2,4-Toluene diisocyanate suppressed the calcium signaling of ligand gated ion channel receptors

Toluene diisocyanate (TDI) is widely used as a chemical intermediate in the production of polyurethane. TDI-induced asthma is related to its disturbance of acetylcholine activity in most affected workers, but the relevant mechanisms are unclear. Toluene diamine (TDA) is the main metabolite of TDI. TDI and TDA have in common the basic toluene structure. Toluene is an abused solvent affecting neuronal signal transduction by influencing the function of ligand gated ion channel receptors, including nicotinic acetylcholine receptors (nAChR), P2X purinoceptors, [gamma]-aminobutyric acid type A (GABA A) receptors, etc. To understand the actions of TDI and TDA on ligand gated ion channels, we investigated their effects on the changes of cytosolic calcium concentration ([Ca 2+] c) while stimulating nAChR in human neuroblastoma SH-SY5Y cells, P2 purinoceptors in PC12 cells, and GABA A receptors in bovine adrenal chromaffin cells. Our results showed that both TDI and TDA suppressed the [Ca 2+] c rise induced by the potent nicotinic ligand, epibatidine, in human SH-SY5Y cells. Similar but stronger suppression of ATP-induced [Ca 2+] c rise occurred in PC12 cells. TDI and TDA also partially suppressed the [Ca 2+] c rise induced by GABA in bovine adrenal chromaffin cells. We conclude that TDI and TDA can act on ligand gated ion channel receptors. Our findings suggest that TDI and TDA might have some neurotoxicity that will need to be investigated.