Comparative study of susceptibility to methylmercury cytotoxicity in cell types composing rat peripheral nerves: a higher susceptibility of dorsal root ganglion neurons

• Published in: Journal of toxicological sciences 2024, Vol.49(5), pp.241-248
• Main Authors: Yoshida, Eiko, Aoki, Kazuhiro, Sasaki, Yu, Izuhara, Hinako, Takahashi, Tsutomu, Fujiwara, Yasuyuki, Fujie, Tomoya, Du, Ke, Eto, Komyo, Shinoda, Yo, Kaji, Toshiyuki
• Format: Article
• Language: English
• Subjects: Accumulation; Amino acids; Animals; ATP-Binding Cassette Transporters; Cell Survival - drug effects; Cell viability; Cells, Cultured; Comparative studies; Cytotoxicity; Damage; Dimethylmercury; Dorsal root ganglia; Dorsal root ganglion neurons; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Glutathione; Intracellular; L-type amino acid transporter 1; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; Male; Mercury; Mercury (metal); Methylmercury; Methylmercury Compounds - toxicity; Minamata disease; Multidrug resistance; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Nervous system; Neurotoxicity; Organometallic compounds; Peripheral nerves; Peripheral Nerves - drug effects; Peripheral Nerves - metabolism; Protein transport; Rats; Schwann cells; Schwann Cells - drug effects; Schwann Cells - metabolism; Sensory neurons; Sensory neuropathy; siRNA; Toxicity
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.49.241

Methylmercury is an environmental polluting organometallic compound that exhibits neurotoxicity, as observed in Minamata disease patients. Methylmercury damages peripheral nerves in Minamata patients, causing more damage to sensory nerves than motor nerves. Peripheral nerves are composed of three cell types: dorsal root ganglion (DRG) cells, anterior horn cells (AHCs), and Schwann cells. In this study, we compared cultured these three cell types derived from the rat for susceptibility to methylmercury cytotoxicity, intracellular accumulation of mercury, expression of L-type amino acid transporter 1 (LAT1), which transports methylmercury into cells, and expression of multidrug resistance-associated protein 2 (MRP2), which transports methylmercury-glutathione conjugates into the extracellular space. Of the cells examined, we found that DRG cells were the most susceptible to methylmercury with markedly higher intracellular accumulation of mercury. The constitutive level of LAT1 was higher and that of MRP2 lower in DRG cells compared with those in AHC and Schwann cells. Additionally, decreased cell viability caused by methylmercury was significantly reduced by either the LAT1 inhibitor, JPH203, or siRNA-mediated knockdown of LAT1. On the other hand, an MRP2 inhibitor, MK571, significantly intensified the decrease in the cell viability caused by methylmercury. Our results provide a cellular basis for sensory neve predominant injury in the peripheral nerves of Minamata disease patients.