Modulation of p53 after maternal exposure to all-trans-retinoic acid in Swiss Webster mouse fetuses.
The response to exposure of all-trans-retinoic acid (RA) during development varies from physiologic to severe teratogenic outcomes and is dependent upon the dose and the stage of development in all species. Effects of RA-mediated teratogenesis may be due to its ability to cause apoptosis. We have recently reported the modulation of p53 in murine stem cells by RA. The aim of this study was to characterize the temporal and spatial pattern of p53 expression in Swiss Webster mouse fetuses following maternal treatment with a single oral dose of 100 mg/kg body weight of RA during organogenesis. RA treatment resulted in a decreased p53 mRNA level in fetuses 24, 48, and 72 h after maternal treatment as detected by semiquantitative reverse transcriptase polymerase chain reaction. Western blot analysis showed a decrease in p53 protein at 24 and 48 h. Immunohistochemistry revealed decreased localization of p53 in the neuroepithelium of fetuses exposed to RA in utero. RA treatment also resulted in decreased nuclear p21 and decreased expression of cytosolic as well as nuclear p27 at 72 h in the fetuses. These results demonstrated that RA-mediated teratogenesis is accompanied by a reduction in the temporal and spatial pattern of p53 gene and protein expression in addition to the disruption of the cell cycle by modulation of p21 and p27.
Sarkar
Suparna A
SA
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7389, USA.
Sharma
Raghubir P
RP
D000014:Abnormalities, Drug-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D016158:Genes, p53 / Q000235:genetics*; D007124:Immunoenzyme Techniques; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D038081:Organogenesis / Q000187:drug effects; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000008:administration & dosage / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C058992:Tagln protein, mouse; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin