Effects of co-exposure to 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin and polychlorinated biphenyls on nonalcoholic fatty liver disease in mice

Shan, Qiuli; Huang, F.; Wang, Jing; Du, Yuguo

doi:10.1002/tox.22006

Cited by 22 publications

(14 citation statements)

References 35 publications

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“…Immune responses play an important role in MLD-STZ-induced diabetes (Gao et al, 2013; Barbu-Tudoran et al, 2013; Yaochite et al, 2013), and in TCDD-mediated toxicity (Mandal, 2005; Shan et al, 2014). Thus, flow cytometric analysis of splenocyte differentials was undertaken.…”

Section: Resultsmentioning

confidence: 99%

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TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

Lefever

Chen

et al. 2016

Toxicology and Applied Pharmacology

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An increasing body of evidence has shown the important role of the gut microbiome in mediating toxicity following environmental contaminant exposure. The goal of this study was to determine if the adverse metabolic effects of chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure would be sufficient to exacerbate hyperglycemia, and to further determine if these outcomes were attributable to the gut microbiota alteration. Adult male CD-1 mice were exposed to TCDD (6 μg/kg body weight biweekly) by gavage and injected (i.p.) with STZ (4 × 50 mg/kg body weight) to induced hyperglycemia. 16S rRNA sequencing was used to characterize the changes in the microbiome community composition. Glucose monitoring, flow cytometry, histopathology, and organ characterization were performed to determine the deleterious phenotypic changes of TCDD exposure. Chronic TCDD treatment did not appear to exacerbate STZ-induced hyperglycemia as blood glucose levels were slightly reduced in the TCDD treated mice; however, polydipsia and polyphagia were observed. Importantly, TCDD exposure caused a dramatic change in microbiota structure, as characterized at the phylum level by increasing Firmicutes and decreasing Bacteroidetes while at the family level most notably by increasing Lactobacillaceae and Desulfovibrionaceae, and decreasing Prevotellaceae and ACK M1. The changes in microbiota were further found to be broadly associated with phenotypic changes seen from chronic TCDD treatment. In particular, the phylum level Bacteroidetes to Firmicutes ratio negatively correlated with both liver weight and liver pathology, and positively associated with %CD3+NK+ T cells, a key mediator of host-microbial interactions. Collectively, these findings suggest that the dysregulated gut microbiome may contribute to the deleterious effects (e.g., liver toxicity) seen with TCDD exposure.

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Section: Resultsmentioning

confidence: 99%

“…Despite the appearing anti-diabetic effects, TCDD has been shown to promote a host of adverse metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), a wasting-like syndrome, and cancer in lab animals. These effects are possibly mediated through the immunotoxicity (Mandal, 2005; Shan et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

Lefever

Chen

et al. 2016

Toxicology and Applied Pharmacology

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“…More than two thirds of the American population is at risk for developing obesity‐associated NAFLD, which is the hepatic arm of metabolic syndrome. Several studies have identified potential interactions between environmental chemicals and experimental NAFLD . Although the mechanisms are incompletely understood, it is likely that these environmental chemicals enhance pathologic responses (e.g., inflammation) and/or sensitize the hepatocytes to injury.…”

Section: Discussionmentioning

confidence: 99%

Vinyl chloride dysregulates metabolic homeostasis and enhances diet‐induced liver injury in mice

Lang

Chen

Poff

et al. 2018

Hepatology Communications

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Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant‐associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (<1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC‐induced liver injury. VC exposure caused no overt liver injury in mice fed a low‐fat diet. However, in mice fed a high‐fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD‐induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low‐fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. Conclusion: The hypothesis that low‐level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co‐exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (Hepatology Communications 2018;2:270‐284)

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“…For example, pre-treatment of rats with TCDD led to the appearance of NAFLD, whilst DEHP reduced the TCDD-induced phenotype 104 . Similarly, the combination of TCDD and Aroclor 1254 seemed to enhance NAFLD in mice, compared with treatment with either EDC alone 105 . Although this approach has been applied in only a few experimental settings, the data are extremely relevant to humans, where exposure to more than one EDC during development and over the course of a lifetime may occur.…”

Section: Liver Fat Metabolism and Edcsmentioning

confidence: 92%

Endocrine-disrupting chemicals and fatty liver disease

et al. 2017

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Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic paralleling the increase in obesity and diabetes mellitus seen in Western diet-consuming countries. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma (HCC), an understanding of factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with fatty liver. Experimental studies have revealed several potential mechanisms by which EDC exposures might contribute to disease pathogenesis, including modulation of nuclear hormone receptor (NR) function and alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease, but for elucidating the molecular mechanisms underpinning NAFLD and the development of new prevention and treatment opportunities.

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Effects of co-exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyls on nonalcoholic fatty liver disease in mice

Cited by 22 publications

References 35 publications

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

TCDD modulation of gut microbiome correlated with liver and immune toxicity in streptozotocin (STZ)-induced hyperglycemic mice

Vinyl chloride dysregulates metabolic homeostasis and enhances diet‐induced liver injury in mice

Endocrine-disrupting chemicals and fatty liver disease

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