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Environ Pollut
2023 Sep 01;332:121710. doi: 10.1016/j.envpol.2023.121710.
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Adverse effects and potential mechanisms of fluxapyroxad in Xenopus laevis on carbohydrate and lipid metabolism.
Zhao Y
,
Jiao F
,
Tang T
,
Wu S
,
Wang F
,
Zhao X
.
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Fungicides are one of significant contributing factors to the rapid decline of amphibian species worldwide. Fluxapyroxad (FLX), an effective and broad-spectrum succinate dehydrogenase inhibitor fungicide, has attracted major concerns due to its long-lasting in the environment. However, the potential toxicity of FLX in the development of amphibians remains mostly unknown. In this research, the potential toxic effects and mechanisms of FLX on Xenopus laevis were investigated. In the acute toxicity test, the 96 h median lethal concentration (LC50) of FLX in X. laevis tadpoles was 1.645 mg/L. Based on the acute toxicity result, tadpoles at the stage 51 were exposed to 0, 0.00822, 0.0822, and 0.822 mg/L FLX during 21 days. Results demonstrated that FLX exposure led to an apparent delay in the growth and development of tadpoles and associated with severe liver injury. Additionally, FLX induced glycogen depletion and lipid accumulation in the liver of X. laevis. The biochemical analysis of plasma and liver indicated that FLX exposure could perturb liver glucose and lipid homeostasis by altering enzyme activity related to glycolysis, gluconeogenesis, fatty acid synthesis, and oxidation. Consistent with the biochemical result, FLX exposure altered the liver transcriptome profile, and the enrichment analysis of differential expression genes highlighted the adverse effects of FLX exposure on steroid biosynthesis, PPAR signaling pathway, glycolysis/gluconeogenesis, and fatty acid metabolism in the tadpoleliver. Overall, our study was the first to reveal that sub-lethal concentrations of FLX could induce liver damage and produce obvious interference effects on carbohydrate and lipid metabolism of Xenopus, providing new insight into the potential chronic hazards of FLX for amphibians.
Fig. 1. Assessment of liver pathology caused by FLX exposure (H&E staining) (A–D) (n = 4). Liver from the control group (A); liver from FLX-L group (B); liver from FLX-M group (C); liver from FLX-H group (D). Black arrows indicate stromal hyperplasia occurs; red arrows indicate vacuolization; blue arrows indicate nuclear pyknosis; scale bars, 25 μm. The plasma alanine aminotransferase (ALT) levels (E) (n = 4). The plasma aspartate aminotransferase (AST) levels (F) (n = 4). One asterisk, P < 0.05; two asterisks, P < 0.01; three asterisks, P < 0.001; error bars indicate ± SEM.
Fig. 2. The biochemical analysis of X. laevis plasma (n = 4). Insulin (INS, A); glucose (Glu, B); triglycerides (TG, C); cholesterol (TC, D); three asterisks, P < 0.001; error bars indicate ± SEM.
Fig. 3. The biochemical analysis of X. laevis liver involved in glucose metabolism (A–F) and lipid metabolism (G–L) (n = 4). Glycogen (A); glucokinase (GK, B); phosphofructokinase (PFK, C); pyruvate kinase (PK, D); glucose-6-phosphatase (G6Pase, E); phosphoenolpyruvate caboxylkinase (PEPCK, F); triglycerides (TG; G); cholesterol (TC, H); fatty acid synthase (FAS, I); acetyl coenzyme A carboxylase (ACC, J); carnitine palmitoyltransterase-1 (CPT-1, K); succinate dehydrogenase (SDH, L); one asterisk, P < 0.05; two asterisks, P < 0.01; three asterisks, P < 0.001; error bars indicate ± SEM.
Fig. 4. Volcano plots of DEGs in the liver of X. laevis exposed to 0.822 mg/L FLX (FLX-H) by the transcriptome analysis (A) (n = 3). KEGG pathway analysis enriched in the statistically significant profiles (B) (n = 3). Red asterisks indicate the pathway related to metabolism. qRT-PCR analysis of mRNA expression related to carbohydrate metabolism (C) and lipid metabolism (D) in X. laevis liver (n = 4). One asterisk, P < 0.05; two asterisks, P < 0.01; three asterisks, P < 0.001; error bars indicate ± SEM.
Fig. S1 Significantly enriched GO terms of DEGs in FLX-H group (A). BP indicate biological process; CC indicate cellular component; MF indicate molecular function. Heatmap of DEGs involved in glucose and lipid metabolism pathway (B). Columns and rows represent treatment groups and genes, respectively. Z-score-normalized value were used for determining the gene expression levels.
Fig. S2 Correlation analysis show a good linearity between RNA-seq results and qRT-PCR results in FLX-H group. Three asterisks indicate P < 0.001.