Dose-dependent responses of metabolism and tissue injuries in clam Ruditapes philippinarum after subchronic exposure to cadmium.

Marine cadmium (Cd) pollution has been globally occurring, which creates a pressing need to characterize toxicological effects and develop biomarkers for Cd. However, the dose-response relationships challenge toxicity characterization and biomarkers selection. Metabolic processes have been frequently targeted by Cd. In this work, we investigated the dose-dependent effects of Cd on metabolic endpoints in whole soft tissues as well as gill and hepatopancreas injuries in clam Ruditapes philippinarum, aiming to better understand the metabolic responses and develop biomarkers. Nuclear magnetic resonance (NMR)-based metabolomic analysis was conducted on clam whole soft tissues to identify metabolites. The enzymes and metabolites associated with tricarboxylic acid (TCA) cycle, glycolysis, and oxidative phosphorylation showed both monotonic and non-monotonic curves with the increase of Cd dose. In details, glutamine, glucose-1-phosphate, hexokinase (HK), and citrate synthase (CS) presented monotonic decreases with the increase of Cd dose, among which glutamine and CS were preferable biomarkers to Cd exposure based on lower benchmark dose (BMD) values. The monotonic decreases of HK and CS activities suggested Cd exposure potentially disrupted glycolysis and TCA cycle via inhibiting rate-limiting enzymes. In contrast, the non-monotonic responses of succinate dehydrogenase (SDH), alanine aminotransferase (ALT), and their substrates (succinate and alanine) were approximate to U- or J-shaped curves, suggesting the adaptive strategy of metabolic responses to different degrees of Cd stress, like induction of anaerobiosis as energy compensation. Especially, the alterations of succinate and SDH presented typical hormetic dose-response curves. What is more, clam hepatopancreas was more sensitive to Cd than gill in terms of injury occurrence. Overall, characterization of dose-dependent effect of Cd on metabolism and tissue injuries provides a new insight into understanding the metabolic adaptation in marine clams and risk assessment of Cd pollution.