Arsenic ions (As³⁺) have been recognized as a hazard that threatens the health of humans. However, previous studies regarding arsenic-induced cytotoxicity were mainly focused on the activation of specific intracellular receptors, the underlying mechanisms still need further investigation, especially at the metabolic level. Additionally, As³⁺ was easily binding to the sulfhydryl groups in protein, which may change the normal function of the protein and resulted in cytotoxicity. Metallothionein (MT) is rich in cysteine which may provide a favorable condition for the chelating of As³⁺. Therefore, the pretense of MT may attenuate arsenic-induced cytotoxicity. However, the influence of MT on As³⁺-induced toxicity and the underlying mechanisms are poorly understood. Herein, the interaction between As³⁺ and MT was investigated by isothermal titration calorimetry. The results demonstrated the formation of As³⁺-MT complex. Cell viability analysis suggested MT alleviate As³⁺-induced cytotoxicity through reduced the production of reactive oxygen species (ROS) and maintain the mitochondrial membrane potential. Furthermore, the metabolic response of PC12 cells to As³⁺ was investigated by lipidomics and metabolomics. The results reveal that As³⁺ disrupt amino acid metabolism, energy metabolism, and phospholipids metabolism. The presence of MT alleviated As³⁺ induced metabolic disorder. Compared with As³⁺ treated group, the level of metabolites in MT-As³⁺ co-exposure groups altered significantly, which were similar to the ones in control groups. The results suggested MT alleviated As³⁺ induced cytotoxicity by scavenging ROS and chelating As³⁺. Our findings obtained in this study were helpful to fill the gap about As³⁺-induced toxicity, which might provide clues for studying other food composition on As³⁺toxicity.

Haitao Wang

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