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Analysis of environmental chemical mixtures and nonalcoholic fatty liver disease: NHANES 1999–2014
2022
Li, Wei | Xiao, Haitao | Wu, Hong | Pan, Cheng | Deng, Ke | Xu, Xuewen | Zhang, Yange
We aimed to investigate the associations between chemical mixtures and the risk of nonalcoholic fatty liver disease (NAFLD) in this study. A total of 127 exposure analytes within 13 chemical mixture groups were included in the current analysis. Associations between chemical mixture exposure and prevalence of NAFLD were examined using weighted quantile sum (WQS) regressions. NAFLD was diagnosed by hepatic steatosis index (HSI) and US fatty liver index (USFLI). In USFLI-NAFLD cohort, chemical mixtures positively associated with NAFLD development included urinary metals (OR: 1.10, 95% CI: 1.04–1.16), urinary perchlorate, nitrate and thiocyanate (OR: 1.06, 95% CI: 1.02–1.11), urinary pesticides (OR: 1.24, 95% CI: 1.09–1.40), urinary phthalates (OR: 1.18, 95% CI: 1.09–1.28), urinary polyaromatic hydrocarbons (PAHs) (OR: 1.08, 95% CI: 1.03–1.14), and urinary pyrethroids, herbicides, and organophosphate pesticides metabolites (OR: 1.32, 95% CI: 1.15–1.51). All of the above mixtures were also statistically significant in WQS regressions in the HSI-NAFLD cohort. Besides, some chemical mixtures were only significant in HSI-NAFLD cohort including urinary arsenics (OR: 1.07, 95% CI: 1.02–1.12), urinary phenols (OR: 1.10, 95% CI: 1.02–1.19) and blood polychlorinated dibenzo-p-dioxins (OR: 1.10, 95% CI: 1.03–1.17). Three types of chemical mixtures only showed significant associations in the healthy lifestyle score (HLS) of 3–4 subgroup, including urinary perchlorate, nitrate and thiocyanate, urinary PAHs and blood polychlorinated dibenzo-p-dioxins. In conclusion, the exposure of specific types of chemical mixtures were associated with elevated NAFLD risk, and the effects of some chemical mixtures on NAFLD development exhibited differences in participants with different lifestyles.
Mostrar más [+] Menos [-]4-Hexylphenol influences adipogenic differentiation and hepatic lipid accumulation in vitro
2021
Sun, Zhendong | Cao, Huiming | Liu, Qian S. | Liang, Yong | Fiedler, H. (Heidelore) | Zhang, Jianqing | Zhou, Qunfang | Jiang, Guibin
Finding the potential environmental obesogens is crucial to explain the prevalence of obesity and the related pathologies. Increasing evidence has showed that many chemicals with endocrine disrupting effects can disturb lipid metabolism. Whether 4-hexylphenol (4-HP), a widely-used surfactant and a potential endocrine disrupting chemical (EDC), is associated to influence adipogenesis and hepatic lipid accumulation remained to be elucidated. In this study, both the 3T3-L1 differentiation model and oleic acid (OA)-treated HepG2 cells were used to investigate the effects of 4-HP on lipid metabolism, and the underlying estrogen receptor (ER)-involved mechanism was explored using MVLN assay, molecular docking simulation and the antagonist test. The results based on lipid droplet staining and triglyceride accumulation assay showed that 4-HP treatment promoted the adipogenic differentiation of 3T3-L1 cells and increased hepatic cellular OA accumulation in exposure concentration-dependent manners. The study on the elaborated transcription networks indicated that 4-HP activated peroxisome proliferator-activated receptor γ (PPARγ) as well as the subsequent adipogenic gene program in 3T3-L1 cells. This chemical also induced the increase of OA uptake and decreases of de novo lipogenesis and fatty acid oxidation in HepG2 cells. The agonistic activity of 4-HP in triggering ER-mediated pathway was shown to correlate with its perturbation in lipid metabolism, as evidenced by the enhanced development of mature lipid-laden adipocytes and suppression of excessive hepatic lipid accumulation upon its co-treatment with ER antagonist. Altogether, these findings provide new insights into the potential health impacts of 4-HP exposure as it may relate to obesity and nonalcoholic fatty liver disease.
Mostrar más [+] Menos [-]Exposure to 2,3,3′,4,4′,5-hexachlorobiphenyl promotes nonalcoholic fatty liver disease development in C57BL/6 mice
2020
Shan, Qiuli | Chen, Ningning | Liu, Wei | Qu, Fan | Chen, Anhui
Previous in vitro studies have indicated that 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB 156) may be a new contributor to metabolic disruption and may further cause the occurrence of nonalcoholic fatty liver disease (NAFLD). However, no study has clarified the specific contributions of PCB 156 to NAFLD progression by constructing an in vivo model. Herein, we evaluated the effects of PCB 156 treatment (55 mg/kg, i.p.) on the livers of C57BL/6 mice fed a control diet (CD) or a high-fat diet (HFD). The results showed that PCB 156 administration increased intra-abdominal fat mass, hepatic lipid levels and dyslipidemia in the CD-fed group and aggravated NAFLD in HFD-fed group. By using transcriptomics studies and biological methods, we found that the genes expression involved in lipid metabolism pathways, such as lipogenesis, lipid accumulation and lipid β-oxidation, was greatly altered in liver tissues exposed to PCB 156. In addition, the cytochrome P450 pathway, peroxisome proliferator-activated receptors (PPARs) and the glutathione metabolism pathway were significantly activated following exposure to PCB 156. Furthermore, PCB 156 exposure increased serum transaminase levels and lipid peroxidation, and the redox-related genes were significantly dysregulated in liver tissue. In conclusion, our data suggested that PCB 156 could promote NAFLD development by altering the expression of genes related to lipid metabolism and inducing oxidative stress.
Mostrar más [+] Menos [-]Long-term bisphenol S exposure aggravates non-alcoholic fatty liver by regulating lipid metabolism and inducing endoplasmic reticulum stress response with activation of unfolded protein response in male zebrafish
2020
Qin, Jingyu | Ru, Shaoguo | Wang, Weiwei | Hao, Liping | Ru, Yiran | Wang, Jun | Zhang, Xiaona
Environmental chemical exposures have been implicated as risk factors for the development of non-alcoholic fatty liver (NAFLD). Bisphenol S (BPS), widely used in multitudinous consumer products, could disrupt lipid metabolism in the liver. This study aimed at examining the hypothesis that long-term exposure to BPS promotes the development of liver fibrosis and inflammation by means of the application of a semi-static exposure experiment that exposed zebrafish to 1, 10, and 100 μg/L BPS from 3 h post fertilization to 120 day post fertilization. Results showed that the 120-d BPS exposure elevated plasma aspartate aminotransferase and alanine aminotransferase activities, increased triacylglycerol (TAG) and total cholesterol levels in male liver, and even induced hepatic apoptosis and fibrosis. Hepatic lipid accumulation observed in the 30-d BPS-exposed zebrafish was recovered after a 90-d depuration phase, thereby indicating that long-term BPS exposure promotes the progression of simple steatosis to non-alcoholic steatohepatitis. Furthermore, BPS exposure for 120-d promoted the synthesis of TAG and lipotoxic free fatty acids by elevating the transcription of srebp1, acc, fasn, and elovl6, induced endoplasmic reticulum (ER) stress with increasing expression levels of unfolded protein response (UPR) genes (perk, hsp5, atf4a, and ddit3), and then stimulated the expression of two key autophagy genes (atg3 and lc3) and inflammatory genes (il1b and tnfα). It is indicated that BPS can induce the development of steatohepatitis via the activation of the PERK-ATF4a pathway of the UPR. Data gathered suggest that environmental pollutants-induced ER stress with the activation of UPR can potentially trigger the NAFLD development in males. Overall, our study provided new sights into understanding of the adverse health effects of metabolism disrupting chemicals.
Mostrar más [+] Menos [-]Redox and global interconnected proteome changes in mice exposed to complex environmental hazards surrounding Doñana National Park
2019
Michán, Carmen | Chicano-Gálvez, Eduardo | Fuentes-Almagro, Carlos A. | Alhama, José
Natural environments are receiving an increasing number of contaminants. Therefore, the evaluation and identification of early responses to pollution in these complex habitats is an urgent and challenging task. Doñana National Park (DNP, SW Spain) has been widely used as a model area for environmental studies because, despite its strictly protected core, it is surrounded by numerous threat sources from agricultural, mining and industrial activities. Since many pollutants often induce oxidative stress, redox proteomics was used to detect redox-based variations within the proteome of Mus spretus mice captured in DNP and the surrounding areas. Functional analysis showed that most differentially oxidized proteins are involved in the maintenance of homeostasis, by eliciting mechanisms to respond to toxic substances and oxidative stress, such as antioxidant and biotransformation processes, immune and inflammatory responses, and blood coagulation. Furthermore, changes in the overall protein abundance were also analysed by label-free quantitative proteomics. The upregulation of phase I and II biotransformation enzymes in mice from Lucio del Palacio may be an alert for organic pollution in the area located at the heart of DNP. Metabolic processes involved in protein turnover (proteolysis, amino acid catabolism, new protein biosynthesis and folding) were activated in response to oxidative damage to these biomolecules. Consequently, aerobic respiratory metabolism increased to address the greater ATP demands. Alterations of cholesterol metabolism that could cause hepatic steatosis were also detected. The proteomic detection of globally altered metabolic and physiological processes offers a complete view of the main biological changes caused by environmental pollution in complex habitats.
Mostrar más [+] Menos [-]Effects of chronic glyphosate exposure to pregnant mice on hepatic lipid metabolism in offspring
2019
Ren, Xin | Dai, Pengyuan | Perveen, Aneela | Tang, Qian | Zhao, Liangyu | Qingyangwanxi, | Li, Yansen | Li, Chunmei
Glyphosate is the active ingredient in Roundup, one of the most popular herbicides in the world, and its toxicity has caused increasing concerns. The present study aims to investigate the toxic effects of prenatal exposure to pure glyphosate or Roundup on lipid metabolism in offspring. During gestational days (GDs), ICR mice (from Institute of Cancer Research) were given distilled water, 0.5% glyphosate solution (w/v, 0.5 g/100 ml) or 0.5%-glyphosate Roundup solution orally. The livers and serum samples of the offspring were collected on gestational day 19 (GD19), postnatal day 7 (PND7) and PND21. The results showed a significant decrease in the body weight and obvious hepatic steatosis with excessive lipid droplet formation in offspring. Moreover, the concentrations of lipids such as triglycerides (TGs), total cholesterol (T-CHO), and low-density lipoprotein cholesterols (LDL-C) increased to a significant extent in both the serum and livers. Furthermore, there were significant differences in the expression levels of the genes SREBP1C, SREBP2, Fasn, Hmgcr, Hmgcs and PPARα, which are related to lipid biosynthesis or catabolism in the liver. These results demonstrate that chronic prenatal exposure to glyphosate can result in lipid metabolism disruption in the offspring of mice, as glyphosate exerts a negative influence on the expression of lipogenesis genes.
Mostrar más [+] Menos [-]An amphibian high fat diet model confirms that endocrine disruptors can induce a metabolic syndrome in wild green frogs (Pelophylax spp. complex)
2022
Veyrenc, Sylvie | Regnault, Christophe | Sroda, Sophie | Raveton, Muriel | Reynaud, Stéphane
A pre-diabetes syndrome induced by endocrine disruptors (ED) was recently demonstrated in the model amphibian Silurana (Xenopus) tropicalis and was suggested to be a potential cause of amphibian population decline. However, such effects have not been found in wild type frogs exposed to ED and the capacity of amphibians to physiologically develop diabetes under natural conditions has not been confirmed. This study showed that a high fat diet (HFD) model displaying the important characteristics of mammal HFD models including glucose intolerance, insulin resistance and nonalcoholic fatty liver disease (NAFLD) can be developed with green frogs (Pelophylax spp.). Wild green frogs exposed to 10 μg L⁻¹ benzo [a]pyrene (BaP) for 18 h also displayed several characteristics of the pre-diabetes phenotype previously observed in Xenopus including glucose intolerance, gluconeogenesis activation and insulin resistance. The study results confirmed that metabolic disorders induced by ED in wild green frogs are typical of the pre-diabetes phenotype and could serve as a starting point for field studies to determine the role of ED in the decline of amphibian populations. From an environmental perspective, the response of wild green frogs to different ED (10 μg L⁻¹) suggests that a simple glucose-tolerance test could be used on wild anurans to identify bodies of water polluted with metabolic disruptors that could affect species fitness.
Mostrar más [+] Menos [-]Targeted metabolomics reveals that 2,3,7,8-tetrachlorodibenzofuran exposure induces hepatic steatosis in male mice
2020
Yuan, Peihong | Dong, Manyuan | Lei, Hehua | Xu, Guangyong | Chen, Gui | Song, Yuchen | Ma, Jianfeng | Cheng, Liming | Zhang, Limin
Environmental exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF), one of typical persistent organic pollutants (POPs) produced from municipal waste combustion, exerts toxic effects on human healthy. In the current study, we mainly used targeted metabolomics combined with untargeted ¹H NMR-based metabolomics to investigate the effects of TCDF exposure on lipid homeostasis in mice. We found that TCDF exposure induced hepatic lipogenesis, the early-stage of non-alcoholic fatty liver disease, manifested by excessive lipids including triglycerides, fatty acids and lipotoxic ceramides accumulated in the liver together with elevated serum very low-density lipoprotein by activating the aryl hydrocarbon receptor (AHR) and its target genes such as Cyp1a1 and Cd36. We also found that TCDF exposure induced alteration of phospholipids and choline metabolites and endoplasmic reticulum (ER) markers in the liver of mice, indicating that disruption of host cell membrane structural integrity and ER stress leading to hepatic steatosis. In addition, complementary information was also obtained from histopathologic assessments and biological assays, strongly supporting toxic effects of TCDF. These results provide new evidence of TCDF toxicity associated with fatty liver disease and further our understanding of health effects of environmental pollutants exposure.
Mostrar más [+] Menos [-]Autophagy mediates perfluorooctanoic acid-induced lipid metabolism disorder and NLRP3 inflammasome activation in hepatocytes
2020
Weng, Zhenkun | Xu, Cheng | Zhang, Xin | Pang, Lu | Xu, Jin | Liu, Qian | Zhang, Liye | Xu, Shuqin | Gu, Aihua
Perfluorooctanoic acid (PFOA) has applications in numerous industrial products and is an industrial waste that is persistently present in the environment. Exposure to PFOA results in nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. In this study, male C57BL/6 mice were exposed to PFOA (1 mg/kg/day) for 4 weeks to evaluate the effect of PFOA, and the human liver cell line (L-02) was used to observe the direct effect of PFOA in vitro. After PFOA exposure, the expression of genes related to hepatic lipogenesis, the NLRP3 inflammasome, and autophagy were measured. We found that exposure to PFOA induced lipid accumulation and stimulated lipogenesis in both mouse livers and L-02 cells. In addition, increased NLRP3 aggregation and enhanced production of IL-1β occurred after PFOA treatment. We also found that PFOA exposure induced autophagosome formation and p62 accumulation, indicating blockage of autophagic flux. Rapamycin alleviated PFOA-induced lipid accumulation and NLRP3 inflammasome activation by activating autophagic flux. Conversely, chloroquine, an autophagic flux inhibitor, exacerbated PFOA-induced lipid accumulation and NLRP3 inflammasome activation. Collectively, these results provide evidence to show that PFOA-induced blockade of autophagic flux causes an increase in lipid synthesis and inflammation in vivo and in vitro.
Mostrar más [+] Menos [-]Fatty liver and impaired hepatic metabolism alter the congener-specific distribution of polychlorinated biphenyls (PCBs) in mice with a liver-specific deletion of cytochrome P450 reductase
2020
Li, Xueshu | Zhang, Chunyun | Wang, Kai | Lehmler, Hans-Joachim
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are linked to adverse health outcomes. PCB tissue levels are determinants of PCB toxicity; however, it is unclear how factors, such as an altered metabolism and/or a fatty liver, affect PCB distribution in vivo. We determined the congener-specific disposition of PCBs in mice with a liver-specific deletion of cytochrome P450 reductase (KO), a model of fatty liver with impaired hepatic metabolism, and wild-type (WT) mice. Eight-week-old male WT (MWT, n = 3), male KO (MKO, n = 5), female WT (FWT, n = 4), and female KO mice (FKO, n = 4) were exposed orally to Aroclor 1254. PCBs were quantified in adipose, blood, brain, and liver tissues by gas chromatography-mass spectrometry. The ΣPCB levels followed the rank order adipose > liver ∼ brain > blood in WT and adipose ∼ liver > brain > blood in KO mice. PCB levels were much higher in the liver of KO than WT mice, irrespective of the sex. A comparison across exposure groups revealed minor genotype and sex-dependent differences in the PCB congener profiles (cos Θ > 0.92). Within each exposure group, tissue profiles showed small differences between tissues (cos Θ = 0.85 to 0.98). These differences were due to a decrease in metabolically more labile PCB congeners and an increase in congeners resistant to metabolism. The tissue-to-blood ratio of PCBs decreased for adipose, increased for the brain, and remained constant for the liver with an increase in chlorination. While these ratios did not follow the trends predicted using a composition-based model, the agreement between experimental and calculated partition coefficients was reasonable. Although the distribution of PCBs differs between KO and WT mice, the magnitude of the partitioning of PCBs from the blood into tissues can be approximated using composition-based models.
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