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

Abstract

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.

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

“…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.…”

“…[98][99][100] An increase in the methylation at the PDX-1 site reduces the expression of PDX-1 protein in the islets which has been confirmed in the model of T2DM rats. 101 Previous studies have shown that an adverse intrauterine environment leads to reduced pancreatic PDX-1 expression and hence impaired insulin secretion and diabetes in adult rats. 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.…”

Evaluation of the Cytotoxic Effect of Bisphenol A and Its Analogs in MCF-7 and HSeC Cell Lines in vitro

“…Several studies have demonstrated that bisphenols are related to several pathological conditions such as endocrine disorders, type II diabetes, reproductive system disorders, cancer (Rahmani, 2020. Accordingly, it was claimed that BPA reduces daily sperm production and causes infertility (Geens, 2012, Gerona, 2013, Aris, 2014).…”

Environmental Epigenetics and Obesity

“…Moreover, Mcllwraith et al recently demonstrated that miR-708-5p mediates the effects of BPA in hypothalamic cells through the reduction of neuronatin levels and the increase in orexigenic Neuropeptide (Npy) [78]. Contrarily, Rahmani et al showed revealed that the expression of miR-375, miR-676, miR-126-a, and miR-340-5p was significantly disrupted by BPA, resulting in aberrant β-cell metabolism and diabetes [79]. More interestingly, the interplay between environment and gene expression seems to be a coordinated action of different ncRNA biotypes, at least lncRNAs and miRNAs.…”