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Screening and validation of biomarkers for cadmium-induced liver injury based on targeted bile acid metabolomics
2022
Tian, Meng | Yan, Jun | Zhang, Honglong | Wei, Yuhui | Zhang, Mingtong | Rao, Zhi | Zhang, Mingkang | Wang, Haiping | Wang, Yanping | Li, Xun
Although cadmium (Cd) is a toxic heavy metal that reportedly causes liver injury, few studies have investigated biomarkers of Cd-induced liver injury. The purpose of this study is to investigate the role of bile acid (BA) in Cd-induced liver injury and determine reliable and sensitive biochemical parameters for the diagnosis of Cd-induced liver injury. In this study, 48 Sprague-Dawley rats were randomly divided into six groups and administered either normal saline or 2.5, 5, 10, 20, and 40 mg/kg/d cadmium chloride for 12 weeks. A total of 403 subjects living in either a control area (n = 135) or Cd polluted area (n = 268) of Dongdagou-Xinglong (DDGXL) cohort were included, a population with long-term low Cd exposure. The BA profiles in rats' liver, serum, caecal contents, faeces, and subjects' serum were detected using high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS). Changes in rats' and subjects' liver injury indices, rats' liver pathological degeneration, and rats' liver and subjects’ blood Cd levels were also measured. Cadmium exposure caused cholestasis and an increase in toxic BAs, leading to liver injury in rats. Among them, glycoursodeoxycholic acid (GUDCA), glycolithocholic acid (GLCA), taurolithocholic acid (TLCA), and taurodeoxycholate acid (TDCA) are expected to be potential biomarkers for the early detect of Cd-induced liver injury. Serum BAs can be used to assess Cd-induced liver injury as a simple, feasible, and suitable method in rats. Serum GUDCA, GLCA, TDCA, and TLCA were verified to be of value to evaluate Cd-induced liver injury and Cd exposure in humans. These findings provided evidence for screening and validation of additional biomarkers for Cd-induced liver injury based on targeted BA metabolomics.
显示更多 [+] 显示较少 [-]Exposure to the fungicide propamocarb causes gut microbiota dysbiosis and metabolic disorder in mice
2018
Wu, Sisheng | Jin, Cuiyuan | Wang, Yueyi | Fu, Zhengwei | Jin, Yuanxiang
Propamocarb (PM) is a widely used fungicide with property of affecting fatty acid and phospholipid biosynthesis in funguses. In this study, we explored its effects on mice gut microbiota and metabolism by exposing mice to 3, 30, and 300 mg/L PM through drinking water for a duration of 28 days. We observed that the transcription of hepatic genes related to regulate lipid metabolism were perturbed by PM exposure. The microbiota in the cecal contents and feces changed during or after PM exposure at phylum or genus levels. 16S rRNA gene sequencing for the cecal content revealed shifted in overall microbial structure after PM exposure, and operational taxonomic unit (OTU) analysis indicated that 32.2% of OTUs changed by 300 mg/mL PM exposure for 28 days. In addition, based on 1H NMR analysis,a total of 20 fecal metabolites mainly including succinate, short chain fatty acids, bile acids and trimethylamine were found to be significantly influenced by exposure to 300 mg/L PM.,. These metabolites were tightly correlated to host metabolism. Our findings indicated that high doses of PM exposure could disturb mice metabolism through, or partly through, altering the gut microbiota and microbial metabolites.
显示更多 [+] 显示较少 [-]Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice
2017
Liu, Qian | Shao, Wentao | Zhang, Chunlan | Xu, Cheng | Wang, Qihan | Liu, Hui | Sun, Haidong | Jiang, Zhaoyan | Gu, Aihua
Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p’-dichlorodiphenyldichloroethylene (p, p’-DDE) and β-hexachlorocyclohexane (β-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p’-DDE and β-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human.
显示更多 [+] 显示较少 [-]Bioaccessibility of nitro- and oxy-PAHs in fuel soot assessed by an in vitro digestive model with absorptive sink
2016
Zhang, Yanyan | Pignatello, Joseph J. | Tao, Shu
Ingestion of soot present in soil or other environmental particles is expected to be an important route of exposure to nitro and oxygenated derivatives of polycyclic aromatic hydrocarbons (PAHs). We measured the apparent bioaccessibility (Bapp) of native concentrations of 1-nitropyrene (1N-PYR), 9-fluorenone (9FLO), anthracene-9,10-dione (ATQ), benzo[a]anthracene-7,12-dione (BaAQ), and benzanthrone (BZO) in a composite fuel soot sample using a previously-developed in vitro human gastrointestinal model that includes silicone sheet as a third-phase absorptive sink. Along with Bapp, we determined the 24-h sheet-digestive fluid partition coefficient (Ks,24h), the soot residue-fluid distribution ratio of the labile sorbed fraction after digestion (Kr,lab), and the maximum possible (limiting) bioaccessibility, Blim. The Bapp of PAH derivatives was positively affected by the presence of the sheet due to mass-action removal of the sorbed compounds. In all cases Bapp increased with imposition of fed conditions. The enhancement of Bapp under fed conditions is due to increasingly favorable mass transfer of target compounds from soot to fluid (increasing bile acid concentration, or adding food lipids) or transfer from fluid to sheet (by raising small intestinal pH). Food lipids may also enhance Bapp by mobilizing contaminants from nonlabile to labile states of the soot. Compared to the parent PAH, the derivatives had larger Kr,lab, despite having lower partition coefficients to various hydrophobic reference phases including silicone sheet. The Blim of the derivatives under the default conditions of the model ranged from 65.5% to 34.4%, in the order, 1N-PYR > ATQ > 9FLO > BZO > BaAQ, with no significant correlation with hydrophobic parameters, nor consistent relationship with Blim of the parent PAH. Consistent with earlier experiments on a wider range of PAHs, the results suggest that a major determinant of bioaccessibility is the distribution of chemical between nonlabile and labile states in the original solid.
显示更多 [+] 显示较少 [-]iTRAQ-based proteomic analysis on the mitochondrial responses in gill tissues of juvenile olive flounder Paralichthys olivaceus exposed to cadmium
2020
Lu, Zhen | Wang, Shuang | Ji, Chenglong | Li, Fei | Cong, Ming | Shan, Xiujuan | Wu, Huifeng
Cadmium (Cd) is an important heavy metal pollutant in the Bohai Sea. Mitochondria are recognized as the key target for Cd toxicity. However, mitochondrial responses to Cd have not been fully investigated in marine fishes. In this study, the mitochondrial responses were characterized in gills of juvenile flounder Paralichthys olivaceus treated with two environmentally relevant concentrations (5 and 50 μg/L) of Cd for 14 days by determination of mitochondrial membrane potential (MMP), observation of mitochondrial morphology and quantitative proteomic analysis. Both Cd treatments significantly decreased MMPs of mitochondria from flounder gills. Mitochondrial morphologies were altered in Cd-treated flounder samples, indicated by more and smaller mitochondria. iTRAQ-based proteomic analysis indicated that a total of 128 proteins were differentially expressed in both Cd treatments. These proteins were basically involved in various biological processes in gill mitochondria, including mitochondrial morphology and import, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), primary bile acid biosynthesis, stress resistance and apoptosis. These results indicated that dynamic regulations of energy homeostasis, cholesterol metabolism, stress resistance, apoptosis, and mitochondrial morphology in gill mitochondria might play significant roles in response to Cd toxicity. Overall, this study provided a global view on mitochondrial toxicity of Cd in flounder gills using iTRAQ-based proteomics.
显示更多 [+] 显示较少 [-]Effects of triphenyl phosphate exposure during fetal development on obesity and metabolic dysfunctions in adult mice: Impaired lipid metabolism and intestinal dysbiosis
2019
Wang, Dezhen | Yan, Sen | Yan, Jin | Teng, Miaomiao | Meng, Zhiyuan | Li, Ruisheng | Zhou, Zhiqiang | Zhu, Wentao
Previous in vitro studies have implied that triphenyl phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000 μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examining body weight, liver weight, histopathology, blood biochemistry, gene expression, and gut microbiota compositions and metabolic functions. Results showed that TPHP exposure led to increased body weight, liver weight, fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metabolism, especially lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatography-mass spectrometry (GC-MS) analysis further supported the changes in fatty acid composition. Intestinal flora measurements by 16S rRNA gene sequencing and ¹H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome composition and influenced host-gut co-metabolism, especially for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice.
显示更多 [+] 显示较少 [-]Effects of fluoride on the histology, lipid metabolism, and bile acid secretion in liver of Bufo gargarizans larvae
2019
Wang, Xianchan | Zheng, Rui | Yao, Qiong | Liang, Zhijia | Wu, Minyao | Wang, Hongyuan
In our study, Bufo gargarizans (B. gargarizans) larvae were exposed to control, 0.5, 5, 10 and 50 mg/L of NaF from Gs 26 to 42. At Gs 42, we evaluated the changes of liver histology and the mRNA levels of target genes in liver. In addition, we also examined the composition and content of fatty acids. Histological analysis revealed that fluoride caused liver injury, such as the increase of number of melanomacrophage centres, atrophy of nucleus, dilation of bile canaliculus, and decrease of quantity, degradation and deposition of lipid droplets. The results of RT-qPCR indicated that exposure to 5, 10 and 50 mg/L of NaF significantly decreased the transcript levels of genes related to fatty acid synthesis (FASN, FAE, MECR, KAR and TECR) in liver. Besides, mRNA expression of genes involved in fatty acid β-oxidation (ECHS1, HADHA, SCP2, CPT2, ACAA1 and ACAA2) and oxidative stress (SOD, GPx, MICU1 and HSP90) was significantly downregulated in 0.5, 5, 10 and 50 mg/L of NaF treatment groups. Also, in the relative expression of genes associated with synthesis and secretion of bile acid, BSEP significantly increased at 0.5, 5 and 50 mg/L of NaF while HSD3B7 significantly reduced in 0.5, 5, 10 and 50 mg/L of NaF. Finally, the fatty acid extraction and GC-MS analysis showed that the content of saturated fatty acids (SFAs) was decreased and the content of polyunsaturated fatty acids (PUFAs) was increased in all fluoride treatment groups. Taken together, the present results indicated that fluoride-induced the histological alterations of liver might be linked to the disorder of lipid metabolism, oxidative damage.
显示更多 [+] 显示较少 [-]Effects of polyethylene microplastics on the microbiome and metabolism in larval zebrafish
2021
Zhao, Yao | Qin, Zhen | Huang, Zhuizui | Bao, Zhiwei | Luo, Ting | Jin, Yuanxiang
Various microplastics (MPs) are found in the environment and organisms. MP residues in organisms can affect health; however, their impacts on metabolism in aquatic organisms remain unclear. In this study, zebrafish embryos were exposed to polyethylene MPs with sizes ranging from 1 to 4 μm at concentrations of 0, 10, 100, and 1000 μg/L for 7 days. Through qPCR technology, the results indicated that zebrafish exposed to polyethylene MPs exhibited significant change in microbes of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia, etc. Moreover, 16S RNA gene sequencing revealed that there was a significant difference in alpha diversity between the control and 1000 μg/L MP-treated groups. At the genus level, the abundance of Aeromonas, Shewanella, Microbacterium, Nevskia and Methyloversatilis have increased remarkably. Conversely, the abundance of Pseudomonas, Ralstonia and Stenotrophomonas were significant reduction after MPs exposure. In addition, the levels of TG (triglyceride), TCHO (total cholesterol), NEFA (nonesterified fatty acid), TBA (total bile acid), GLU (glucose) and pyruvic acid significantly changed in MP-treated larval zebrafish, indicating that their metabolism was disturbed by MPs. Transcriptional levels of glucose and lipid metabolism-related genes showed a decreasing trend. Furthermore, LC/MS-based nontargeted metabolomics analysis demonstrated that a total of 59 phospholipid-related substances exhibited significant changes in larval fish treated with 1000 μg/L MPs. The mRNA levels of phospholipid metabolism-related genes were also obviously changed. Pearson correlation analysis indicated that the abundance of Aeromonas, Shewanella and Chitinibacter bacteria showed a negative correlation with most phospholipids, while Nevskia, Parvibacter and Lysobacter showed a positive correlation with most phospholipids. Based on these results, it is suggested that 1–4 μm PE-MPs could impact the microbiome and metabolism of larval zebrafish. All of these results indicated that the health risk of MPs cannot be ignored.
显示更多 [+] 显示较少 [-]Environmental level bisphenol A accelerates alterations of the reno-cardiac axis by the MAPK cascades in male diabetic rats: An analysis based on transcriptomic profiling and bioinformatics
2021
Wu, Bin | Zhao, Qiangqiang | Li, Zuoneng | Min, Zhiteng | Shi, Mengdie | Nie, Xinmin | He, Qingnan | Gu̇i, Ru̇ng
In humans and animal models, the kidneys and cardiovascular systems are negatively affected by BPA from the environment. It is considered that BPA have some potential estrogen-like and non-hormone-like properties. In this study, RNA-sequencing and its-related bioinformatics was used as the basic strategy to clarify the characteristic mechanisms of kidney–heart axis remodeling and dysfunction in diabetic male rats under BPA exposure. We found that continuous BPA exposure in diabetic rats aggravated renal impairment, and caused hemodynamic disorders and dysfunctions. There were 655 and 125 differentially expressed genes in the kidney and heart, respectively. For the kidneys, functional annotation and enrichment, and gene set enrichment analyses identified bile acid secretion related to lipid synthesis and transport, and MAPK cascade pathways. For the heart, these bioinformatics analyses clearly pointed to MAPKs pathways. A total of 12 genes and another total of 6 genes were identified from the kidney tissue and heart tissue, respectively. Western blotting showed that exposure to BPA activated MAPK cascades in both organs. In this study, the exacerbated remodeling of diabetic kidney–heart axis under BPA exposure and diabetes might occur through hemodynamics, metabolism disorders, and the immune-inflammatory response, as well as continuous estrogen-like stimulation, with focus on the MAPK cascades.
显示更多 [+] 显示较少 [-]Mobilization and bioaccessibility of cadmium in coastal sediment contaminated by microplastics
2019
Martin, Kye | Turner, Andrew
Cadmium has had a number of historical applications in plastics but is now highly regulated. In this study, plastics containing pigmented or recycled Cd at concentrations up to 16,300 μg g⁻¹ were processed into microplastic-sized fragments and added to clean estuarine sediment. Plastic-sediment mixtures (mass ratio = 1:100) were subsequently exposed to fluids simulating the digestive conditions encountered in marine deposit-feeding invertebrates prepared from a protein and a bile acid surfactant in seawater and the mobilization of Cd measured as a function of time. Kinetic profiles over a six-hour period were complex, with some fitted using a diffusion model and others exhibiting evidence of Cd interactions between the plastic and sediment surface. The maximum concentration of Cd released from plastic-sediment mixtures was about 0.8 μg g⁻¹ and orders of magnitude greater than Cd mobilization from sediment alone. It is predicted that large communities of deposit-feeders could mobilize significant quantities of Cd from historical microplastics.
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