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Archives of Toxicology

, Volume 93, Issue 11, pp 3099–3109 | Cite as

Arsenic is more potent than cadmium or manganese in disrupting the INS-1 beta cell microRNA landscape

  • Rowan Beck
  • Mohit Chandi
  • Matt Kanke
  • Miroslav Stýblo
  • Praveen SethupathyEmail author
Inorganic Compounds

Abstract

Diabetes is a metabolic disorder characterized by fasting hyperglycemia and impaired glucose tolerance. Laboratory and population studies have shown that inorganic arsenic (iAs) can impair these pathways. Other metals including cadmium (Cd) and manganese (Mn) have also been linked to diabetes phenotypes. MicroRNAs, short non-coding RNAs that regulate gene expression, have emerged as potential drivers of metabolic dysfunction. MicroRNAs responsive to metal exposures in vitro have also been reported in independent studies to regulate insulin secretion in vivo. We hypothesize that microRNA dysregulation may associate with and possibly contribute to insulin secretion impairment upon exposure to iAs, Cd, or Mn. We exposed insulin secreting rat insulinoma cells to non-cytotoxic concentrations of iAs (1 µM), Cd (5 µM), and Mn (25 µM) for 24 h followed by small RNA sequencing to identify dysregulated microRNAs. RNA sequencing was then performed to further investigate changes in gene expression caused by iAs exposure. While all three metals significantly inhibited glucose-stimulated insulin secretion, high-throughput sequencing revealed distinct microRNA profiles specific to each exposure. One of the most significantly upregulated microRNAs post-iAs treatment is miR-146a (~ + 2-fold), which is known to be activated by nuclear factor κB (NF-κB) signaling. Accordingly, we found by RNA-seq analysis that genes upregulated by iAs exposure are enriched in the NF-κB signaling pathway and genes down-regulated by iAs exposure are enriched in miR-146a binding sites and are involved in regulating beta cell function. Notably, iAs exposure caused a significant decrease in the expression of Camk2a, a calcium-dependent protein kinase that regulates insulin secretion, has been implicated in type 2 diabetes, and is a likely target of miR-146a. Further studies are needed to elucidate potential interactions among NF-kB, miR-146a, and Camk2a in the context of iAs exposure.

Keywords

miRNA Arsenic Diabetes RNA Cadmium Manganese 

Notes

Funding

This work was funded by NIH (Grant Number R01DK105965), NIEHS (Grant Number R01ES022697), UNC Superfund by NIEHS (Grant Number 3P42ES005948-22S2), and NIGMS (Grant Number 5T32 GM007092).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2019_2574_MOESM1_ESM.docx (131 kb)
Supplementary material 1 (DOCX 131 kb)

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Genetics, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Department of Biomedical Sciences, College of Veterinary MedicineCornell UniversityIthacaUSA
  3. 3.Department of Nutrition, Gillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillUSA

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