Molecular mechanisms of toxicity and detoxification of copper-ciprofloxacin complexes in lettuce (Lactuca sativa L.)

Animal manures and organic fertilizers often contain elevated residues of transition metals (e.g., Cu and Zn) and antibiotics, and their complexation complicates the phytotoxicity evaluation and risk attribution in agricultural ecosystems. This study systematically elucidated the toxicity and detoxification mechanisms of copper-ciprofloxacin complexes (CuCIP²⁺, CuCIP₂⁺, and CuCIP₂²⁺) in lettuce (Lactuca sativa L.). Exposure to copper-ciprofloxacin complexes caused significant reduction in plant growth and physiological parameters, including chlorophyll content, antioxidant enzyme activity, and membrane integrity, with CuCIP²⁺ exhibited the highest acute toxicity. Integrated transcriptomic and metabolomic analyses reveal that these complexes could induce systemic oxidative stress, activate the stress responsive signaling pathways, and trigger coordinated metabolic reprogramming associated with antioxidant defense and energy compensation. These responses result from a reactive oxygen species (ROS)-centered metabolic feedback loop that includes lipid peroxidation signaling, flavonoid-mediated antioxidant defense, and glycolysis-driven energy compensation. The distinct physiological and molecular responses induced by copper-ciprofloxacin complexes, in contrast to those of free Cu(II) and CIP, are indicative of their involvement in disrupting plant's redox homeostasis and stress-related signaling pathways. These findings demonstrate that the complexes of transition metals and antibiotics could induce distinct toxicological effects and indicate the need for considering their interaction in ecological risk evaluation.