Modeling Methylmercury’s Nutrient-Mimic Uptake Using a Selenomethionine Transporter Competition Assay in C. elegans

Overview

Methylmercury, a bioaccumulative toxin linked to neurological damage, enters cells by mimicking essential nutrients. Its L-cysteine conjugate structurally resembles L-methionine, hijacking large neutral amino acid transporters for cellular uptake.This study tested whether transporter saturation with a competing amino acid could reduce nutrient-mimic toxicity in vivo. Due to lab safety restrictions, L-selenomethionine (SeMet), a structural methionine analog, served as an experimental proxy. Locomotor function in Caenorhabditis elegans was measured as thrashes per minute immediately following a 30-minute exposure to increasing SeMet concentrations (0-280 µM). Data from each biological replicate were normalized to their controls and analyzed using a constrained four-parameter logistic model. SeMet produced a concentration-dependent decline in locomotion, with an IC50 of 150.3 µM (95% CI: 123.9-204.9 µM; n=3 biological replicates, 10 worms per replicate). Co-exposure with 10 mM L-methionine shifted the dose-response curve rightward, increasing the IC50 to 235.3 µM (95% CI: 216.5–309.5 µM), representing a 1.57-fold rightward shift. At a fixed SeMet concentration (160 µM), increasing levels of methionine produced graded protection of locomotor function, (p = 0.034 at 5 mM; p < 0.001 at 10 mM). In contrast, L-leucine, a structurally related neutral amino acid control, did not significantly alter toxicity (IC50 ≈ 158 µM; overlapping CI). When methionine was added after SeMet exposure, locomotor function did not recover, confirming that protection requires transporter competition at the time of exposure. These findings suggest transporter competition as a targetable mechanism for limiting methylmercury uptake before intracellular damage occurs.