Teratogenic Effects of Blue Cohosh is Mediated through GATA2 Signaling Pathway

Blue cohosh (Caulophyllum thalictroides) (BC) is a perennial herb used by Native American Indian women to induce labor and for the treatment of other uterine complications. Several studies indicated that BC was not absolutely safe for the fetus and able to induce perinatal stroke and ischemia in newborn babies [1]. A recent chemical analysis identified 15 alkaloid-triterpene compounds present in BC [2] and some of them are potential teratogens. We used Japanese medaka (Oryzias latipes) embryo-larval development as our experimental model to verify the teratogenic potency of BC during embryogenesis. We observed that BC was able to induce cardiovascular defects in medaka embryo during development; however, total protein, RNA and several transcription factor mRNAs (emx², en², iro³, otx², shh1, wnt1 and zic5) which were expressed in central nervous system (CNS) of medaka embryo during embryogenesis remained unaltered. Further, we have used subtractive hybridization technique to identify BC-sensitive genes in medaka embryogenesis. We have observed that transcription factor GATA2 was over expressed by BC and in situ hybridization analysis indicated that GATA2 over expression was occurred in CNS. Analysis by semi-quantitative reverse transcriptase polymerase Chain reaction (rt-PCR) indicated that GATA2 mRNA expression was very rapid (significantly increased within 15 min of BC exposure). We predict that teratogenic effects of BC are due to over expression of GATA2 gene that can induce the expression of endothelin-1 mRNA in the cerebral microvessels and peripheral vessels, and thus cause dysfunction of cerebrovascular and cardiovascular system of Japanese Medaka during development.

Fig. 1 Effect of BC on GATA2 (panel A) and endothelin-1 (panel B) mRNA expression in medaka embryo. Fertilized medaka eggs on 3-day post fertilization were exposed to 10 µg/ml BC for 0, 0.25, 0.5, 1, 2, 4, 6, and 8 h, and the extracted mRNA was used for semi-quantitative reverse transcriptase polymerase chain reaction (rtPCR). Lowercase “a” indicates that the values are significantly different (p < 0.05, n = 4) after 0.25 h of BC treatment.