Rat embryos express transcripts for cyclooxygenase‐1 and carbonic anhydrase‐4, but not for cyclooxygenase‐2, during organogenesis

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Abstract
BACKGROUND: Acetylsalicylic acid (ASA) is a rat teratogen, and exposures on gestational days (GDs) 9 and 10 induce diaphragm, cardiac, and midline defects. ASA inhibits members of the cyclooxygenase (COX) family and potentially members of the carbonic anhydrase (CA) family. The objective of this study was to determine whether the mRNA developmental expression pattern for any COX or CA isoform was consistent with a model in which ASA teratogenicity is mediated through direct interaction with one of these enzymes within embryos or within the adjacent ectoplacental cone (EPC) or yolk sac. METHODS: Staged embryos, over a range (GD 9.5–12) that included ASA‐sensitive and ASA‐insensitive stages of organogenesis, were assayed for COX and CA mRNA levels by three techniques: microarrays; in situ hybridization quantitated by a micro‐imager; and quantitative reverse transcription polymerase chain reaction. ASA‐ and vehicle‐treated embryos also were compared to determine whether inhibition led to upregulated COX or CA mRNA expression. RESULTS: COX‐2 mRNA was undetectable in embryos throughout organogenesis by any assay (although it was abundant in EPC). In contrast, COX‐1 mRNA was moderately abundant in embryos throughout organogenesis. One CA isoform, CA‐4, demonstrated developmentally regulated embryonic mRNA expression that coincided with ASA sensitivity. ASA exposure failed to induce upregulation of any of these mRNAs. CONCLUSIONS: Although ASA may affect the embryo indirectly through interaction with COX‐2 within EPC, failure to detect embryonic COX‐2 mRNA argues against COX‐2 functioning as a direct mediator of ASA teratogenic activity in induction of cardiac, diaphragm, and midline defects. Correlation of COX‐1 and CA‐4 expression with ASA sensitivity suggested that embryonic COX‐1 and possibly CA‐4 are much more likely candidates for mediators of ASA developmental toxicity. Birth Defects Research (Part B) 68:57–69, 2003.

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