Skip Navigation



ToxSci Advance Access published online on October 26, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl143
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
95/1/257    most recent
kfl143v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hosako, H.
Right arrow Articles by Mirkes, P. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hosako, H.
Right arrow Articles by Mirkes, P. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 20, 2006
Accepted October 23, 2006

Reproductive and Developmental Toxicology

Teratogen-Induced Activation of p53 in Early Postimplantation Mouse Embryos

Hiromi Hosako 1, Sally A. Little 2, Marianne Barrier 1, and Philip E. Mirkes 1 *

1 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843
2 Birth Defects Research Laboratory, Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195

* To whom correspondence should be addressed.
Philip E. Mirkes, E-mail: pmirkes{at}cvm.tamu.edu


  Abstract

Hyperthermia (HS) and 4-hydroperoxycyclophosphamide (4CP) activate the mitochondrial apoptotic pathway in day 9 mouse embryos. Microarray analyses revealed that several p53 target genes are upregulated after exposure to HS or 4CP, suggesting a role for p53 in teratogen-induced apoptosis. To explore the role of p53, we assessed the activation of p53 in day 9 mouse embryos exposed to HS or 4CP in vitro. Both teratogens induced the accumulation of p53 and phosphorylation of p53 at ser-15, two hallmarks of p53 activation. HS and 4CP also induced an increase in Noxa and Puma mRNAs, transcripts of two known pro-apoptotic p53 target genes; however, these two teratogens did not induce significant increases in NOXA and PUMA proteins, suggesting that p53 does not activate the mitochondrial apoptotic pathway by transcriptionally upregulating the expression of NOXA and PUMA proteins. HS and 4CP also induced the expression of p21 mRNA and protein, suggesting a role for p53 in teratogen-induced cell cycle arrest. Previously, we also showed that HS and 4CP activate the apoptotic pathway in the embryo proper (head and trunk) but not in the heart. We now show that HS and 4CP induce a robust activation of p53 in the embryo proper but an attenuated induction in the heart. HS and 4CP induce the expression of p21 protein in majority of the cells in the embryo; however, expression of NOXA and PUMA proteins were not significantly induced in heads, hearts, or trunks of day 9 embryos. Overall, our results suggest that p53 may play a transcription-dependent role in teratogen-induced cell cycle arrest but a transcription-independent role in teratogen-induced apoptosis in day 9 mouse embryos exposed to HS or 4CP.

Keywords: day 9 mouse embryo; hyperthermia; 4-hydroperoxycyclophosphamide; embryotoxicity; p53; apoptosis; Noxa; Puma; cell cycle arrest; p21.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
J. F. Robinson, X. Yu, S. Hong, W. C. Griffith, R. Beyer, E. Kim, and E. M. Faustman
Cadmium-Induced Differential Toxicogenomic Response in Resistant and Sensitive Mouse Strains Undergoing Neurulation
Toxicol. Sci., January 1, 2009; 107(1): 206 - 219.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.