Down-regulation of adhesion receptors on cells of primate embryos as a probable mechanism of the teratogenic action of thalidomide.
In spite of ongoing speculation, there has been no evidence that adhesion receptors are expressed on the cells of mammalian embryos. In this report, we provide the first proof that a variety of such receptor (beta 1-, beta 2-, and beta 3-integrins and selectin) are indeed expressed on cells of essentially all primordia of marmoset embryos at early organogenesis (developmental stages 11 to 13, or even earlier). Treatment with low doses (20 or as little as 1 mg/kg body weight) of a highly teratogenic derivative (EM12) of thalidomide, the most notorious human teratogen, triggers a dramatic and statistically highly significant down-regulation of several surface adhesion receptors (e.g. CD11a/CD18, CD49d/CD29, CD61, etc.) on early limb bud cells and on cells of some other primordia during early organogenesis of embryos of a primate (marmoset, Callithrix jacchus). Some of these receptors almost disappear, or they are expressed at a lower epitope density in the exposed embryos. These down-regulations of surface adhesion receptors may be expected to alter cell-cell- and cell-extracellular matrix interactions, and they are suggested to be a long-sought primary mechanism of the teratogenic action of thalidomide-type substances.
Neubert
R
R
Department of Toxicology and Embryopharmacology, University Medical Center, Free University Berlin, Germany.
Hinz
N
N
Thiel
R
R
Neubert
D
D
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000378:metabolism; D002144:Callithrix; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D005260:Female; D005434:Flow Cytometry; D005552:Forelimb / Q000196:embryology / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D019038:Platelet Glycoprotein GPIb-IX Complex; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000633:toxicity
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016023:Integrins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D013723:Teratogens; C094990:adhesion receptor; D019041:L-Selectin; C001079:2-(2,6-dioxopiperidin-3-yl)phthalimidine; D013792:Thalidomide