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

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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.