Physiologically based toxicokinetic and toxicodynamic (PBTK-TD) modelling of cis-bifenthrin in Carassius auratus and Xenopus laevis accounting for reproductive toxicity.

Pyrethroid insecticides are a class of endocrine disruptors and are believed to exhibit reproductive toxicity to aquatic organisms. Pyrethroids are widely detected in aquatic environments and can accumulate in aquatic organisms, but studies on their accumulation and the associated reproductive toxicity in aquatic organisms are still limited. We utilized Carassius auratus and Xenopus laevis as models for fish and amphibians, respectively, and developed and validated a physiologically based toxicokinetic and toxicodynamic (PBTK-TD) model for adult fish and frogs exposed to typical pyrethroid pesticides cis-bifenthrin (cis-BF). The model includes the brain, kidney, liver, gonads, gills/lungs, well-perfused tissue, and poorly-perfused tissue, which are interconnected by blood circulation in the PBTK process. There are also dynamic relationships between target organ concentrations and reproductive-related endpoints in the TD process. Results showed that the PBTK sub-model accurately described and predicted the uptake, distribution, and disposition kinetics in fish and frogs. In fish, the kidney exhibited the fastest accumulation rate, while in frogs, the skin showed the fastest accumulation rate, followed by the kidney. Sensitivity analysis indicated that parameters such as blood flow and blood distribution coefficients had significant effects on chemical concentrations. A sigmoid Emax model was employed to describe the relationship between the reproductive toxicity effects of cis-BF and its dose-concentration variations. We found that testosterone (T) exhibited the highest correlation coefficient, suggesting that T could serve as an effective biomarker for cis-BF reproductive toxicity. The PBTK-TD model established in this study is beneficial for predicting the toxicological effects of pyrethroids in fish and amphibians.

Lipid Metabolic Disorder Induced by Pyrethroids in Nonalcoholic Fatty Liver Disease of Xenopus laevis.

Pyrethroids, an effective and widely used class of pesticides, have attracted considerable concerns considering their frequent detection in environmental matrices. However, their potential health risks to amphibians remain unclear. In our study, female Xenopus laevis were exposed to 0, 0.06, and 0.3 µg/L typical pyrethroid, cis-bifenthrin (cis-BF), for 3 months. Elevated activities of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed, indicating an ongoing liver injury. Furthermore, exposure to cis-BF led to hyperlipidemia and lipid accumulation in the liver of Xenopus. The targeted lipidomic analysis further revealed that treatment with cis-BF perturbed liver steroid homeostasis, as evidenced by the enriched lipids in the steroid biosynthesis pathway. Consistent with the targeted lipidomic result, treatment with cis-BF changed the liver transcriptome profile with induction of 808 and 1230 differentially expressed genes. Kyoto Encyclopedia of Genes and Genomes analysis underlined the adverse effects of cis-BF exposure on steroid biosynthesis, primary bile acid biosynthesis, and the PPAR signaling pathway in the Xenopus liver. Taken together, our study revealed that exposure to cis-BF at environmentally relevant concentrations resulted in lipid metabolic disorder associated with nonalcoholic fatty liver disease of X. laevis, and our results provided new insight into the potential long-term hazards of pyrethroids.

Mitochondrial dynamics disruption: Unraveling Dinotefuran's impact on cardiotoxicity.

Exposure to pesticides has been associated with several cardiovascular complications in animal models. Neonicotinoids are now the most widely used insecticide globally, while the impact of neonicotinoids on cardiovascular function and the role of mitochondrial dynamics in neonicotinoids-induced cardiotoxicity is unclear. In the present study, Xenopus laevis tadpoles were exposed to environmental related concentrations (0, 5, and 50 µg/L) of typical neonicotinoid dinotefuran, with two enantiomers, for 21 days. We evaluated the changes in heart rate and cardiomyocyte apoptosis in exposed tadpoles. Then, we performed the transcriptome, metabolomics, transmission electron microscopy (TEM), and protein immunoblot to investigate the potential adverse impact of two enantiomers of dinotefuran on cardiotoxicity associated with mitochondrial dynamics. We observed changes in heart rate and increased cardiomyocyte apoptosis in exposed tadpoles, indicating that dinotefuran had a cardiotoxic effect. We further found that the cardiac contractile function pathway was significantly enriched, while the glucose metabolism-related pathways were also disturbed significantly. TEM observation revealed that the mitochondrial morphology of cardiomyocytes in exposed tadpoles was swollen, and mitophagy was increased. Mitochondria fusion was excessively manifested in the enhanced mitochondrial fusion protein. The mitochondrial respiratory chain was also disturbed, which led to an increase in ROS production and a decrease in ATP content. Therefore, our results suggested that dinotefuran exposure can induce cardiac disease associated mitochondrial disorders by interfering with the functionality and dynamics of mitochondria. In addition, both two enantiomers of dinotefuran have certain toxicity to tadpole cardiomyocytes, while R-dinotefuran exhibited higher toxicity than S-enantiomer, which may be attributed to disparities in the activation capacities of the respiratory chain.