osteosarcoma cancer survivors\u2019 male fertility, sperm, and endocrine parameters"],"prefix":"10.1093","volume":"12","author":[{"given":"Margarett","family":"Shnorhavorian","sequence":"first","affiliation":[{"name":"Seattle Children\u2019s Hospital , Seattle, WA 98105 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K","family":"Amory","sequence":"additional","affiliation":[{"name":"University of Washington, Center for Research in Reproduction and Contraception , Seattle, WA 98195 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center , Seattle, WA 98109 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7755-5683","authenticated-orcid":false,"given":"Smita","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Institute for Cancer Outcomes and Survivorship, University Alabama at Birmingham , Birmingham, AL 35233 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2604-8603","authenticated-orcid":false,"given":"Saro","family":"Armenian","sequence":"additional","affiliation":[{"name":"City Hope Hospital, Comprehensive Cancer Center, Department of Pediatrics , Duarte, CA 91010 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holcombe E","family":"Grier","sequence":"additional","affiliation":[{"name":"Dana-Farber, Boston Children\u2019s Center , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J","family":"Chow","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center , Seattle, WA 98109 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Joshi","sequence":"additional","affiliation":[{"name":"Center for Reproductive Biology, School of Biological Sciences, Washington State University , Pullman, WA 99164 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Beck","sequence":"additional","affiliation":[{"name":"Center for Reproductive Biology, School of Biological Sciences, Washington State University , Pullman, WA 99164 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8224-2078","authenticated-orcid":false,"given":"Michael K","family":"Skinner","sequence":"additional","affiliation":[{"name":"Center for Reproductive Biology, School of Biological Sciences, Washington State University , Pullman, WA 99164 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"2026082409020793200_bib1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s10815-020-01983-4","article-title":"A View from the past into our collective future: the oncofertility consortium vision statement","volume":"38","author":"Woodruff","year":"2021","journal-title":"J Assist Reprod Genet"},{"key":"2026082409020793200_bib2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0170085","article-title":"Differential DNA methylation regions in adult human sperm following adolescent chemotherapy: potential for epigenetic inheritance","volume":"12","author":"Shnorhavorian","year":"2017","journal-title":"PLoS One"},{"key":"2026082409020793200_bib3","doi-asserted-by":"publisher","first-page":"105570","DOI":"10.1016\/j.isci.2022.105570","article-title":"Examination of generational impacts of adolescent chemotherapy: ifosfamide and potential for epigenetic transgenerational inheritance","volume":"25","author":"Thompson","year":"2022","journal-title":"iScience"},{"key":"2026082409020793200_bib4","article-title":"Impact of childhood chemotherapy on adult reproductive hormones, sperm parameters, and epigenetics in pediatric osteosarcoma survivors","author":"Shnorhavorian","year":"2026","journal-title":"BMC Cancer"},{"key":"2026082409020793200_bib5","article-title":"Impact of childhood chemotherapy on adult sperm epigenetics in pediatric osteosarcoma cancer survivors","author":"Shnorhavorian","year":"2026","journal-title":"BMC Cancer"},{"key":"2026082409020793200_bib6","doi-asserted-by":"publisher","first-page":"e11637","DOI":"10.1371\/journal.pone.0011637","article-title":"Gene bionetwork analysis of ovarian primordial follicle development","volume":"5","author":"Nilsson","year":"2010","journal-title":"PLoS One"},{"key":"2026082409020793200_bib7","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1080\/10543400903572753","article-title":"Weighted gene coexpression network analysis: state of the art","volume":"20","author":"Zhao","year":"2010","journal-title":"J Biopharm Stat"},{"key":"2026082409020793200_bib8","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1093\/bioinformatics\/bty882","article-title":"Disease gene identification based on generic and disease-specific genome networks","volume":"35","author":"Nam","year":"2019","journal-title":"Bioinformatics"},{"key":"2026082409020793200_bib9","doi-asserted-by":"publisher","first-page":"31736","DOI":"10.1038\/s41598-024-82319-5","article-title":"Analysis of diagnostic genes and molecular mechanisms of Crohn\u2019s disease and colon cancer based on machine learning algorithms","volume":"14","author":"Xiao","year":"2024","journal-title":"Sci Rep"},{"key":"2026082409020793200_bib10","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s43556-024-00237-4","article-title":"Profiling immune cell-related gene features and immunoregulatory ceRNA in ischemic stroke","volume":"5","author":"Li","year":"2024","journal-title":"Mol Biomed"},{"key":"2026082409020793200_bib11","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s13073-017-0466-5","article-title":"Parkinson\u2019s disease is associated with DNA methylation levels in human blood and saliva","volume":"9","author":"Chuang","year":"2017","journal-title":"Genome Med"},{"key":"2026082409020793200_bib12","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1080\/15592294.2021.1924970","article-title":"Genome-wide CpG density and DNA methylation analysis method (MeDIP, RRBS, and WGBS) comparisons","volume":"17","author":"Beck","year":"2022","journal-title":"Epigenetics"},{"key":"2026082409020793200_bib13","doi-asserted-by":"publisher","first-page":"e0008223","DOI":"10.1128\/msphere.00082-23","article-title":"Infection of ferrets with wild type-based recombinant canine distemper virus overwhelms the immune system and causes fatal systemic disease","volume":"8","author":"Laksono","year":"2023","journal-title":"mSphere"},{"key":"2026082409020793200_bib14","doi-asserted-by":"publisher","first-page":"877537","DOI":"10.3389\/fendo.2022.877537","article-title":"Fertility preservation and restoration options for pre-pubertal male cancer patients: current approaches","volume":"13","author":"Eugeni","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026082409020793200_bib15","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1097\/OGX.0000000000000835","article-title":"Current fertility preservation options for female patients with Hodgkin lymphoma","volume":"75","author":"Hutchcraft","year":"2020","journal-title":"Obstet Gynecol Surv"},{"key":"2026082409020793200_bib16","first-page":"318","article-title":"Changes in gonadal function in post-pubertal male survivors of acute lymphoblastic leukemia and Hodgkin\u2019s disease","volume":"53","author":"Soriano\u00a0Guillen","year":"2000","journal-title":"An Esp Pediatr"},{"key":"2026082409020793200_bib17","doi-asserted-by":"publisher","first-page":"e0223274","DOI":"10.1371\/journal.pone.0223274","article-title":"Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome","volume":"14","author":"Arroyo","year":"2019","journal-title":"PLoS One"},{"key":"2026082409020793200_bib18","doi-asserted-by":"publisher","first-page":"e70189","DOI":"10.1111\/andr.70189","article-title":"Busulfan-induced male infertility: mechanisms, therapeutic interventions, and future directions","author":"Li","year":"2026","journal-title":"Andrology"},{"key":"2026082409020793200_bib19","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1111\/andr.13485","article-title":"Sperm DNA methylation dynamics after chemotherapy: a longitudinal study of a patient with testicular germ cell tumor treatment","volume":"12","author":"Neyroud","year":"2024","journal-title":"Andrology"},{"key":"2026082409020793200_bib20","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13148-022-01417-1","article-title":"Sperm DNA methylome abnormalities occur both pre- and post-treatment in men with Hodgkin disease and testicular cancer","volume":"15","author":"Chan","year":"2023","journal-title":"Clin Epigenetics"},{"key":"2026082409020793200_bib21","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1093\/toxsci\/kfr307","article-title":"Epigenetic alterations in sperm DNA associated with testicular cancer treatment","volume":"125","author":"Chan","year":"2012","journal-title":"Toxicol Sci"},{"key":"2026082409020793200_bib22","doi-asserted-by":"publisher","first-page":"dvac001","DOI":"10.1093\/eep\/dvac001","article-title":"Role of epigenetic transgenerational inheritance in generational toxicology","volume":"8","author":"Nilsson","year":"2022","journal-title":"Environ Epigenetics"},{"key":"2026082409020793200_bib23","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1126\/science.1108190","article-title":"Epigenetic transgenerational actions of endocrine disruptors and male fertility","volume":"308","author":"Anway","year":"2005","journal-title":"Science"},{"key":"2026082409020793200_bib24","doi-asserted-by":"publisher","first-page":"5452","DOI":"10.1038\/s41598-022-09336-0","article-title":"Environmental induced transgenerational inheritance impacts systems epigenetics in disease etiology","volume":"12","author":"Beck","year":"2022","journal-title":"Sci Rep"},{"key":"2026082409020793200_bib25","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1007\/s10552-009-9347-6","article-title":"Physical activity in adolescence and testicular germ cell cancer risk","volume":"20","author":"Littman","year":"2009","journal-title":"Cancer Causes Control"},{"key":"2026082409020793200_bib26","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1002\/cncr.24159","article-title":"Association of marijuana use and the incidence of testicular germ cell tumors","volume":"115","author":"Daling","year":"2009","journal-title":"Cancer"},{"key":"2026082409020793200_bib27","volume-title":"World Health Organization WHO Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction","author":"WHO","year":"1999","edition":"4th ed."},{"key":"2026082409020793200_bib28","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1056\/NEJMoa003005","article-title":"Sperm morphology, motility, and concentration in fertile and infertile men","volume":"345","author":"Guzick","year":"2001","journal-title":"N Engl J Med"},{"key":"2026082409020793200_bib29","doi-asserted-by":"publisher","first-page":"e13100","DOI":"10.1371\/journal.pone.0013100","article-title":"Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome","volume":"5","author":"Guerrero-Bosagna","year":"2010","journal-title":"PLoS One"},{"key":"2026082409020793200_bib30","doi-asserted-by":"publisher","first-page":"e31901","DOI":"10.1371\/journal.pone.0031901","article-title":"Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures","volume":"7","author":"Manikkam","year":"2012","journal-title":"PLoS One"},{"key":"2026082409020793200_bib31","article-title":"FastQC: a quality control tool for high throughput sequence data","author":"Andrews"},{"key":"2026082409020793200_bib32","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: a flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"2026082409020793200_bib33","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat Methods"},{"key":"2026082409020793200_bib34","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2026082409020793200_bib35","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2026082409020793200_bib36","doi-asserted-by":"publisher","first-page":"D199","DOI":"10.1093\/nar\/gkt1076","article-title":"Data, information, knowledge and principle: back to metabolism in KEGG","volume":"42","author":"Kanehisa","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2026082409020793200_bib37","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1038\/nprot.2013.092","article-title":"Large-scale gene function analysis with the PANTHER classification system","volume":"8","author":"Mi","year":"2013","journal-title":"Nat Protoc"},{"key":"2026082409020793200_bib38","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2202\/1544-6115.1128","article-title":"A general framework for weighted gene co-expression network analysis","volume":"4","author":"Zhang","year":"2005","journal-title":"Stat Appl Genet Mol Biol"},{"key":"2026082409020793200_bib39","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"}],"container-title":["Environmental Epigenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eep\/advance-article-pdf\/doi\/10.1093\/eep\/dvag029\/70632973\/dvag029.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eep\/article-pdf\/12\/1\/dvag029\/70632973\/dvag029.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eep\/article-pdf\/12\/1\/dvag029\/70632973\/dvag029.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T13:02:12Z","timestamp":1787576532000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eep\/article\/doi\/10.1093\/eep\/dvag029\/8760926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,2,16]]}},"URL":"https:\/\/doi.org\/10.1093\/eep\/dvag029","relation":{},"ISSN":["2058-5888"],"issn-type":[{"value":"2058-5888","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"dvag029"}}