Direct and transgenerational effects of simvastatin on the metabolism of the amphipod Gammarus locusta

In this study, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was applied for the first time, to our knowledge, to assess the metabolic impact of direct and transgenerational exposure (F0 and F3 generations, respectively) of amphipods Gammarus locusta to simvastatin (SIM), a pharmaceutical widely prescribed for the treatment of hypercholesterolemia. Results revealed the important gender-dependent nature of each of these effects. Directly exposed males showed enhanced glucose catabolism and tricarboxylic acid (TCA) cycle activity, in tandem with adaptations in osmotic regulation and glyoxylate metabolism. Exposed females exhibited only a small osmoregulatory effect. It is suggested that the response of exposed males may reflect reported high levels of methyl farnesoate hormone (low levels in females) and alterations in apical factors, namely decreased growth. Conversely, transgenerational effects were identified only in females, with impact on energy metabolism (glycolysis and TCA cycle enhancement) and osmoregulatory response. This expresses the ability of female gametes to transmit the effects of direct SIM exposure. Such effects were putatively related to reported delayed maturation and transcriptomic deviations impacting on carbohydrate and lipid metabolisms, possibly specifically engaging phenylalanine/tyrosine and choline in dopamine and choline metabolisms. These findings reflect the importance of untargeted metabolomics in addressing not only direct exposure of contaminants, but also their transgenerational effects, potentially contributing towards improving hazard and risk assessment of biologically active compounds.