{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:43:15Z","timestamp":1791283395974,"version":"4.1.0"},"reference-count":77,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2005,9,9]],"date-time":"2005-09-09T00:00:00Z","timestamp":1126224000000},"content-version":"vor","delay-in-days":7191,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratog Carcinog Mutagen"],"published-print":{"date-parts":[[1986,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although hyperthermia is teratogenic in birds, all the common laboratory animals, farm animals, and primates and satisfies defined criteria as a teratogen, its study as a human teratogen has been neglected. Homeothermic animals, including humans, can experience body temperature elevations induced by febrile infections, heavy exercise and hot environments which exceed the thresholds (1.5\u20132.5\u00b0C elevation) which are known to cause a syndrome of embryonic resorptions, abortions, and malformations in experimental animals. Hyperthermia is particularly damaging to the central nervous system, and if a threshold exposure occurs at the appropriate stages of embryonic development, exencephaly, anencephaly, encephalocoele, micrencephaly, microphthalmia, neurogenic talipes, and arthrogryposis can be produced in a high proportion of exposed embryos, the incidence and type of defect depending on the species and strain within species, the stage of development, and the severity of hyperthermic exposure. Other defects which can be induced experimentally include exomphalos, hypoplasia of toes and teeth, renal agenesis, vertebral anomalies, maxillary hypoplasia, facial clefting, cataract, coloboma, and heart and vascular defects. Proliferating cells are particularly sensitive to temperature elevations, resulting in arrest of mitotic activity and immediate death of cells in mitosis with threshold elevations (1.5\u20132.5\u00b0C) and delayed death of cells probably in S phase with higher elevations (3.5\u00b0C). In general, lower temperature elevations (2.5\u00b0C) require longer durations of elevation to cause defects than a simple spike at a higher elevation (4.5\u00b0C). The death of cells is largely confined to the brain and in the day 21 guinea pig embryo to the alar regions of the brain. Cell death probably accounts for most of the defects in the central nervous system, but microvascular disturbances leading to leakage, oedema and haemorrhage, placental necrosis, and infarction are other known effects of hyperthermia; and these are probably involved in the pathogenesis of many defects of the heart, limbs, kidneys, and body wall. Recent experiments have demonstrated protection of rat embryos in culture against a known teratogenic exposure by a brief nonteratogenic exposure given at least 15 min earlier. This protection is associated with the synthesis of heat\u2010shock proteins, and temporary arrest of the cell proliferative cycle. Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents. With minimally teratogenic doses of heat plus arsenic, lead, or vitamin A, the combined responses with heat have been clearly augmented compared with the additive responses of single treatments. The contribution of hyperthermia to abortions is well documented, and its effect on human birth defects needs careful evaluation.<\/jats:p>","DOI":"10.1002\/tcm.1770060610","type":"journal-article","created":{"date-parts":[[2006,2,4]],"date-time":"2006-02-04T01:23:01Z","timestamp":1139016181000},"page":"563-582","source":"Crossref","is-referenced-by-count":213,"title":["Hyperthermia as a teratogen: A review of experimental studies and their clinical significance"],"prefix":"10.1002","volume":"6","author":[{"given":"M. J.","family":"Edwards","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,9,9]]},"reference":[{"key":"e_1_2_1_2_2","volume-title":"Temperature and Animal Life","author":"Hardy RN","year":"1979"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-0813.1954.tb07617.x"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420250307"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1090670306"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1977.42.6.909"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1966.21.6.1757"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/404745"},{"key":"e_1_2_1_9_2","first-page":"557","article-title":"Thermal injury due to normal body temperature","volume":"66","author":"Johnson HA","year":"1972","journal-title":"Am J Pathol"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-185X.1978.tb00993.x"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1090150604"},{"key":"e_1_2_1_12_2","first-page":"102","volume-title":"Teratology","author":"Nielsen NO","year":"1969"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420300211"},{"key":"e_1_2_1_14_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1071\/BI9650097","article-title":"The effects of acute exposure to high temperatures on prenatal development in the mouse with particular reference to secondary vibrissae","volume":"18","author":"Pennycuik PR","year":"1965","journal-title":"Aust J Biol Sci"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01900945"},{"key":"e_1_2_1_16_2","volume-title":"Heat induced neural tube defects in C3H\/lg\u2010M1 mice. Proc Greenwood Genetic Centre","author":"Chernoff GF","year":"1983"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420290313"},{"key":"e_1_2_1_18_2","unstructured":"ChernoffGF GoldenJA SeymourMA:Neural tube closure in mouse embryos following a hyperthermic exposure. Santa Fe New Mexico: Proc DW Smith Conference June 12\u201314 1985."},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420330213"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1177\/00220345530320041801"},{"key":"e_1_2_1_21_2","first-page":"311","article-title":"Developmental abnormalities in the rat induced by heat\u2010shock","volume":"5","author":"Skreb N","year":"1963","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_22_2","first-page":"3214","article-title":"Temperature critique provoquant des malformations pendant le developpement embryonnaire du rat et ses effets immediats","volume":"261","author":"Skreb N","year":"1965","journal-title":"CR Acad Sci Paris"},{"key":"e_1_2_1_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420010206"},{"key":"e_1_2_1_24_2","first-page":"378","article-title":"Aborte and Missildungen nach Kurzwellendurchflutung in der Schwangerschaft","volume":"26","author":"Hofmann D","year":"1966","journal-title":"Gerburtsh Frauenheilk"},{"key":"e_1_2_1_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420190216"},{"key":"e_1_2_1_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/258604a0"},{"key":"e_1_2_1_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420170306"},{"key":"e_1_2_1_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420020407"},{"key":"e_1_2_1_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420310109"},{"key":"e_1_2_1_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420310212"},{"key":"e_1_2_1_31_2","first-page":"65","article-title":"The induction of heat\u2010shock proteins during early mammalian development","volume":"17","author":"Walsh DA","year":"1985","journal-title":"Proc Aust Biochem Soc 14\u201327 May"},{"key":"e_1_2_1_32_2","first-page":"92","article-title":"The induction of heat shock protein during early mammalian development","volume":"2","author":"Walsh DA","year":"1985","journal-title":"Heat Shock (Cold Spring Harbour Symposium, August 28\u2010 September 1)"},{"key":"e_1_2_1_33_2","first-page":"30a","article-title":"Heat shock and thermotolerance during early rat embryo development","volume":"31","author":"Walsh DA","year":"1985","journal-title":"Teratology"},{"key":"e_1_2_1_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420320214"},{"key":"e_1_2_1_35_2","doi-asserted-by":"publisher","DOI":"10.1109\/T-UFFC.1986.26819"},{"key":"e_1_2_1_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420140307"},{"key":"e_1_2_1_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420160207"},{"key":"e_1_2_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0013-9351(77)90055-X"},{"key":"e_1_2_1_39_2","doi-asserted-by":"publisher","DOI":"10.1159\/000241223"},{"key":"e_1_2_1_40_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-198502000-00022"},{"key":"e_1_2_1_41_2","first-page":"154","article-title":"Zur Teratogenetischen Wirkung von Unspezifischem Fieber aud den sich Entwickelnden Kaninchemembryo","volume":"117","author":"Brinsmade AB","year":"1957","journal-title":"Beitr Path Anat"},{"key":"e_1_2_1_42_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0021859600015616"},{"key":"e_1_2_1_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420090309"},{"key":"e_1_2_1_44_2","doi-asserted-by":"publisher","DOI":"10.1136\/vr.103.20.443"},{"key":"e_1_2_1_45_2","unstructured":"DoneJT:Fetopathogenicity of hyperthermia at mid\u2010gestation. Proc Int Pig Vet Soc July 26\u201331 Mexico 1982p252."},{"key":"e_1_2_1_46_2","first-page":"42","article-title":"Congenital defects in guinea\u2010pigs following induced hyperthermia during gestation","volume":"84","author":"Edwards MJ","year":"1967","journal-title":"Arch Path"},{"key":"e_1_2_1_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420020406"},{"key":"e_1_2_1_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711030107"},{"key":"e_1_2_1_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711040403"},{"key":"e_1_2_1_50_2","first-page":"90","volume-title":"Experimental Embryology and Teratology","author":"Edwards MJ","year":"1974"},{"key":"e_1_2_1_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/dev.420060603"},{"key":"e_1_2_1_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(84)90306-7"},{"key":"e_1_2_1_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01921690"},{"key":"e_1_2_1_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(76)90056-3"},{"key":"e_1_2_1_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/0147-7552(77)90036-5"},{"key":"e_1_2_1_56_2","first-page":"421","volume-title":"Fetal Brain Disorders\u2014Recent Approaches to the Problem of Mental Deficiency","author":"Edwards MJ","year":"1981"},{"key":"e_1_2_1_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420290217"},{"key":"e_1_2_1_58_2","doi-asserted-by":"publisher","DOI":"10.1259\/0007-1285-56-661-33"},{"key":"e_1_2_1_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420300314"},{"key":"e_1_2_1_60_2","first-page":"1","article-title":"The lesions of lead encephalitis in children","volume":"61","author":"Blackman SS","year":"1937","journal-title":"Johns Hopkins Hosp Bull"},{"key":"e_1_2_1_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420190208"},{"key":"e_1_2_1_62_2","first-page":"171","article-title":"Hyperthermia as a teratogenic agent","volume":"55","author":"Poswillo D","year":"1974","journal-title":"Ann R Coll Surg Engl"},{"key":"e_1_2_1_63_2","first-page":"593","article-title":"Mitotic cell death and delay of mitotic activity in guinea\u2010pig embryos following brief maternal hyperthermia","volume":"32","author":"Edwards MJ","year":"1974","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711180406"},{"key":"e_1_2_1_65_2","unstructured":"UpfoldJ SmithMJR EdwardsMJ: in preparation 1986."},{"key":"e_1_2_1_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.1976.tb00518.x"},{"key":"e_1_2_1_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a114054"},{"key":"e_1_2_1_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(84)90788-5"},{"key":"e_1_2_1_69_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.148.3673.1092"},{"key":"e_1_2_1_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(65)90012-1"},{"key":"e_1_2_1_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(78)92859-3"},{"key":"e_1_2_1_72_2","first-page":"78a","article-title":"Teratogenicity of maternal fever in women\u2014a retrospective survey","volume":"25","author":"Spraggett K","year":"1982","journal-title":"Teratology"},{"key":"e_1_2_1_73_2","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1542\/peds.67.6.785","article-title":"Central nervous system and facial defects associated with maternal hyperthermia at 4\u201314 weeks gestation","volume":"67","author":"Pleet H","year":"1981","journal-title":"Pediatrics"},{"key":"e_1_2_1_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(79)80092-X"},{"key":"e_1_2_1_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420250212"},{"key":"e_1_2_1_76_2","first-page":"252","volume-title":"Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke. The Women and Their Pregnancies","author":"Neswander KR","year":"1972"},{"key":"e_1_2_1_77_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420170212"},{"key":"e_1_2_1_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(82)80338-7"}],"container-title":["Teratogenesis, Carcinogenesis, and Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Ftcm.1770060610","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tcm.1770060610","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T22:25:12Z","timestamp":1697927112000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tcm.1770060610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1986,1]]},"references-count":77,"journal-issue":{"issue":"6","published-print":{"date-parts":[[1986,1]]}},"alternative-id":["10.1002\/tcm.1770060610"],"URL":"https:\/\/doi.org\/10.1002\/tcm.1770060610","archive":["Portico"],"relation":{},"ISSN":["0270-3211","1520-6866"],"issn-type":[{"value":"0270-3211","type":"print"},{"value":"1520-6866","type":"electronic"}],"subject":[],"published":{"date-parts":[[1986,1]]}}}