Prevention of ochratoxin A-induced neural tube defects by folic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn.
The gene responsible for the polydactyly/arhinencephaly (Pdn/Pdn) mouse, which exhibits polysyndactyly and arhinencephaly and has a 13.2% risk of neural tube defects (NTD), has been identified as Gli3. Ochratoxin A (OTA) is a teratogen causing NTD in mice. When Pdn/Pdn embryos were exposed to 2 mg/kg of OTA on day 7.5, the incidence of NTD in Pdn/Pdn fetuses increased to 51.6%. Pre-treatment with folinic acid (FA), metabolically the most active form of folic acid, before OTA-treatment decreased the incidence of NTD to 20.8%. We investigated the effect of OTA and FA on gene expression in day 9 embryos using whole-mount in situ hybridization and real-time PCR. Over-expression of Fgf8 was observed at the anterior neural ridge (ANR) in the non-treated Pdn/Pdn. Over-expression at the ANR expanded in the OTA-treated Pdn/Pdn, and it was ameliorated by pretreatment with FA. Emx2 signal was observed in the dorsal forebrain in the non-treated +/+, but disappeared in the OTA-treated +/+, and was recovered by FA. The Emx2 signal was pale and the expression amount was depressed in the non-treated and OTA-treated Pdn/Pdn embryos. It was suggested that down-regulation of Gli3 induced the over-expression of Fgf8 at the ANR, that OTA treatment accelerated the over-expression, and that pretreatment with FA ameliorated the OTA-induced over-expression of Fgf8 in the Pdn/Pdn. It was also suggested that down-regulation of Gli3 induced the down-regulation of Emx2 in the Pdn/Pdn. It was further speculated that the over-expression of Fgf8 at the ANR and down-regulation of Emx2 in the dorsal forebrain may contribute to NTD induction.
Katagiri
Ryu-ichi
R
School of Health Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
Kurome
Maho
M
Teshima
Yuko
Y
Ueta
Etsuko
E
Naruse
Ichiro
I
D000818:Animals; D015536:Down-Regulation; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D016142:Holoprosencephaly / Q000150:complications / Q000235:genetics*; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009436:Neural Tube Defects / Q000517:prevention & control*; D009793:Ochratoxins / Q000633:toxicity*; D017689:Polydactyly / Q000150:complications / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009793:Ochratoxins; C025589:ochratoxin A; D012313:RNA; D005492:Folic Acid