Gene-Environmental Interplay in Bisphenol A Subchronic Animal Exposure: New Insights into the Epigenetic Regulation of Pancreatic Islets.,Chemical Research in Toxicology

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Gene-Environmental Interplay in Bisphenol A Subchronic Animal Exposure: New Insights into the Epigenetic Regulation of Pancreatic Islets.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-07-23 , DOI: 10.1021/acs.chemrestox.0c00109
Soheila Rahmani ₁ , Faezeh Vakhshiteh ₂ , Mahshid Hodjat ₃ , Parisa Sahranavardfard ₄ , Shokoufeh Hassani ₁ , Elmira Ghafour Broujerdi ₁ , Mahban Rahimifard ₁ , Mahdi Gholami ₁ , Maryam Baeeri ₁ , Mohammad Abdollahi ₁

Affiliation

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.

中文翻译：

双酚 A 亚慢性动物暴露中的基因环境相互作用：对胰岛表观遗传调控的新见解。

内分泌干扰化学物质 (EDC)，例如广泛用于塑料行业的双酚 A (BPA)，最近被认为与代谢紊乱（包括肥胖和糖尿病）的发病机制有关。本研究旨在检查双酚 A 在表观遗传水平上对葡萄糖和能量代谢的潜在不利影响。评估了在 28 天内接受不同口服剂量的 BPA 的 Wistar 大鼠的血糖曲线。处理结束时，分离纯化朗格汉斯胰岛，提取其RNA含量。使用下一代测序 (NGS) 方法评估 MicroRNA (miRNA) 分析。在对 NGS 数据进行生物信息学分析后，通过不同的数据库（包括 Enrichr 和 DIANA 工具）对显着受扰的 miRNA 方面的基因本体和数据富集进行了评估。此外，还评估了 DNA 甲基化和葡萄糖代谢中两个关键基因（PPARγ、Pdx1）的表达水平。亚慢性 BPA 暴露（406 毫克/公斤/天）扰乱了 Wistar 大鼠的血糖曲线（空腹血糖和口服葡萄糖耐量），并导致相当大的细胞毒性。NGS 数据分析显示，一些参与 β 细胞代谢和糖尿病发生发展的关键 miRNA，包括 miR-375、miR-676、miR-126-a 和 miR-340-5p 的表达受到显着干扰。根据 DNA 甲基化评估，PPARγ 和 Pdx1 基因在基因启动子上的特定位点的甲基化水平都发生了变化。这些基因的表达水平分别上调和下调。总体而言，亚慢性 BPA 暴露可能导致基因水平的表观遗传失调，并干扰关键 miRNA 的表达和参与葡萄糖稳态的基因的甲基化过程。了解 BPA 和其他 EDC 诱发内分泌紊乱的确切潜在机制对于寻找新的预防和治疗方法具有重要意义。亚慢性 BPA 暴露可能导致基因水平的表观遗传失调，并干扰关键 miRNA 的表达和参与葡萄糖稳态的基因的甲基化过程。了解 BPA 和其他 EDC 诱发内分泌紊乱的确切潜在机制对于寻找新的预防和治疗方法具有重要意义。亚慢性 BPA 暴露可能导致基因水平的表观遗传失调，并干扰关键 miRNA 的表达和参与葡萄糖稳态的基因的甲基化过程。了解 BPA 和其他 EDC 诱发内分泌紊乱的确切潜在机制对于寻找新的预防和治疗方法具有重要意义。

更新日期：2020-09-21

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