The binary combined toxicity of lithium, lead, and manganese on the proliferation of murine neural stem cells using two different models

As persistent environmental pollutants, more than thirty metals impose a potential global threat to the environment and humans, which has raised scientific concerns. Although the toxic effects of metals had been extensively studied, there is a paucity of information on their mixture toxicity. In this study, we examined the individual and binary combined toxicity of three common metals such as lithium (Li), lead (Pb), and manganese (Mn) on the proliferation of murine neural stem cells (mNSCs), respectively. Li, Pb, and Mn reduced cell proliferation at the concentration of 5.00 mM, 2.50 μM, and 5.00 μM, respectively (all p < 0.050), in a dose-dependent manner of each metal solely on mNSCs with the cytotoxicity rank as Pb > Mn > Li. Furthermore, the interactions of metal mixtures on mNSCs were determined by using response-additivity and dose-additivity models. Pb + Mn mixtures showed a more than additive effect (synergistic) of toxicity in both two methods. In the dose-additivity method, Pb + Li and Li + Mn mixtures exhibited synergistic effects in the compound with a high ratio of Li (25.0% Pb/75.0% Li, 75.0% Li/25.0% Mn), whereas they are antagonistic in the lower or equal ratio of Li (such as 75.0% Pb/25.0% Li, 25.0% Li/75.0% Mn). Besides, the interactions of Li + Mn mixtures showed some discrepancies between different endpoints. In conclusion, our study highlights the complexity of the mixtures' interaction patterns and the possible neuroprotective effect of Li under certain conditions. In the future, more research on different levels of metal mixtures, especially Li metal, is necessary to evaluate their underlying interactions and contribute to establishing risk assessment systems.