Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

Ke, Zhang-Hong; Pan, Jiexue; Jin, Long-Fei; Xu, Haiyan; Yu, Tiantian; Ullah, Kalim; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xinyan; Sheng, Jian‐Zhong; Huang, He‐Feng

doi:10.1038/srep31331

Cited by 94 publications

(71 citation statements)

References 31 publications

(41 reference statements)

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“…It is noted that the liver is also important for systemic lipid metabolism and is the primary target organ of BPA. A recent study in mice has shown that BPA exposure significantly increased the expression levels of genes related to lipid synthesis such as HMG-CoA reducase, the key enzyme responsible for cholesterol synthesis in liver [27]. Take together, there results indicate that BPA can increase the cholesterol levels by two mechanisms, one in the intestine to enhance the absorption via NPC1L1 transporter, and the other in the liver to increase the synthesis by HMG-CoA reducase.…”

Section: Discussionmentioning

confidence: 99%

“…Ke et al has recently shown that the promoters of SREBP-2 and HMG-CoA reducase were hypomethylated in the BPA-exposed mice, which is very likely to contribute to the promoted transcription of SREBP-2 and its targets. Because DNA methyltransferase knockdown led to the promoter hypomethylation and increased mRNA expression of SREBP-2 and HMG-CoA reducase [27]. These results indicated that SREBP-2 was up-regulated by BPA via reprogramming the DNA methylation patterns.…”

Section: Discussionmentioning

confidence: 99%

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Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression

Feng

Zou²,

Zhang

et al. 2017

Lipids Health Dis

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BackgroundBisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear. Since intestinal cholesterol absorption plays a major role in maintaining total body cholesterol homeostasis, the present study is to investigate whether BPA affects cholesterol absorption in the intestinal Caco-2 cells. Methods: The Caco-2 cells were pretreated with BPA at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and sterol regulatory element binding protein-2 (SREBP-2) was analyzed by Western blot and qPCR.ResultsWe found that confluent Caco-2 cells expressed NPC1L1, and the absorption of cholesterol in the cells was inhibited by ezetimibe, a specific inhibitor of NPC1L1. We then pretreated the cells with 0.1–10 nM BPA for 24 h and found that BPA at 1 and 10 nM doses promoted cholesterol absorption. In addition, we found that the BPA-induced promotion of cholesterol absorption was associated with significant increase in the levels of NPC1L1 protein and NPC1L1 mRNA. Moreover, the stimulatory effects of BPA on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the SREBP-2 pathway.ConclusionsThis study provides the first evidence that BPA promotes cholesterol absorption in the intestinal cells and the stimulatory effect of BPA is mediated, at least in part, by SREBP-2-NPC1L1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression

Feng

Zou²,

Zhang

et al. 2017

Lipids Health Dis

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“…157 Bisphenol A, commonly found in plastic, stimulates hepatic fat accumulation by modulating DNA methylation patterns. 158 Avoidance of these chemicals might be useful in the treatment of WD.…”

Section: Modifiers Of Epigenetic Regulation: Diet Exercise Stresmentioning

confidence: 99%

“…Common toxins, including those that are found in pesticides and plastics, 158,182 stimulate hepatic fat accumulation and disrupt mitochondrial function. 157 Copper-induced mitochondrial damage and hepatic fat accumulation might be exacerbated in the presence of chemicals with known mitochondrial toxicities.…”

Section: Multifaceted Treatment Approachmentioning

confidence: 99%

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

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“…BPA exposure leads to excessive lipid accumulation in the liver, decreases the levels of autophagy, and induces nonalcoholic fatty liver disease and their associated complications [114][115][116][117]. Long-term BPA exposure (0.5 µg BPA/kg/day, 10 months) on male mice induces hepatic lipid accumulation, which may be due to the epigenetic reprogramming of genes involved in lipid metabolism, such as alterations of DNA methylation patterns [119]. BPA (15 µg/L for 3 and 6 weeks) exposure to Gobiocypris rarus fish disturbed the expressions of acetyl-CoA carboxylase, fatty acid synthase, and carnitine palmitoyltransferase 1α, by altering the sterol regulatory element-binding protein 1 binding to their sterol regulatory elements, subsequently affecting triglyceride synthesis.…”

Section: Hepatotoxicitymentioning

confidence: 99%

Bisphenols as a Legacy Pollutant, and Their Effects on Organ Vulnerability

Kim

Kumar

et al. 2019

IJERPH

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Bisphenols are widely used in the synthesis of polycarbonate plastics, epoxy resins, and thermal paper, which are used in manufacturing items of daily use. Packaged foods and drinks are the main sources of exposure to bisphenols. These chemicals affect humans and animals by disrupting the estrogen, androgen, progesterone, thyroid, and aryl hydrocarbon receptor functions. Bisphenols exert numerous harmful effects because of their interaction with receptors, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial dysfunction, and cell signal alterations. Both cohort and case-control studies have determined an association between bisphenol exposure and increased risk of cardiovascular diseases, neurological disorders, reproductive abnormalities, obesity, and diabetes. Prenatal exposure to bisphenols results in developmental disorders in animals. These chemicals also affect the immune cells and play a significant role in initiating the inflammatory response. Exposure to bisphenols exhibit age, gender, and dose-dependent effects. Even at low concentrations, bisphenols exert toxicity, and hence deserve a critical assessment of their uses. Since bisphenols have a global influence on human health, the need to discover the underlying pathways involved in all disease conditions is essential. Furthermore, it is important to promote the use of alternatives for bisphenols, thereby restricting their uses.

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Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

Cited by 94 publications

References 31 publications

Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression

Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Bisphenols as a Legacy Pollutant, and Their Effects on Organ Vulnerability

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