The present study was performed to determine experimental conditions for thalidomide
induction of fetal malformations and to understand the molecular mechanisms underlying
thalidomide teratogenicity in cynomolgus monkeys. Cynomolgus monkeys were orally administered
thalidomide at 15 or 20mg/kg-d on days 26-28 of gestation, and fetuses were examined
on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion,
polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses.
Cynomolgus monkeys were orally administered thalidomide at 20mg/kg on day 26 of gestation,
and whole embryos were removed from the dams 6h after administration. Three embryos
each were obtained from the thalidomide-treated and control groups. Total RNA was
isolated from individual embryos, amplified to biotinylated cRNA and hybridized to
a custom Non-Human Primate (NHP) GeneChip((R)) Array. Altered genes were clustered
into genes that were up-regulated (1281 genes) and down-regulated (1081 genes) in
thalidomide-exposed embryos. Functional annotation by Gene Ontology (GO) categories
revealed up-regulation of actin cytoskeletal remodeling and insulin signaling, and
down-regulation of pathways for vasculature development and the inflammatory response.
These findings show that thalidomide exposure perturbs a general program of morphoregulatory
processes in the monkey embryo. Bioinformatics analysis of the embryonic transcriptome
following maternal thalidomide exposure has now identified many key pathways implicated
in thalidomide embryopathy, and has also revealed some novel processes that can help
unravel the mechanism of this important developmental phenotype.
Copyright 2009 Elsevier Inc. All rights reserved.