{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T19:08:28Z","timestamp":1780945708534,"version":"3.54.1"},"reference-count":54,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,9,9]],"date-time":"2005-09-09T00:00:00Z","timestamp":1126224000000},"content-version":"vor","delay-in-days":6826,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratog Carcinog Mutagen"],"published-print":{"date-parts":[[1987,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Benomyl, a benzimidazole fungicide, produced craniocerebral and systemic malformations in fetal rats when administered by gavage in doses of 31.2, 62.5, and 125 mg\/kg of maternal body weight on days 7\u201321 of gestation. Malformations increased in incidence and severity with increasing benomyl dosage and nearly doubled when coupled with a protein\u2010deficient diet. Protein deficiency alone produced only decreased fetal weight. High benomyl doses produced higher percentages of fetal resorptions and late fetal deaths, and these percentages also increased with protein deficiency. A benomyl dose of 62.5 mg\/kg in proteindeficiency dams, the optimal combination for a high incidence of anomalies and low fetal wastage, produced hydrocephalus in 69.4% of fetuses, meningocele in 8.2%, encephalocele in 14.3%, exencephaly in 44.9%, anencephaly in 14.3%, corpus callosum agenesis in 26.5%, periventricular necrosis in 26.5%, and periventricular cellular \u201covergrowth\u201d in 55.1%. The most common combination of anomalies was hydrocephalus, exencephaly, and periventricular \u201covergrowth.\u201d Common systemic malformations included cleft palate, micromelia, hydroureter, and misshapen tails. No fetus was entirely normal at the highest benomyl dose.<\/jats:p><jats:p>Benomyl has been shown by others to bind tubulin and inhibit the formation of microtubules that are important in neurulation, mitosis, and cell migration during early brain development. Thus, it is suggested that benomyl, coupled with a protein\u2010deficient diet, offers a teratogenic model with a spectrum of abnormalities similar to hypervitaminosis A but with a higher yield of specific craniocerebral anomalies.<\/jats:p>","DOI":"10.1002\/tcm.1770070404","type":"journal-article","created":{"date-parts":[[2006,2,4]],"date-time":"2006-02-04T01:18:34Z","timestamp":1139015914000},"page":"357-375","source":"Crossref","is-referenced-by-count":27,"title":["Benomyl\u2010induced craniocerebral anomalies in fetuses of adequately nourished and protein\u2010deprived rats"],"prefix":"10.1002","volume":"7","author":[{"given":"William G.","family":"Ellis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet L.","family":"Semple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R.","family":"Hoogenboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Kavlock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances J.","family":"Zeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,9,9]]},"reference":[{"key":"e_1_2_1_2_2","first-page":"483","volume-title":"Microtubules and Microtubule Inhibitors","author":"Davidse LC","year":"1975"},{"key":"e_1_2_1_3_2","first-page":"85","article-title":"The benzimidazole anthelmintics\u2014chemistry and biological activity","volume":"27","author":"Sharma S","year":"1983","journal-title":"Prog Drug Res"},{"key":"e_1_2_1_4_2","first-page":"39","article-title":"On the interrelationship of general toxic, embryotic and teratogenic action of chemicals extraneous for the organism and the possibilities of prognosticating their influence on the antenatal period of ontogenesis","volume":"3","author":"Shtenberg AI","year":"1972","journal-title":"Vestn Akad Med Nauk SSSR"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(82)90100-4"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1080\/15287398609530835"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(86)90172-1"},{"key":"e_1_2_1_8_2","first-page":"5","volume-title":"Anencephaly","author":"Lemire RJ","year":"1978"},{"key":"e_1_2_1_9_2","first-page":"89","article-title":"The normal and abnormal development of the nervous system in the early human embryo","volume":"2","author":"O'Rahilly R","year":"1986","journal-title":"J Pediatr Neurosci"},{"key":"e_1_2_1_10_2","first-page":"697","article-title":"The neural cell cycle in the looptail (Lp) mutant mouse","volume":"32","author":"Wilson DB","year":"1974","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(74)90368-0"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(77)90364-5"},{"key":"e_1_2_1_13_2","first-page":"122","article-title":"Experiments on the \u201covergrowth\u201d phenomenon in the brain of chick embryos","volume":"7","author":"Bergquist H","year":"1959","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_14_2","volume-title":"SAS User's Guide","author":"Helwig JT","year":"1979"},{"key":"e_1_2_1_15_2","volume-title":"Elementary Statistics with Applications in Medicine and the Biological Sciences","author":"Croxton FE","year":"1953"},{"key":"e_1_2_1_16_2","first-page":"505","article-title":"Propri\u00e9t\u00e9s embryotoxiques et antimitotiques en s\u00e9ries benzimidazole","volume":"31","author":"Delatour P","year":"1976","journal-title":"Th\u00e9rapie"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(75)90221-5"},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01625540"},{"key":"e_1_2_1_19_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/jn\/51.1.71","article-title":"Relations of dietary protein levels to reproduction in the rat","volume":"51","author":"Nelson MM","year":"1953","journal-title":"J Nutr"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/93.2.167"},{"key":"e_1_2_1_21_2","first-page":"398","article-title":"The effect of suboptimal protein diets on the teratogenic properties of trypan blue administered to pregnant rats","volume":"121","author":"Grunberg DL","year":"1955","journal-title":"Anat Rec"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(77)90140-5"},{"key":"e_1_2_1_23_2","first-page":"125","article-title":"A further report on congenital anomalies in the rat produced by trypan blue","volume":"16","author":"Gillman J","year":"1951","journal-title":"S Afr J Med Sci"},{"key":"e_1_2_1_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091330202"},{"key":"e_1_2_1_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420040104"},{"key":"e_1_2_1_26_2","first-page":"315","article-title":"Experimental production of congenital malformations in rats by salicylate poisoning","volume":"35","author":"Warkany J","year":"1959","journal-title":"Am J Pathol"},{"key":"e_1_2_1_27_2","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1542\/peds.13.6.556","article-title":"Congenital anomalies in the rat produced by excessive uptake of vitamin A during pregnancy","volume":"13","author":"Cohlan SQ","year":"1954","journal-title":"Pediatrics"},{"key":"e_1_2_1_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1030430404"},{"key":"e_1_2_1_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1000920105"},{"key":"e_1_2_1_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-7314-2_3"},{"key":"e_1_2_1_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(77)90199-5"},{"key":"e_1_2_1_32_2","first-page":"252","volume-title":"Congenital Malformations","author":"Warkany J","year":"1971"},{"key":"e_1_2_1_33_2","first-page":"272","article-title":"Developmental malformations produced by radiation: a timetable of their development","volume":"69","author":"Hicks SP","year":"1953","journal-title":"Am J Roentgen"},{"key":"e_1_2_1_34_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-196010000-00002"},{"key":"e_1_2_1_35_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-195610000-00006"},{"key":"e_1_2_1_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-194407000-00003"},{"key":"e_1_2_1_37_2","first-page":"41","article-title":"Brain pathology following fetal vascular occlusion: an experimental study","volume":"8","author":"Myers RE","year":"1969","journal-title":"Invest Ophthalmol"},{"key":"e_1_2_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(76)90060-5"},{"key":"e_1_2_1_39_2","first-page":"222","article-title":"Neoplasia induced in rat embryos by roentgen irradiation","volume":"12","author":"Wilson JG","year":"1952","journal-title":"Cancer Res"},{"key":"e_1_2_1_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901280102"},{"key":"e_1_2_1_41_2","first-page":"308","article-title":"Developmental neuropathology of mouse neocortex following early fetal X\u2010irradiation","volume":"19","author":"Schmahl W","year":"1981","journal-title":"Bibl Anat"},{"key":"e_1_2_1_42_2","first-page":"20","article-title":"Experimental neoplastic formation in embryonic chick brains","volume":"8","author":"Kallen B","year":"1960","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00690798"},{"key":"e_1_2_1_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091130402"},{"key":"e_1_2_1_45_2","first-page":"119","article-title":"Cerebral complications in embryopathic rubeolosa","volume":"59","author":"Ariens Kappers J","year":"1956","journal-title":"Folia Psychiatr Neerl"},{"key":"e_1_2_1_46_2","first-page":"43","volume-title":"Recent Advances in the Developmental Biology of Central Nervous System Malformations","author":"Kallen B","year":"1979"},{"key":"e_1_2_1_47_2","first-page":"555","article-title":"An investigation of the relationship between foetal death and foetal malformation","volume":"97","author":"Beck F","year":"1963","journal-title":"J Anat"},{"key":"e_1_2_1_48_2","first-page":"77","article-title":"Teratogenese par hautes doses de vitamine A en fonction des stades du developpement","volume":"45","author":"Giroud A","year":"1956","journal-title":"Arch Anat Microsc Morphol Exp"},{"key":"e_1_2_1_49_2","first-page":"13","article-title":"Trypan blue induced anomalies in the genito\u2010urinary system of rats","volume":"22","author":"Goldstein DJ","year":"1957","journal-title":"S Afr J Med Sci"},{"key":"e_1_2_1_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091230306"},{"key":"e_1_2_1_51_2","first-page":"53","volume-title":"Teratology of the Central Nervous System: Induced and Spontaneous Malformations of Laboratory, Agricultural and Domestic Animals","author":"Kalter H","year":"1968"},{"key":"e_1_2_1_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(81)90040-X"},{"key":"e_1_2_1_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-69652-7"},{"key":"e_1_2_1_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)60927-4"},{"key":"e_1_2_1_55_2","first-page":"273","article-title":"Effect of microtubule inhibitors on the expansion of hypoblast and margin of overgrowth of chick blastoderms","volume":"81","author":"Mareel M","year":"1984","journal-title":"J Embryol Exp Morphol"}],"container-title":["Teratogenesis, Carcinogenesis, and Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Ftcm.1770070404","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tcm.1770070404","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T04:08:43Z","timestamp":1697861323000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tcm.1770070404"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1987,1]]},"references-count":54,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1987,1]]}},"alternative-id":["10.1002\/tcm.1770070404"],"URL":"https:\/\/doi.org\/10.1002\/tcm.1770070404","archive":["Portico"],"relation":{},"ISSN":["0270-3211","1520-6866"],"issn-type":[{"value":"0270-3211","type":"print"},{"value":"1520-6866","type":"electronic"}],"subject":[],"published":{"date-parts":[[1987,1]]}}}