Intergenerational consequences of valproic acid exposure: Dose- and sex-specific effects in Drosophilamelanogaster

Valproic acid (VPA) is a widely used anticonvulsant and mood stabilizer that is notable for its role as a histone deacetylase (HDAC) inhibitor and its potential impact on epigenetic modulation. However, its intergenerational impacts are not fully understood. In this study, we investigated the dose- and sex-dependent intergenerational effects of VPA using Drosophila melanogaster as a model organism. Parental (F0) flies - both male and female - were exposed to varying VPA concentrations, while their offspring (F1) were raised on standard food. We assessed several phenotypic outcomes such as lifespan, metabolic changes, fitness, and gene expression. Our findings show that VPA induces significant intergenerational effects, with outcomes strongly influenced by both, dose and sex. For instance, F1 progenies displayed significant differences in lifespan, metabolism and gene expression depending on the parental VPA-treatment and sex. In addition, median lifespan was prolonged after paternal feeding, but not after maternal feeding. An increase of the protein levels in the F1 offspring depended on both, the compound's concentration and the sex of the parents fed with VPA. These results underscore the importance of considering both, sex and dosage, when evaluating the biological and clinical implications of VPA exposure. Such insights are critical for understanding the risks associated with epigenetically active drugs like VPA and highlight the need for further research into their long-term and intergenerational effects.