Some adverse actions of chlorothalonil at sublethal levels in rat thymic lymphocytes: Its relation to Zn²

Chlorothalonil, a polychlorinated aromatic fungicide, is considered non-toxic to small mammals. However, chlorothalonil inactivates sulfhydryl enzymes and depletes cellular glutathione. Chlorothalonil increases intracellular Zn²⁺ concentration ([Zn²⁺]i) in mammalian cells possibly because intracellular Zn²⁺ is released via zinc-thiol/disulfide interchange. The effects of chlorothalonil at sublethal concentrations on the cellular content of nonprotein thiols ([NPT]i) and [Zn²⁺]i were examined using flow cytometry in rat thymocytes. Low concentrations (0.3-1 μM) of chlorothalonil increased, but high concentrations (3-10 μM) decreased [NPT]i. These effects of chlorothalonil were partly attenuated by an intracellular Zn²⁺ chelator. Chlorothalonil at 0.3-10 μM increased [Zn²⁺]i in a concentration-dependent manner, which was largely dependent on the release of intracellular Zn²⁺. Both the decrease in [NPT]i and increase in [Zn²⁺]i increase the vulnerability of cells to oxidative stress. Chlorothalonil at 1-10 μM potentiated the cytotoxicity of H₂O₂ (300 μM). It was also the case for 10 μM pentachloronitrobenzene, but not 10 μM pentachlorophenol. In conclusion, chlorothalonil at low (sublethal) micromolar concentrations is cytotoxic to mammalian cells under oxidative stress.