title: Developmental toxicity of valproic acid assessed in a sequential culture of hepatocytes and embryos.
abstract: The absence of maternal metabolism in the whole rodent embryo culture (WEC) may partially be considered as a limitation when chemicals are tested for teratogenicity. In the present study, the possibility to combine incubation of rat hepatocytes and WEC in a sequential way was investigated, and valproic acid (VPA) was used as a model compound. Rat hepatocytes were incubated at a density of 2 x 10(6) cells/ml in a mixture of Waymouth medium and human and rat serum (5:4:1, by vol.). After 4 hr the culture medium was recovered and used to culture 8.5-day-old mouse embryos for 24 hr. When VPA (1 mm) was added at the beginning of embryo culture, the rates of mortality and dysmorphogenesis were 87 and 100%, respectively. When VPA was added at the beginning of the incubation of hepatocytes, these values were 18 and 78%, respectively. Moreover, the differentiation of embryos was less affected when VPA was added at the beginning of the hepatocyte culture. The concentration of VPA decreased during the incubation of hepatocytes and glucurono-VPA reached 56% at the end of the incubation. Five other unconjugated metabolites were also detected. It is concluded that addition of an exogenous metabolic activation system to embryo culture results in a decrease of the teratogenic potential of VPA.
authors.affiliation: Laboratory of Developmental Genetics, Catholic University of Louvain, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Gofflot
authors.forename: B
authors.initials: B
authors.lastname: Nihoul
authors.forename: G
authors.initials: G
authors.lastname: Van Maele-Fabry
authors.forename: F
authors.initials: F
authors.lastname: Goethals
authors.forename: J J
authors.initials: JJ
authors.lastname: Picard