L-System Transporters Control Uptake and Toxicity of Methylmercury Cysteine Complexes in Larval Zebrafish

Abstract Transport of methylmercury species has long been attributed to the L-type large neutral amino acid transporters LAT1 and LAT2. However, the effects of perturbing this pathway on tissue-specific mercury accumulation in vivo have not been visualized directly. Here, we used synchrotron X-ray fluorescence imaging to examine the consequences of competitive disruption of L-system transport on methylmercury uptake in larval zebrafish (Danio rerio). Zebrafish larvae were exposed to methylmercury-l-cysteine (MeHg-l-Cys) in the presence and absence of the LAT inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) or the competing LAT substrates l-phenylalanine and l-methionine. Co-exposure with each LAT competitor resulted in markedly increased larval survival relative to MeHg-l-Cys alone, accompanied by decreased mercury accumulation in major target tissues, including the eye lens and brain. Exposure to methylmercury-d-cysteine (MeHg-d-Cys) also resulted in substantially reduced toxicity and altered tissue mercury distribution compared with exposure to MeHg-l-Cys. In contrast to previous observations with methylmercury chloride, MeHg-l-Cys exposure did not cause significant selenium depletion, whereas MeHg-d-Cys caused selenium depletion comparable to that observed for other mercury forms. These findings demonstrate that L-system transport is a major determinant of methylmercury uptake and toxicological outcome in vivo and further indicate that the initial ligand environment of methylmercury exerts a persistent influence on intracellular trafficking and downstream elemental modulation.