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

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. © 2003 Wiley‐Liss, Inc.

Analysis of the nonsteroidal anti‐inflammatory drug literature for potential developmental toxicity in rats and rabbits

“…This finding suggested that the developmental toxicity is mediated by COX-1 or COX-2 inhibition, where irreversible inhibition produces a greater developmental toxicity signal. Subsequent to this review, two studies strengthened the conclusion that COX-1 mediates these developmental signals (Cappon et al, 2003a;Streck et al, 2003). Cappon et al (2003a) selected a series of NSAIDs with different capacities to inhibit COX-1 and COX-2 and administered them to pregnant rats and rabbits during the sensitive period for heart development and midline closure.…”

“…Hence, studies conducted well below the MTD and those conducted with doses exceeding the MTD may be unable to detect low-incidence developmentally toxic effects of NSAIDs. The potential association of NSAIDs with developmental toxicity, as shown by the literature, and the limitations of this data set, as discussed above, led to us to reinvestigate the developmental toxicity of aspirin in rats and rabbits in a series of studies by using two different dosing paradigms (Cappon et al, 2003b;Gupta et al, 2003), to assess the developmental toxicity of NSAIDs with different COX-1 and COX-2 specificities (Cappon et al, 2003a), and to examine the expression of COX-1 and COX-2 in developing rat embryos (Streck et al, 2003). Concurrent with these studies, a metaanalysis of the human epidemiologic data was conducted examining the use of aspirin during pregnancy by analyzing first-trimester outcomes (Kozer et al, 2002) and second-and third-trimester outcomes (Kozer et al, 2003).…”

“…A selective COX-2 inhibitor did not induce these malformations. Streck et al (2003) examined COX-1 and COX-2 mRNA expression in rat embryos during the period in which heart and midline development are sensitive to aspirin. COX-1 but not COX-2 was detected during the critical period of heart and midline development.…”

Effects of modified Shoutaiwai recipe on integrin β3 and leukemia-inhibitory factor in endometrium of controlled ovarian hyperstimulation mice during the implantation window

“…Carnovale et al (2001) reported that aspirin could inhibit prostaglandin in a dose-dependent manner, which is the main prostaglandin involved in cultivation and decidualization, cytokine production, and ovulation. In addition, aspirin induces embryo teratogenicity (Streck et al, 2003), drawing attention to its toxicity. Kozer et al (2002) conducted a meta-analysis showing that aspirin exposure during the first trimester may be associated with an increased risk of gastroschisis.…”

Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

“…Обе изоформы ЦОГ имеют разные уровни экспрессии. Так, у эмбрионов крыс на про-тяжении органогенеза обнаруживается только мРНК ЦОГ-1 [76]. Отмечается, что нежелательные побочные реакции неселективных НПВП связаны главным образом с ингибированием ЦОГ-1.…”