A toxicokinetic–toxicodynamic model with a transgenerational damage to explain toxicity changes over generations (in Daphnia magna exposed to depleted uranium)

We used a toxicokinetic–toxicodynamic (TKTD) model to analyze chronic effects, in Daphnia magna exposed to waterborne depleted uranium (DU) for two or three successive generations (F0, F1 and F2). Our aim was to understand how DU toxicity for growth and reproduction increased across generations. For the first time in a TKTD model, we introduced a novel transgenerational damage compartment, whose level was transmitted from parents to progeny upon egg deposition. Various exposure regimes took account of differences in exposure among generations. We used a simplified dynamic energy budget applied to toxicology (DEBtox) including two independent physiological modes of action (pMoA). The first pMoA, a reduction in assimilation linked to internal concentration, was previously confirmed by complementary analyses (direct measurements of carbon assimilation, histological observations of gut epithelium alterations). The second pMoA, an increase in costs for growth and maturation linked to transgenerational damage, was the most likely among three possible pMoA affecting both growth and reproduction. Modelling results showed that internal concentration and transgenerational damage followed strongly different kinetics across generations, suggesting that the two pMoA played very contrasting roles in long-term DU toxicity for D. magna. Internal concentration only increased between generations F0 and F1, showing no further difference between generations F1 and F2. Our model was able to correctly describe and predict DU toxicity data, in all tested generations and concentrations, and provided a mechanistic explanation for the increase in DU toxicity across generations. [Display omitted] •We use a TKTD model, to mechanistically explain U toxicity changes over generations.•Maternal levels of internal concentration and damage are transmitted to eggs.•Our model is fitted using experimental datasets for Daphnia exposed to depleted U.•An accumulation of damage explains why U toxicity increases over generations.•Damage most likely affects DEB through increased costs for growth and maturation.