A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression.
Valproate (VPA) is one of several effective anti-epileptic and mood-stabilizing drugs, many of which are also potent teratogens in humans and several other mammalian species. Variable teratogenicity among inbred strains of laboratory mice suggests that genetic factors influence susceptibility. While studying the genetic basis for VPA teratogenicity in mice, we discovered that parental factors influence fetal susceptibility to induced malformations. Detailed examination of these malformations revealed that many were homeotic transformations. To test whether VPA, like retinoic acid (RA), alters HOX expression, pluripotent human embryonal carcinoma cells were treated with VPA or RA and Hox expression assessed. Altered expression of specific Hox genes may thus account for the homeotic transformations and other malformations found in VPA-treated fetuses.
Faiella
A
A
DIBIT and Department of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Wernig
M
M
Consalez
G G
GG
Hostick
U
U
Hofmann
C
C
Hustert
E
E
Boncinelli
E
E
Balling
R
R
Nadeau
J H
JH
D000014:Abnormalities, Drug-Induced / Q000235:genetics*; D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000235:genetics*; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D018236:Carcinoma, Embryonal / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005801:Genes, Homeobox / Q000187:drug effects*; D005804:Genes, Lethal; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011247:Pregnancy; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D014635:Valproic Acid