Sub-chronic exposure to hexaconazole affects the lipid metabolism of rats through mTOR-PPAR-γ/SREBP1 signaling pathway mediated by oxidative stress.

Hexaconazole (Hex) is a widely used and high frequency detected triazole fungicide in agricultural products and environment which may pose potential toxicity to the nontargeted organisms. Hex had been reported to affect lipid homeostasis while the mechanism was undefined. This study aims to explore the characteristic lipidomic profiles and clarify the underlying signaling pathways of Hex-induced lipid metabolism disorder in rat liver. The results showed that sub-chronic exposure to environmental related concentrations of Hex caused histopathological changes, oxidative stress, fat accumulation, lipid biochemical parameter increase in rats. Moreover, the untargeted lipidomic analysis showed that the levels of TAG, PC, and PE and the pathway of glycerophospholipid metabolism were heavily altered by Hex. We further analyzed the lipid metabolism related genes and proteins which revealed that Hex exposure increased amount of lipogenesis by activating oxidative stress-mediated mTOR-PPAR-γ/SREBP1 signaling pathways. The imbalance of lipid homeostasis induced by Hex exposure might further lead to obesity, cardiovascular diseases (CVDs), and hyperlipidemia. Our results provided systematic and comprehensive evidence for the mechanism of Hex-induced lipid metabolism disorder at environmental concentrations and supplied a certain basis for its health risks assessment.

Low dosage fluorine ameliorates the bioaccumulation, hepatorenal dysfunction and oxidative stress, and gut microbiota perturbation of cadmium in rats.

Many "hot spot" geographic areas around the world with soils and crops co-polluted with cadmium (Cd) and fluorine (F), two of the most representative pollutants in the environment. However, it still exists argumentative on the dose-effect relationship between F and Cd so far. To explore this, a rat model was established to evaluate the effects of F on Cd-mediated bioaccumulation, hepatorenal dysfunction and oxidative stress, and the disorder of intestinal microbiota as well. 30 healthy rats were randomly assigned to Control group (C group), Cd 1 mg/kg (Cd group), Cd 1 mg/kg and F 15 mg/kg (L group), Cd 1 mg/kg and F 45 mg/kg (M group), and Cd 1 mg/kg and F 75 mg/kg (H group) for 12 weeks by gavage. Our results showed that Cd exposure could accumulate in organs, cause hepatorenal function damage and oxidative stress, and disorder of gut microflora. However, different dosages of F showed various effects on Cd-induced damages in liver, kidney, and intestine, and only the low supplement of F showed a consistent trend. After low supplement of F, Cd levels were declined by 31.29% for liver, 18.31% for kidney, and 2.89% for colon, respectively. The serum aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and N-acetyl-ß-glucosaminidase (NAG) were significantly reduced (p < 0.01); The activity of superoxide dismutase (SOD) was elevated and mRNA expression level of NAD(P)H quinone oxidoreductase 1 (NQO1) was decreased in the liver and kidney (p < 0.05). Moreover, low F dosage up-regulated the abundance of Lactobacillus from 15.56% to 28.73% and the 6.23% of F/B ratio was declined to 3.70%. Collectively, this highlights that low dosage of F might be a potential strategy to ameliorate the hazardous effects by Cd-exposed in the environment.

Stereoselective Toxicokinetic and Distribution Study on the Hexaconazole Enantiomers in Mice.

Hexaconazole (Hex) has been widely used in agricultural products, and its residues may pose a potential risk to human health. However, the metabolic behavior of Hex enantiomers in mammal organisms is still unknown, which is important for evaluating the differences in their toxicity. In this study, the distribution of S-(+)- and R-(-)-Hex in mice was detected by an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and the mechanism differences in the toxicokinetic behavior were analyzed by molecular docking. Good linearities, accuracies, and precisions were achieved for S-(+)- and R-(-)-Hex, with recoveries of 88.7~104.2% and RSDs less than 9.45% in nine tissues of mice. This established method was then used to detect the toxicokinetic of Hex enantiomers in mice after oral administration within 96 h. The results showed that the half-lives of S-(+)- and R-(-)-Hex were 3.07 and 3.71 h in plasma. Hex was mainly accumulated in the liver, followed by the kidneys, brain, lungs, spleen, and heart. The enantiomeric fraction (EF) values of Hex enantiomers in most of the samples were below 1, indicating that S-(+)-Hex decreased faster than its antipode. The molecular docking showed that the binding of S-(+)-Hex with P450arom was much more stable than R-(-)-Hex, which verified the fact that S-(+)-Hex was prefer to decrease in most of the tissues. The results of this study could be helpful for further evaluating the potential toxic risk of Hex enantiomers and for the development and usage of its pure monomer.

Accumulation and risk assessment of heavy metals in rice: a case study for five areas of Guizhou Province, China.

In the present study, the concentration and accumulation abilities of five heavy metals (Cd, Hg, As, Pb, Cr) in rice were assessed and their human health risk to local citizens had been evaluated. Soil and rice samples (125 samples) were collected from Guiyang (GY), Qiannan (QN), Bijie (BJ), Tongren (TR), and Zunyi (ZY) in Guizhou Province. Heavy metals were measured by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion. The mean concentrations of Cd, Hg, As, Pb, and Cr were 0.58, 0.65, 12.31, 38.70, and 87.30 mg/kg in soil and were 0.05, 0.005, 0.11, 0.07, and 0.34 mg/kg in rice, respectively. The bioconcentration factors (BCF) decreased with the order Cd > Hg > As > Cr > Pb. Non-carcinogenic risk in this study was evaluated using the method of the hazard quotient (HQ) and hazard index (HI). The mean HQ values for Cd, Hg, Pb, and Cr were all lower than the standard limit (1.0) for children and adults, except As with the mean HQ for children of 2.79. The mean HI values for children and adults were 4.22 and 1.42, which exceeded 1.0. The mean carcinogenic risk (CR) values of As and Pb for children and adults were higher than the upper limit of the acceptable range (1 × 10-4) established by the United States Environmental Protection Agency (USEPA). In a conclusion, the non-carcinogenic and carcinogenic risks induced by heavy metals for children were higher than that for adults. This study revealed that consumption of rice in study areas may pose potential non-carcinogenic and carcinogenic risks to humans, and As was the largest contributor.

The discovery of combined toxicity effects and mechanisms of hexaconazole and arsenic to mice based on untargeted metabolomics.

The high detected frequencies of hexaconazole (Hex) and arsenic (As) increased the probabilities of their co-existence in agricultural products. However, the combined toxicity effect and mechanism of action for these two pollutants were still unclear. In this study, an untargeted metabolomics method with ultra high performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) was developed to monitor the changes of endogenous metabolites and metabolism pathways in mice liver. Our study revealed that significant differences in metabolomics profiles were observed after Hex, As, and Hex+As exposure for 90 d. Hex exposure altered 54 metabolites and 11 pathways significantly which were mainly lipid-related. For As exposure, 63 metabolites and 9 pathways were affected most of which were amino acid-related. Hex+As induced 93 metabolites changes with 34% was lipids and lipid-like molecules and 22% was organic acids and derivatives. Hex+As exposure shared the pathways that altered by Hex and As indicated that the interaction of Hex and As might be independent action. The results of this study could provide an important insight for understanding the mechanism of combined toxicity for Hex and As and be helpful for evaluating their health risk to human.