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Lipinski RJ, Hutson PR, Hannam PW, Nydza RJ, Washington IM,
Moore RW, Girdaukas GG, Peterson RE, Bushman W.
Dose- and route-dependent teratogenicity,
toxicity, and pharmacokinetic profiles of the hedgehog signaling
antagonist cyclopamine in the mouse.
Toxicol Sci. 2008 Jul;104(1):189-97
Molecular and Environmental Toxicology Center,
School of Medicine and Public Health, University of Wisconsin,
Madison WI 53703, USA.
The Hedgehog (Hh) signaling pathway is an essential regulator of
embryonic development and appears to play important roles in
postnatal repair and cancer progression and metastasis. The
teratogenic Veratrum alkaloid cyclopamine is a potent Hh
antagonist and is used experimentally both in vitro and in vivo
to investigate the role of Hh signaling in diverse biological
processes. Here, we set out to establish an administration
regimen for cyclopamine-induced teratogenicity in the mouse. The
dysmorphogenic concentration of cyclopamine was determined in
vitro via mouse whole-embryo culture assays to be 2.0 microM. We
administered cyclopamine to female C57BL/6J mice at varied doses
by oral gavage, ip injection, or osmotic pump infusion and
assessed toxicity and pharmacokinetic (PK) models. Bolus
administration was limited by toxicity and rapid clearance. In
vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum
steady-state concentration of approximately 2 microM with a
corresponding amniotic fluid concentration of approximately 1.5
microM. Gross facial defects were induced in 30% of
cyclopamine-exposed litters, with affected embryos exhibiting
cleft lip and palate. This is the first report describing the
PKs and teratogenic potential of cyclopamine in the mouse and
demonstrates that transient Hh signaling inhibition induces
facial clefting anomalies in the mouse that mimic common human
birth defects.
PMID: 18411234
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