{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:39:47Z","timestamp":1791056387782,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,1,12]],"date-time":"2009-01-12T00:00:00Z","timestamp":1231718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND<\/jats:bold>: Hyperthermia (HS) is a well\u2010studied teratogen that induces serious malformations, including neural tube defects. Our previous studies have shown that HS induces apoptosis by activating the mitochondrial apoptotic pathway. Prior to activation of the mitochondrial apoptotic pathway, HS also activates p53 and its target genes. In the present study, we determine whether p53 and\/or p21 play a role as teratogen suppressors or inducers of HS\u2010induced malformations.<jats:bold>METHODS<\/jats:bold>: Pregnant mice carrying all three<jats:italic>p53<\/jats:italic>or<jats:italic>p21<\/jats:italic>genotype embryos were exposed to HS on day 8.5. Subsequently, fetuses were collected on day 15.5, and genotyped. In addition to genotype, we also determined the number of resorptions and dead fetuses as well as the number and types of external malformations.<jats:bold>RESULTS<\/jats:bold>: In the absence of HS exposure, fetuses exhibiting exencephaly and spina bifida were observed in approximately 11% of<jats:italic>p53<\/jats:italic>\u2212\/\u2212 fetuses, whereas no malformations were observed among<jats:italic>p21<\/jats:italic>\u2212\/\u2212 fetuses. Exposure to HS resulted in an increase in exencephaly and polydactyly in fetuses of all three<jats:italic>p53<\/jats:italic>genotypes. However, the incidence of these malformations was statistically significantly higher in<jats:italic>p53<\/jats:italic>\u2212\/\u2212 compared to<jats:italic>p53<\/jats:italic>+\/\u2212 and<jats:italic>p53<\/jats:italic>+\/+ fetuses. Exencephaly was the only malformation observed in<jats:italic>p21<\/jats:italic>fetuses exposed to HS, with an approximately 2\u2010fold increase among<jats:italic>p21<\/jats:italic>+\/\u2212 and a 3\u2010fold increase among<jats:italic>p21<\/jats:italic>\u2212\/\u2212 compared to<jats:italic>p21<\/jats:italic>+\/+ fetuses.<jats:bold>CONCLUSIONS<\/jats:bold>: Our study confirms that p53 plays a role in normal development and has shown, for the first time that p53 and p21 function to suppress HS\u2010induced malformations.<jats:italic>Birth Defects Res (Part B)<\/jats:italic>86:40\u201047, 2009. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.20180","type":"journal-article","created":{"date-parts":[[2009,1,12]],"date-time":"2009-01-12T17:25:52Z","timestamp":1231781152000},"page":"40-47","source":"Crossref","is-referenced-by-count":13,"title":["The roles of p53 and p21 in normal development and hyperthermia\u2010induced malformations"],"prefix":"10.1002","volume":"86","author":[{"given":"Hiromi","family":"Hosako","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liezl E.","family":"Francisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail S.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip E.","family":"Mirkes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,23]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(95)00183-7"},{"key":"e_1_2_5_3_1","first-page":"215","article-title":"Developmental abnormalities induced by X\u2010irradiation in p53 deficient mice","volume":"16","author":"Baatout S","year":"2002","journal-title":"In Vivo"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2005.05.010"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.16.2395"},{"key":"e_1_2_5_6_1","first-page":"91","article-title":"Polydactyly in the American Indian","volume":"27","author":"Bingle GJ","year":"1975","journal-title":"Am J Hum Genet"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1667\/0033-7587(2002)158[0449:RITEIF]2.0.CO;2"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.31.5.383"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20581"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s000180050268"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1181"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/210223a0"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20277"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/0265673021000039628"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7455686"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420330213"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06886.x"},{"key":"e_1_2_5_18_1","first-page":"672","volume-title":"Oxford desk reference of clinical genetics","author":"Firth H","year":"2005"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.12.4210-4223.2000"},{"key":"e_1_2_5_20_1","volume-title":"Central nervous system and craniofacial malformations. Vol. 7 in Advances in the Study of Birth Defects","author":"Golding J","year":"1982"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.6.1381"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20333"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2004.02.009"},{"key":"e_1_2_5_24_1","article-title":"Gene and miRNA expression in p53\u2010deficient day 8.5 mouse embryos","author":"Hosako H","journal-title":"Birth Defects Res"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfl143"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.5.2147"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.6.993"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-7580.1997.19110057.x"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a114054"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.6.1391"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/358015a0"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401910"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2002.9414"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:CBTO.0000003828.61418.d4"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4781(88)90136-4"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.10044"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/190372a0"},{"key":"e_1_2_5_38_1","first-page":"2575","article-title":"The p53 response to ionising radiation in adult and developing murine tissues","volume":"13","author":"MacCallum DE","year":"1996","journal-title":"Oncogene"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2199-4-7"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh080"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400390"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1999.8849"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30057"},{"key":"e_1_2_5_44_1","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1242\/dev.125.16.3225","article-title":"The role of p53 and cell death by apoptosis and necrosis in 4\u2010hydroperoxycyclophosphamide\u2010induced limb malformations","volume":"125","author":"Moallem SA","year":"1998","journal-title":"Development"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ede.0000152903.55579.15"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1667\/RR0644.1"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0695-181"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0596-577"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81656-6"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990129)82:3<219::AID-AJMG5>3.0.CO;2-S"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.2006.00104.x"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.969302"},{"key":"e_1_2_5_53_1","first-page":"67","article-title":"Hypothesis: anencephaly and spina bifida are usually preventable by avoidance of a specific but unidentified substance present in certain potato tubers","volume":"26","author":"Renwick JH.","year":"1972","journal-title":"Br J Prev Soc Med"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.5.10.2851"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0695-175"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.113.3.857"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320260325"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320580406"},{"key":"e_1_2_5_59_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0065-3101(24)00308-6","article-title":"Human teratogenicity","volume":"33","author":"Shepard TH.","year":"1986","journal-title":"Adv Pediatr"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320120306"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx000199t"},{"key":"e_1_2_5_62_1","first-page":"631","article-title":"The role of mammalian DNA methyltransferases in the regulation of gene expression","volume":"10","author":"Turek\u2010Plewa J","year":"2005","journal-title":"Cell Mol Biol Lett"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1269\/jrr.42.1"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00422-0"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.1.4.24"}],"container-title":["Birth Defects Research Part B: Developmental and Reproductive Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdrb.20180","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdrb.20180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:08:38Z","timestamp":1709942918000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdrb.20180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,2]]}},"alternative-id":["10.1002\/bdrb.20180"],"URL":"https:\/\/doi.org\/10.1002\/bdrb.20180","archive":["Portico"],"relation":{},"ISSN":["1542-9733","1542-9741"],"issn-type":[{"value":"1542-9733","type":"print"},{"value":"1542-9741","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2]]}}}