As the most commonly used organochlorine pesticide nowadays, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet. This study found that the CHI based on ADI level could induce obesity in mice. In addition, CHI could induce an imbalance in the gut microbiota of mice. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the CHI could induce obesity in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, CHI could disturb the bile acids (BAs) metabolism of mice, causing the inhibition of the signal response of BAs receptor FXR and leading to glycolipid metabolism disorders in liver and epiWAT of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the CHI-induced obesity in mice. In conclusion, CHI was found to induce obesity in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of obesity, demonstrating the key role of gut microbiota in the toxic effects of pesticides.
Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl 4 ) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl 4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-β (TGF-β) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl 4 -induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1β, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl 4 -induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1β expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1β expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.
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