PMID- 12730623
OWN - NLM
STAT- MEDLINE
DCOM- 20040302
LR  - 20151119
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 74
IP  - 1
DP  - 2003 Jul
TI  - Genotoxic stress response gene expression in the mid-organogenesis rat conceptus.
PG  - 157-64
AB  - The ability of the conceptus to respond to genotoxic stress may be critical for 
      normal development, particularly after exposure to genotoxic teratogens. Members 
      of the phosphatidylinositol 3-kinase (PI3K) superfamily are involved in 
      controlling cell cycle activity and maintaining genomic stability. The expression 
      of PI3K family members ATM, ATR, and DNA-PKcs, and downstream genes p53, GADD45, 
      and p21, was examined in the mid organogenesis rat conceptus in vivo on 
      gestational days (GD) 10 through 12 and in vitro following exposure to genotoxic 
      stress. ATM was the most highly expressed PI3K family member in both yolk sac and 
      embryo proper, with transcript levels increasing ~fourfold in the embryo from GD 
      10 to 12. Transcript concentrations for ATR, DNA-PKcs, and downstream genes were 
      low in both tissues; all genes had increased transcript levels exclusively in the 
      GD 12 embryo. Transient oxidative stress, induced by short-term, in vitro embryo 
      culture, had no effect on transcript levels in either tissue. Culture for 24 or 
      44 h significantly decreased ATM transcript levels in both embryo and yolk sac, 
      but downstream genes were unaffected compared to GD-11 and -12 in vivo levels, 
      respectively. Exposure to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated 
      form of the nitrogen mustard cyclophosphamide (CPA), had no effect on transcript 
      levels for any of the genes examined. Therefore, while transcripts for genotoxic 
      stress-response genes are present in the mid organogenesis rat conceptus, their 
      expression is not regulated by exposure in culture to either transient oxidative 
      stress or a genotoxic alkylating agent. The inability of the conceptus to 
      upregulate transcripts in response to insult may contribute to an increased 
      susceptibility to stressors during organogenesis.
FAU - Vinson, Robert K
AU  - Vinson RK
AD  - Department of Pharmacology and Therapeutics, 3655 Promenade Sir William Osler, 
      McGill University, Montreal, Quebec, Canada H3G 1Y6.
FAU - Hales, Barbara F
AU  - Hales BF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030502
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (RNA, Antisense)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - U880A4FUDA (perfosfamide)
SB  - IM
MH  - Animals
MH  - Cyclophosphamide/*analogs & derivatives/toxicity
MH  - DNA Damage/drug effects
MH  - Female
MH  - Gene Expression Regulation, Developmental/*genetics/*physiology
MH  - In Situ Hybridization
MH  - Mutation/*genetics/*physiology
MH  - Oligonucleotide Array Sequence Analysis
MH  - Oxidative Stress/genetics/physiology
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Pregnancy
MH  - RNA, Antisense
MH  - Rats
MH  - Stress, Physiological/*genetics/*physiopathology
EDAT- 2003/05/06 05:00
MHDA- 2004/03/03 05:00
CRDT- 2003/05/06 05:00
PHST- 2003/05/06 05:00 [pubmed]
PHST- 2004/03/03 05:00 [medline]
PHST- 2003/05/06 05:00 [entrez]
AID - kfg097 [pii]
AID - 10.1093/toxsci/kfg097 [doi]
PST - ppublish
SO  - Toxicol Sci. 2003 Jul;74(1):157-64. doi: 10.1093/toxsci/kfg097. Epub 2003 May 2.