Insights into pesticide toxicity against aquatic organism: QSTR models on Daphnia Magna.

The toxicities of agrochemicals to non-target aquatic organisms are key items in chemical ecological risk assessment. However, it is still an urgent need to develop new tools to assess the agrochemical aquatic toxicity efficiently and accurately. In this work, QSTR studies were performed on a data set containing 639 diverse pesticides with measured EC50 toxicity against Daphnia magna, by using five machine learning methods combined with seven fingerprints and a set of molecular descriptors. The imbalance problem of the data set was successfully solved by clustering analysis. The top-10 QSTR models displayed greater predicative abilities than ECOSAR. The optimal model, Ext-SVM, showed the best performance in 10-fold cross validation (Qhigh=0.807, Qmoderate=0.806, Qlow=0.755, Qtotal=0.794), and also in the test set verification (Qhigh=0.865, Qmoderate=0.783, Qlow=0.931, Qtotal=0.848). The relevance of the key physical-chemical properties with the toxicity was also investigated, in which the MW, a_np, logP(o/w), GCUT_SLOGP_1, chilv and SMR_VSA7 values displayed positive correlation with Daphnia magna toxicity, whereas the logS and a_don showed negative correlation. The robust QSTR models provided efficient tools for assessing agrochemical aquatic toxicity, and the revealed different physical-chemical properties between the high and low toxic compounds might be useful in the discovery and design of low aquatic toxic pesticides.

Interactions of Fipronil within Fish and Insects: Experimental and Molecular Modeling Studies.

Fipronil is an efficient phenylpyrazole insecticide that acts on insect γ-aminobutyric acid (GABA) receptors (GABARs) and has low toxicity to mammals but high toxicity to nontarget organisms such as fish. To develop novel efficient low-toxicity insecticides, it is necessary to determine the detailed toxic mechanism at the molecular target level. In this work, methods including affinity chromatography, fluorescent-labeled binding assays, and molecular modeling were integrated to explore the binding of fipronil to GABARs in fish ( Aristichthys nobilis) and insects ( Musca domestica). Affinity chromatography revealed that fipronil acts on two different subunits of GABARs in fish and M. domestica. Moreover, fluorescence assays revealed that fipronil exhibits similar affinity to the two GABARs. The Kd and Bmax of fipronil binding to the A. nobilis GABAR were 346 ± 6 nmol/L and 40.6 ± 3.5 pmol/mg of protein, respectively. And the Kd and Bmax of fipronil binding to the GABAR in M. domestica brain were 109 ± 9 nM and 21.3 ± 2.5 pmol/mg of protein, respectively. In addition, similar fipronil binding positions but different binding modes were observed in docking studies with Brachydanio rerio var. and M. domestica GABARs. These findings indicated similar interactions of fipronil with fish and insects, leading to high toxicity. The different binding features of fipronil between the two species might be helpful for the design and development of highly selective insecticides with low toxicity to fish.