STAGE-DEPENDENT SKELETAL MALFORMATIONS INDUCED BY VALPROIC ACID IN RAT

In this work we study the skeletal teratogenic response in rats expose d to NaVP at different embryonic stages. Crl:CD female rats were treat ed 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 Ill-VIII). The females on group I were treated with saline and served as controls. N o 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 th e period of treatment. In particular, groups II and III showed a signi ficant increase of alterations of cervical vertebrae (mainly 1(st) to 3(rd) segment) and a decrease of the frequency of extra lumbar ribs in comparison to control. Group IV showed sew re abnormalities localized at the 4(th) to 7(th) cervical segment and at the level of the 1(st) and 2(nd) thoracic segments, including duplications of thoracic segmen ts 1, 2 or 3. The fetuses of group V were characterized by several alt erations of the thoracic segments distributed without a clear specific ity. In group VI, the thoracic region was also affected with some spec ificity at the level of the segments 4(th) to 9(th); in group VII, las t thoracic and lumbar segments were affected (mainly duplications) and in group VIII only lumbo-sacral abnormalities were recorded. These re sults confirm the specific effect of NaVP at the level of the axial sk eleton and suggest a possible interaction with the expression of genes identifying the vertebral segments.