Developmental Toxicity and Structure-Activity Relationships of Aliphatic Acids, Including Dose-Response Assessment of Valproic Acid in Mice and Rats

摘要

The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. VPA and 14 related chemicals were screened for developmental toxicity using the Chernoff/Kavlock assay. Sprague-Dawley rats were gavaged with the test agent in corn oil once daily organogensis. The dams were allowed to deliver and the pups were examined postnatally. Segment II studies were also conducted using VPA and pentanoic acid in rats, and with VPA in CD-1 mice. For both species, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. All congeners tested induced maternal respiratory effects and six compounds caused motor depression. These data indicate a broader specificity for activity in the maternal system than in the embryo and suggest differing mechanisms for the two effects.