Expression of base excision, mismatch, and recombination repair genes in the organogenesis-stage rat conceptus and effects of exposure to a genotoxic teratogen, 4-hydroperoxycyclophosphamide.

Abstract

DNA repair capability may influence the outcome of genotoxic teratogen exposure. The goals of this study were to assess the expression of base excision repair (BER), mismatch repair (MMR), and recombination repair (RCR) genes in the mid-organogenesis rat conceptus and to determine the effects on expression of exposure to the genotoxic teratogen, 4-hydroperoxycyclophosphamide (4-OOHCPA). The expression of 17 BER, MMR, and RCR genes was examined in gestational day (GD) 10-12 rat conceptuses using the antisense RNA (aRNA) technique. Embryos were cultured with 10 microM 4-OOHCPA to examine effects on gene expression. Yolk sacs and embryos had similar gene expression patterns for all three DNA repair pathways from GD10-12. Transcripts for APNG, PMS1, and RAD54 were present at high concentrations in both tissues. The remainder of the genes were expressed at low levels in yolk sac, with a few not detected on GD10 and 11. In the embryo, transcripts for most genes were low on GD10 and 11; several increased by GD12. After exposure to 4-OOHCPA for 24 hr, XRCC1 and RAD57 expression decreased in yolk sac, whereas only RAD51 transcripts decreased in the embryo. By 44 hr, transcripts for all BER genes decreased in yolk sac; in the embryo, most BER, MMR, and RCR genes decreased, many below the level of detection. The expression of DNA repair genes in the mid-organogenesis rat conceptus is varied and subject to down-regulation by 4-OOHCPA. DNA repair gene expression may determine the consequences of genotoxicant exposure during development.