New molecular bioassays for the estimation of the teratogenic potency of valproic acid derivatives in vitro: Activation of the peroxisomal proliferator-activated receptor (PPAR delta)

Therapy with the antiepileptic drug valproic acid (2-propylpentanoic acid, VPA) during early pregnancy can cause teratogenic effects (neural tube defe cts) in humans and in mice. VPA and a teratogenic derivative specifically i nduce differentiation of F9 teratocarcinoma cells and activate PPAR delta. We have now studied structure-activity relationships of 11 VPA-related comp ounds by quantitatively comparing their teratogenic potency with their effe cts in the two novel in vitro systems. Based on the induction of a Rous sar coma virus (RSV) promoter-driven reporter gene, which is associated with th e differentiation of F9 cells, a system suitable for high-throughput and qu antitative screening was established, Structure-activity investigations sho wed that only teratogenic derivatives of VPA induced the response in F9 cel ls as well as activated the PPAR delta-dependent reporter system in Chinese hamster ovary (CHO) cells. Increases in the length of the side chain in th e VPA-related 2-alkyl-pentynoic acid generate more potent inducers in the c ell-culture-based assays, which also show higher teratogenicity and embryon ic lethality rates. Activation of PPAR delta correlated well with the effec ts in the F9 cell assay and with teratogenic potency in vivo (p < 0.007). E valuation of the effects of the presented set of compounds allows the concl usion that the in vitro systems faithfully reflect teratogenicity of VPA-re lated compounds. Whether the activation of PPAR delta is causally related t o the disruption of proper embryonic development or whether it reflects oth er yet unknown VPA-induced events remains to be established. (C) 1999 Acade mic Press.