{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:39:09Z","timestamp":1791041949831,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2003,9,15]],"date-time":"2003-09-15T00:00:00Z","timestamp":1063584000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2003,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Perinatal exposure to diethylstilbestrol (DES) induces reproductive tract cancers later in life in both humans and animals. Because there is no clear evidence that perinatal DES exposure induces gene mutation, we proposed that perinatal DES exposure causes epigenetic methylation changes that result in persistent alterations in gene expression, leading to tumorigenesis. The proto\u2010oncogene c\u2010<jats:italic>fos<\/jats:italic> is one of the immediately induced genes in uterine epithelium after estrogen simulation and a key player in uterine carcinogenesis. Here, we investigated c\u2010<jats:italic>fos<\/jats:italic> expression in mice neonatally exposed to DES (2 \u03bcg\/pup\/day on postnatal days 1\u20135). The mRNA levels of c\u2010<jats:italic>fos<\/jats:italic> in uteri of neonatal DES\u2010treated mice were persistently 1.4\u20131.9\u2010fold higher than that in the control mice from day 5 to day 60. Overall, the uterine c\u2010<jats:italic>fos<\/jats:italic> expression level in the neonatal DES\u2010exposed group was significantly higher than that in the control group. After examination of the methylation status of the c\u2010<jats:italic>fos<\/jats:italic> gene, we found that the CpGs in promoter and intron\u20101 regions were completely unmethylated. In exon\u20104, from day 17 to day 60, the percentage of unmethylated CpGs was higher in neonatal DES\u2010exposed mice uteri than that in control (42%, 51%, 47%, and 42% in DES\u2010exposed mice vs 33%, 34%, 33%, and 21% in control mice at day 17, 21, 30, and 60, respectively). These results suggest that perinatal DES exposure may permanently alter gene expression and methylation, and the methylation modification may occur in either the promoter regions or other regulatory sites in the gene. Published 2003 Wiley\u2010Liss, Inc.\u2020<\/jats:p>","DOI":"10.1002\/mc.10147","type":"journal-article","created":{"date-parts":[[2003,9,17]],"date-time":"2003-09-17T14:20:40Z","timestamp":1063808440000},"page":"78-84","source":"Crossref","is-referenced-by-count":167,"title":["Neonatal diethylstilbestrol exposure induces persistent elevation of c\u2010<i>fos<\/i> expression and hypomethylation in its exon\u20104 in mouse uterus"],"prefix":"10.1002","volume":"38","author":[{"given":"Shuanfang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Hansman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Retha","family":"Newbold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"McLachlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Carl","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,9,15]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197104222841604"},{"key":"e_1_2_7_3_2","first-page":"25","article-title":"Prenatal diethylstilbestrol exposure and human genital tract abnormalities","volume":"51","author":"Herbst AL","year":"1979","journal-title":"Natl Cancer Inst Monog"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(99)70411-4"},{"key":"e_1_2_7_5_2","first-page":"3988","article-title":"Long\u2010term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol","volume":"40","author":"McLachlan JA","year":"1980","journal-title":"Cancer Res"},{"key":"e_1_2_7_6_2","first-page":"7677","article-title":"Uterine adenocarcinoma in mice following developmental treatment with estrogens: A model for hormonal carcinogenesis","volume":"50","author":"Newbold RR","year":"1990","journal-title":"Cancer Res"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1159\/000242690"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(88)90150-3"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(92)90007-6"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-7192-6_4"},{"issue":"1","key":"e_1_2_7_11_2","first-page":"303","article-title":"Endometrium cell surface abnormalities in the Syrian hamster as a result of in utero exposure to diethylstilbestrol","author":"Gilloteaux J","year":"1985","journal-title":"Scand Electron Microsc"},{"key":"e_1_2_7_12_2","first-page":"595","article-title":"Exposure to diethylstilbestrol during a critical developmental period of the mouse reproductive tract leads to persistent induction of two estrogen\u2010regulated genes","volume":"5","author":"Nelson KG","year":"1994","journal-title":"Cell Growth Differ"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1211432"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0185(199607)245:3<459::AID-AR2>3.0.CO;2-N"},{"key":"e_1_2_7_15_2","first-page":"131","article-title":"Effects of neonatal diethylstilbestrol exposure on c\u2010fos and c\u2010jun protooncogene expression in the mouse uterus","volume":"16","author":"Yamashita S","year":"2001","journal-title":"Histol Histopathol"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02877056"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.8907"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.14.9.1101"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0413"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6262919"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19960201)77:3<507::AID-CNCR12>3.0.CO;2-8"},{"key":"e_1_2_7_22_2","first-page":"4356","article-title":"Developmental exposure to diethylstilbestrol elicits demethylation of estrogen\u2010responsive lactoferrin gene in mouse uterus","volume":"57","author":"Li S","year":"1997","journal-title":"Cancer Res"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/mc.10015"},{"key":"e_1_2_7_24_2","first-page":"1129","article-title":"Exon\u2010specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine. 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