Nucleotide excision repair gene expression in the rat conceptus during organogenesis.
DNA repair may be a determinant of the susceptibility of the conceptus to DNA damaging teratogens. The nucleotide excision repair (NER) pathway repairs a substantial amount of chemically induced DNA damage. The goals of this study were to assess the coordinate expression of NER genes in the midorganogenesis-stage rat conceptus and determine the consequences of exposure to the genotoxic teratogen, 4-hydroperoxycyclophosphamide (4-OOHCPA), on NER gene expression. Most NER genes were expressed at low levels in both yolk sac and embryo on gestational day (GD) 10, with the exception of XPD, XPE and PCNA. No significant alterations in gene expression occurred between GDs 10 and 11; in the yolk sac XPB expression increased on GD12 compared to either GD10 or 11. In the embryo, XPE expression increased between GDs 10 and 12, while hHR23B, XPB, ERCC1, and DNA polymerase epsilon expression increased on GD12 relative to both GDs 10 and 11. Contrary to gene expression data, XPB protein was found at high levels and XPD at low levels in GDs 10-12 embryos and yolk sacs. Mirroring gene expression, high levels of PCNA protein were found in both tissues; XPA protein levels were minimal in yolk sac from GDs 10-12 but increased in the embryo from moderate on GD10 to high on GD12. Therefore, NER gene expression during organogenesis was regulated in a developmental stage- and tissue-specific manner. Exposure of the conceptus to a teratogen, 4-OOHCPA, induced malformations without affecting NER transcript levels. Thus, NER gene expression in the conceptus was unresponsive to regulation by DNA alkylation.
Vinson
R K
RK
Department of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montréal, H3G-1Y6, Québec, Canada.
Hales
B F
BF
D000818:Animals; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000633:toxicity*; D004260:DNA Repair / Q000235:genetics*; D004622:Embryo, Mammalian / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005786:Gene Expression Regulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D003520:Cyclophosphamide; C011272:perfosfamide