{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T17:35:28Z","timestamp":1760204128319},"reference-count":25,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,9,9]],"date-time":"2005-09-09T00:00:00Z","timestamp":1126224000000},"content-version":"vor","delay-in-days":7922,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratog Carcinog Mutagen"],"published-print":{"date-parts":[[1984,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Retinoic acid, suspended in cottonseed oil, was administered via gavage to pregnant mice (ICR strain) on day 11 (E 11) of gestation at doses of either 20, 40, or 80 mg\/kg. Fetuses were examined for external malformations on day 17 (E 17). Retinoic acid treatment induced micromelia (with the elimination of several long bones at higher doses) and digital defects (ectrodactyly and syndactyly) in a dose\u2010dependent manner in fetuses examined on day 17. Hindlimbs were affected more than forelimbs. In another group of experiments, limbs exposed to retinoic acid treatment in utero on E 11 were cultured on E 12 and maintained for 3 days in submerged culture. Cultured limbs were examined qualitatively for digital and long bone defects, and image analysis of the area and form of bone anlagen of cultured limbs was used to quantitatively evaluate the teratogenic potential of retinoic acid. The qualitative evaluation indicated that the retinoic acid\u2010induced effects obtained in vivo and with pretreated, cultured limbs were essentially the same, except that the severity of regional effects changed as a result of culture. The incidence of ectrodactyly was higher with cultured limbs than with E 17 fetal limbs, but fewer cultured limbs were missing long bones. These results suggest that culturing limbs, after they have been pretreated in utero, modifies their response to a teratogen and demonstrates that the paw skeleton is extremely sensitive to teratogen treatment under these experimental conditions. Therefore, care must be exercised when attempting to compare in vivo and in vitro teratogenic data. This study also clearly demonstrates the power and usefulness of image analysis for quantitative evaluation of both the area and form of a cultured specimen such as the developing limb bud. Quantitative, image analysis of cultured limbs showed a dose\u2010dependent decrease in area of both fore\u2010 and hindlimbs. The effect was most severe in hindlimbs. In the forelimb, the paw was affected more than the long bones; as the dose increased, this disparity of effect also increased. With the hindlimb, a greater effect on the paw occurred only at 80 mg\/kg. Computing the soft tissue\/bone ratio illustrated that retinoic acid had a greater effect on chondrogenic tissue than on soft tissue.<\/jats:p>","DOI":"10.1002\/tcm.1770040306","type":"journal-article","created":{"date-parts":[[2006,2,4]],"date-time":"2006-02-04T11:55:23Z","timestamp":1139054123000},"page":"311-326","source":"Crossref","is-referenced-by-count":29,"title":["Mouse limb bud development in submerged culture: Quantitative assessment of the effects of in vivo exposure to retinoic acid"],"prefix":"10.1002","volume":"4","author":[{"given":"T. E.","family":"Kwasigroch","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. G.","family":"Skalko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. K.","family":"Church","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,9,9]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.117.3046.535"},{"key":"e_1_2_1_3_2","first-page":"77","article-title":"Teratogenese par hautes doses de vitamin A en fonction des stades du development","volume":"45","author":"Giroud A","year":"1956","journal-title":"Arch Anat Micr"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-2850-6_7"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00304671"},{"key":"e_1_2_1_6_2","first-page":"721","article-title":"Susceptible stages and abnormal morphogenesis in the developing mouse limb, analyzed in organ culture after transplacental exposure to vitamin A (retinoic acid)","volume":"31","author":"Kochhar DM","year":"1974","journal-title":"J Embryol Exp 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Morphol"},{"key":"e_1_2_1_13_2","first-page":"335","volume-title":"Limb Development and Regeneration, Part A","author":"Kwasigroch TE","year":"1983"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01945474"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1401480302"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420070310"},{"key":"e_1_2_1_17_2","first-page":"257","volume-title":"Advances in the Detection of Congenital Malformations","author":"Kwasigroch TE","year":"1977"},{"key":"e_1_2_1_18_2","first-page":"241","volume-title":"Methods in Prenatal Toxicology","author":"Neubert D","year":"1977"},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/1520-6866(1990)2:1<61::AID-TCM1770020107>3.0.CO;2-O"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02796334"},{"key":"e_1_2_1_21_2","first-page":"105","article-title":"A standardized automatic procedure to evaluate cell numbers in low cell density tissues by image analysis Application to the staggerer mutant mouse cerebellum","volume":"86","author":"Gardette R","year":"1982","journal-title":"Microsc Acta"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/tcm.1770010207"},{"key":"e_1_2_1_23_2","first-page":"235","article-title":"Control of form and pattern in the vertebrate limb","volume":"25","author":"Ede DA","year":"1971","journal-title":"Symp Soc Exp Biol"},{"key":"e_1_2_1_24_2","first-page":"245","article-title":"Patterns of cell division, cell death and chondrogenesis in cultured aggregates of normal and talpid3 mutant chick limb mesenchyme cells","volume":"27","author":"Ede DA","year":"1972","journal-title":"J Embryol Exp Morphol"},{"key":"e_1_2_1_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(75)90551-0"},{"key":"e_1_2_1_26_2","first-page":"325","article-title":"Vitamin A alters the adhesiveness of limb bud mesenchymal cells","volume":"59","author":"Kwasigroch 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