Polycomb homologs are involved in teratogenicity of valproic acid in mice.
BACKGROUND
Valproic acid (VPA) is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its teratogenic mechanisms are unknown. We have attempted to describe a fundamental role of the Polycomb group (Pc-G) in VPA-induced transformations of the axial skeleton.


METHODS
Pregnant NMRI mice were given a single subcutaneous injection of vehicle or VPA (800 mg/kg) on gestation day (GD) 8. The expression of genes encoding Polycomb and trithorax groups was measured by quantitative real-time RT-PCR using total RNA isolated from the embryos exposed to vehicle or VPA for 1, 3, and 6 hr. In addition, the use of two less teratogenic antiepileptic chemicals valpromide (VPD) and valnoctamide (VCD) provide reliable evidence to support the relationship between VPA teratogenicity and the Polycomb group.


RESULTS
At a teratogenic level, VPA inhibits the expression of the Polycomb group genes, including Eed, Ezh2, Zfp144, Bmi1, Cbx2, Rnf2, and YY1 in the mouse embryos. In contrast, neither VPD nor VCD have significant effects on the expression of those genes affected by VPA. The trithorax group (trx-G) gene MLL, which is known to be required to maintain homeobox gene expression such as the Polycomb gene, is not affected by a teratogenic dose of VPA.


CONCLUSIONS
We propose that, during embryonic development, VPA may affect the gene silencing pathway mediated by the Polycomb group complex. The epigenetic mechanism of VPA teratogenicity on anteroposterior patterning is suspected.
Okada
Akinobu
A
Safety Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Aoki
Yoshinobu
Y
Kushima
Kiyoshi
K
Kurihara
Hiroshi
H
Bialer
Meir
M
Fujiwara
Michio
M
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011247:Pregnancy; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D016335:Zinc Fingers
D000577:Amides; D000927:Anticonvulsants; C570426:Cbx2 protein, mouse; D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C045179:valnoctamide; D014635:Valproic Acid; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D063150:Polycomb Repressive Complex 1; C004651:dipropylacetamide