Mechanistic investigation of the differential synergistic neurotoxicity between pesticide metam sodium and copper or zinc.

Epidemiological studies suggest neurological disorders have been associated with the co-exposure to certain pesticides and transition metals. The present study aims to investigate whether co-exposure to the widely-used pesticide metam sodium and copper (Cu) or zinc ion (Zn) is able to cause synergistic neurotoxicity in neural PC12 cells and its possible mechanism(s). We found that both metam/Cu and metam/Zn synergistically induced apoptosis, intracellular Cu/Zn uptake, reactive oxygen species (ROS) accumulation, double-strand DNA breakage, mitochondrial membrane potential decrease, and nerve function disorder. In addition, metam/Cu was shown to release cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytoplasm and nucleus, respectively, and activate the caspase 9, 8, 3, 7. However, metam/Zn induced caspase 7 activation and AIF translocation and mildly activated cytochrome c/caspase 9/caspase 3 pathway. Furthermore, metam/Cu activated caspase 3/7 by the p38 pathway, whereas metam/Zn did so via both the p38 and JNK pathways. These results demonstrated that metam/Cu or metam/Zn co-exposure cause synergistic neurotoxicity via different mechanisms, indicating a potential risk to human health when they environmentally co-exist.