PMID- 19301244
OWN - NLM
STAT- MEDLINE
DCOM- 20100201
LR  - 20121115
IS  - 1099-1263 (Electronic)
IS  - 0260-437X (Linking)
VI  - 29
IP  - 5
DP  - 2009 Jul
TI  - Cyclopamine-induced synophthalmia in sheep: defining a critical window and 
      toxicokinetic evaluation.
PG  - 414-21
LID - 10.1002/jat.1427 [doi]
AB  - Cyclopamine, a steroidal alkaloid, from the plant Veratrum californicum is 
      teratogenic, causing a range of different birth defects. The critical window for 
      cyclopamine-induced synophthalmia formation has been reported to be gestational 
      day (GD) 14. The objectives of this study were to better describe 
      cyclopamine-induced craniofacial deformities, to better define the window of 
      susceptibility to synophthalmia formation, and to characterize cyclopamine 
      toxicokinetics in sheep. Ewes were dosed i.v. with purified cyclopamine for 
      toxicokinetic analysis. Another four groups of ewes were dosed orally twice daily 
      with 0.88 g/kg of V. californicum on GD 13, 14 or 15 or consecutively on GD days 
      13-15. Pregnancy and pre-partum fetal malformations were determined by ultrasound 
      imaging on GD 60. At parturition lambs were assessed for gross malformations. The 
      elimination half-life of cyclopamine in ewes was determined to be 1.1 +/- 0.1 h. 
      The rapid clearance of cyclopamine indicates that ingestion of V. californicum 
      must occur during a very narrow window for synophthalmia formation to occur. Ewes 
      dosed with V. californicum on GD 13 or 14 had lambs with various craniofacial 
      malformations including cyclopia, maxillary dysplasia and mandibular 
      micrognathia. Ewes dosed on GD 15 delivered normal lambs. Ewes dosed 
      consecutively on GD 13-15 were not pregnant at GD 60 and Veratrum-induced 
      embryonic death was assumed to be the cause. Interestingly, lambs with cyclopia 
      were smaller, under-developed and appeared premature even though their twin 
      appeared fully developed. Initial evaluations suggest this was due to placental 
      dysplasia.
CI  - 2009 by John Wiley & Sons, Ltd.
FAU - Welch, K D
AU  - Welch KD
AD  - Unites States Department of Agriculture, Logan, UT 84341, USA. 
      Kevin.Welch@ars.usda.gov
FAU - Panter, K E
AU  - Panter KE
FAU - Lee, S T
AU  - Lee ST
FAU - Gardner, D R
AU  - Gardner DR
FAU - Stegelmeier, B L
AU  - Stegelmeier BL
FAU - Cook, D
AU  - Cook D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Appl Toxicol
JT  - Journal of applied toxicology : JAT
JID - 8109495
RN  - 0 (Teratogens)
RN  - 0 (Veratrum Alkaloids)
RN  - ZH658AJ192 (cyclopamine)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gestational Age
MH  - Holoprosencephaly/*chemically induced/embryology
MH  - Maternal Exposure/*adverse effects
MH  - Plant Roots/chemistry
MH  - Pregnancy
MH  - Sheep/*abnormalities/embryology
MH  - Teratogens/isolation & purification/pharmacokinetics/*toxicity
MH  - Time Factors
MH  - Veratrum/chemistry
MH  - Veratrum Alkaloids/isolation & purification/pharmacokinetics/*toxicity
EDAT- 2009/03/21 09:00
MHDA- 2010/02/02 06:00
CRDT- 2009/03/21 09:00
PHST- 2009/03/21 09:00 [entrez]
PHST- 2009/03/21 09:00 [pubmed]
PHST- 2010/02/02 06:00 [medline]
AID - 10.1002/jat.1427 [doi]
PST - ppublish
SO  - J Appl Toxicol. 2009 Jul;29(5):414-21. doi: 10.1002/jat.1427.