{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T17:24:18Z","timestamp":1760203458862},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2002,1,4]],"date-time":"2002-01-04T00:00:00Z","timestamp":1010102400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pharmacological antagonism of VLA\u20104 (Very Late Antigen 4, \u03b1<jats:sub>4<\/jats:sub>\u03b2<jats:sub>1<\/jats:sub> integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the \u03b1<jats:sub>4<\/jats:sub>\u2010integrin subunit of VLA\u20104 or its cell surface ligand, VCAM\u20101, however, have been shown to result in embryo\u2010lethality in homozygous null mice due to defects in chorio\u2010allantoic or epi\u2010myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA\u20104 antagonists might cause embryo\u2010lethality or drug\u2010induced malformations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra\u2010coelomic microinjection of a VLA\u20104 blocking antibody or in the presence of small molecule VLA\u20104 antagonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Defects in chorio\u2010allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio\u2010allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio\u2010allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC<jats:sub>\u223c95<\/jats:sub>, as determined in 90% plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Based on these data, VLA\u20104 antagonism might represent a significant risk to the developing embryo\/fetus. In vitro exposure, however, is \u201cconstant\u201d and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA\u20104 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA\u20104. Therefore, state\u2010selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA\u20104 antagonists on embryo\/fetal development in vivo. Teratology 65:26\u201337, 2002. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/tera.1095","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T22:16:03Z","timestamp":1030313763000},"page":"26-37","source":"Crossref","is-referenced-by-count":18,"title":["Effects of VLA\u20104 antagonists in rat whole embryo culture"],"prefix":"10.1002","volume":"65","author":[{"given":"Stan","family":"Spence","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William K.","family":"Hagmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Van 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