Assessment of arsenic-induced modifications in the DNA methylation of insulin-related genes in rat pancreatic islets

Khan, Fazlullah; Hodjat, Mahshid; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Azizi, Masoumeh; Baeeri, Maryam; Bayrami, Zahra; Gholami, Mahdi; Hassani, Shokoufeh; Abdollahi, Mohammad

doi:10.1016/j.ecoenv.2020.110802

Cited by 21 publications

(11 citation statements)

References 59 publications

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“…62 An explanation for this phenotype is that epigenetic modifications of PDX-1, including both increased DNA methylation and histone modifications, are associated with reduced gene transcription in rat islets. 62,[101][102][103] Collectively, all these studies evidently support a crucial role of epigenetic modification of PDX-1 in the occurrence and development of T2DM.…”

Section: Changes In Pdx-1 Methylation Status Are Related To Diabetesmentioning

confidence: 56%

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Liu¹,

Lang²,

Shi³

2021

DMSO

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Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM. In recent years, a growing body of molecular and genetic studies in diabetes have been focused on the ways to restore the numbers or function of β-cells in order to reverse a range of metabolic consequences of insulin deficiency. The pancreatic duodenal homeobox 1 (PDX-1) is a transcriptional factor that is essential for the development and function of islet cells. A number of studies have shown that there is a significant increase in the level of DNA methylation of PDX-1 resulting in reduced activity in T2DM islets. The decrease in PDX-1 activity may be a critical mediator causing dysregulation of pancreatic β cells in T2DM. This article reviews the epigenetic mechanisms of PDX-1 involved in T2DM, focusing on diabetes and DNA methylation, and discusses some potential strategies for the application of PDX-1 in the treatment of diabetes.

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Section: Changes In Pdx-1 Methylation Status Are Related To Diabetesmentioning

confidence: 56%

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Liu¹,

Lang²,

Shi³

2021

DMSO

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“…Environmental contaminants are considered to play major roles in the etiology and progression of NAFLD. Endocrine-disrupting compounds were first described as inducing reproductive disorders but can be involved in the etiology of diabetes and other metabolic disorders independently of their hormone signaling effects [116][117][118][119][120][121][122]. In addition to contaminants such as polychlorinated biphenyls (PCBs), other compounds such as dioxins [123], bisphenol A [122], and pesticides are suspected to contribute to the increased prevalence of NAFLD.…”

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confidence: 99%

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.

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“…This is the first report on the BPA-induced epigenetic disturbance of glucose metabolism disorders. Due to the fact that epigenetic changes can occur in both short-term and long-term exposures, , we decided to conduct a subchronic experiment. Since there have been little data on the adverse effects of BPA on rats, we first determined the appropriate dose for rats to mimic the pattern of BPA human toxicity.…”

Section: Discussionmentioning

confidence: 99%

Gene–Environmental Interplay in Bisphenol A Subchronic Animal Exposure: New Insights into the Epigenetic Regulation of Pancreatic Islets

Rahmani

Vakhshiteh

Hodjat

et al. 2020

Chem. Res. Toxicol.

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Endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA), which is widely used in the plastic industry, have recently been considered to be involved in the pathogenesis of metabolic disorders, including obesity and diabetes. The present study aimed to examine the potentially detrimental effects of BPA on glucose and energy metabolism at the epigenetic level. The blood glucose profile of Wistar rats receiving different oral doses of BPA over 28 days was assessed. At the end of the treatment, the islets of Langerhans were isolated and purified, and their RNA content was extracted. MicroRNA (miRNA) profiling was evaluated using the next generation sequencing (NGS) method. After performing bioinformatic analysis of the NGS data, the gene ontology and data enrichment in terms of significantly disturbed miRNAs were evaluated through different databases, including Enrichr and DIANA tools. Additionally, the DNA methylation and the level of expression of two critical genes in glucose metabolism (PPARγ, Pdx1) were assessed. Subchronic BPA exposure (406 mg/kg/day) disturbed the blood glucose profile (fasting blood glucose and oral glucose tolerance) of Wistar rats and resulted in considerable cytotoxicity. NGS data analyses revealed that the expression of some crucial miRNAs involved in β-cell metabolism and diabetes occurrence and development, including miR-375, miR-676, miR-126-a, and miR-340-5p, was significantly disrupted. According to the DNA methylation evaluation, both PPARγ and Pdx1 genes underwent changes in the methylation level at particular loci on the gene's promoter. The expression levels of these genes were upregulated and downregulated, respectively. Overall, subchronic BPA exposure could cause epigenetic dysregulation at the gene level and interfere with the expression of key miRNAs and the methylation process of genes involved in glucose homeostasis. Understanding the exact underlying mechanisms by which BPA and other EDCs induce endocrine disturbance could be of great importance in the way of finding new preventive and therapeutic approaches.

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Assessment of arsenic-induced modifications in the DNA methylation of insulin-related genes in rat pancreatic islets

Cited by 21 publications

References 59 publications

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

Gene–Environmental Interplay in Bisphenol A Subchronic Animal Exposure: New Insights into the Epigenetic Regulation of Pancreatic Islets

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