Stage-dependent skeletal malformations induced by valproic acid in rat.
In this work we study the skeletal teratogenic response in rats exposed to NaVP at different embryonic stages. Crl:CD female rats were treated subcutaneously with 400 mg/Kg b.w. NaVP at presomitic stage (group II) or nearly at 2, 6, 10, 14, 18 or 22 somites (groups III-VIII). The females on group I were treated with saline and served as controls. No treatment-related effects were observed at the level of resorptions, live fetuses and fetal or placental weight. The skeletal examination showed characteristic patterns of malformations strictly related to the period of treatment. In particular, groups II and III showed a significant increase of alterations of cervical vertebrae (mainly 1st to 3rd segment) and a decrease of the frequency of extra lumbar ribs in comparison to control. Group IV showed severe abnormalities localized at the 4th to 7th cervical segment and at the level of the 1st and 2nd thoracic segments, including duplications of thoracic segments 1, 2 or 3. The fetuses of group V were characterized by several alterations of the thoracic segments distributed without a clear specificity. In group VI, the thoracic region was also affected with some specificity at the level of the segments 4th to 9th; in group VII, last thoracic and lumbar segments were affected (mainly duplications) and in group VIII only lumbo-sacral abnormalities were recorded. These results confirm the specific effect of NaVP at the level of the axial skeleton and suggest a possible interaction with the expression of genes identifying the vertebral segments.
Menegola
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E
Department of Biology, University of Milan, Italy.
Broccia
M L
ML
Prati
M
M
Giavini
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E
D000423:Alcian Blue / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities* / Q000196:embryology; D004396:Coloring Agents; D004622:Embryo, Mammalian / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013131:Spine / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D013723:Teratogens / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
D000880:Anthraquinones; D004396:Coloring Agents; D013723:Teratogens; C010078:alizarin; D014635:Valproic Acid; D000423:Alcian Blue