Comparative cytotoxicity of novel mercury species α-mercuri-acetaldehyde and α-mercuri-acetic acid versus methylmercury in SH-SY5Y cells

Recently, α-mercuri-acetaldehyde (HgCH2CHO) and α-mercuri-acetic acid (HgCH2COOH) have been proposed as potential causative agents of Minamata disease. However, their toxicological profiles remain largely unknown. This study aimed to characterize the cytotoxicity, cellular uptake, and efflux mechanisms of these compounds in SH-SY5Y neuroblastoma cells and to compare these properties with those of methylmercury (MeHg). Cell viability was assessed after 24 hr of exposure to MeHg (1-10 µM), HgCH2CHO (10-50 µM), or HgCH2COOH (10-50 µM) using the CCK-8 assay. The roles of L-type amino acid transporter 1 (LAT1) and multidrug resistance-associated proteins (MRPs) were evaluated using the inhibitors JPH203 (1 µM) and MK571 (10 µM), respectively. Intracellular mercury accumulation was quantified after 24 hr of exposure to 3 µM of each compound using thermal decomposition-amalgamation atomic absorption spectrometry. All compounds exhibited dose-dependent cytotoxicity, with a relative toxicity order of MeHg (LC50: 6.4 µM) > HgCH2CHO (LC50: 14.6 µM) > HgCH2COOH (LC50: 39.2 µM). LAT1 inhibition had minimal effect on MeHg toxicity but slightly attenuated that of HgCH2CHO and HgCH2COOH. Conversely, MRP inhibition markedly enhanced MeHg toxicity, modestly increased that of HgCH2CHO, and slightly increased that of HgCH2COOH. Cellular mercury accumulation was consistent with cytotoxicity patterns, showing 10-20-fold lower levels for HgCH2CHO and HgCH2COOH than for MeHg. HgCH2CHO and HgCH2COOH were approximately 2-5-fold less cytotoxic than MeHg and exhibited substantially lower intracellular mercury levels. Our findings suggest that HgCH2CHO and HgCH2COOH are unlikely to have neurotoxic potential comparable to that of MeHg.