Coupling strategies for ecotoxicological assessment of neonicotinoid insecticides based on their selective lethal effects: Design, screening, and regulation.

The recently recognized adverse environmental and toxic effects of neonicotinoid insecticides (NNIs) on non-target organisms are alarming. A comprehensive design, screening, and regulatory system was developed to generate NNI derivatives and mutant receptors with selective-ecotoxicological effects to overcome such adverse effects. For ligand design, taking ACE-09 derivative as an example, the toxicity on non-target animals (aboveground: bees; underground: earthworms), plant absorption, and soil absorption decreased by 4.80% and 13.7%, 10.0%, and 121%, while the toxicity on target animals (aboveground: aphids; underground: B. odoriphagas), plant metabolism, and soil degradation increased by 70.2% and 51.7%, 5.08%, and 8.28%. For receptor modification, the ability of mutants to absorb ACE-09 derivative decreased by 31.0%, while the ability of mutants to metabolize ACE-09 derivative increased by 28.0% in scenario 2 (mainly plant selectivity); the ability of mutants to degrade ACE-09 derivative increased by 11.6% in scenario 3 (mainly soil selectivity). The above results indicated that the selective-ecotoxicological effects of ligand design and receptor modification were both improved. Additionally, the combined effects of the ACE-09 derivative on plant absorption and metabolic mutants improved by 31.1% and 31.4% in scenario 2, respectively, while the effect on microbial degradation mutant improved by 14.9%, indicating that there was a synergistic effect between ligand design and receptor modification. Finally, based on the interaction between the ACE-09 derivative and mutants, the optimal environmental factors that improved the selectivity of their ecotoxicological effects were determined. For example, alternate application of nitrogen and phosphorus fertilizers effectively reduced the oxidative damage to plants caused by NNI residues. The novel ligand-receptor joint modification method, combined with the regulation of environmental factors under multiple scenarios, can biochemically address the ecotoxicological concern and highlight the harmful effects of pesticides on the environment and non-target organisms.