Bisphenol A and octylphenol exacerbate type 1 diabetes mellitus by disrupting calcium homeostasis in mouse pancreas

Toxicol Lett. 2018 Oct 1;295:162-172. doi: 10.1016/j.toxlet.2018.06.1071. Epub 2018 Jun 20.

Abstract

In pancreatic β cells, which produce and secrete insulin, Ca2+ signals contribute to insulin production and secretion. Bisphenol A (BPA) and octylphenol (OP) are reported to increase plasma insulin levels and insulin transcription factors, but regulation of plasma glucose levels did not decrease proportionally to the insulin increase. We hypothesized that BPA and OP disrupt calcium homeostasis resulting in insulin resistance through induction of endoplasmic reticulum (ER) stress. BPA and OP treatment leads to survival of pancreatic β cells against streptozotocin, but despite an increased insulin level, serum glucose regulation is not properly regulated. The expression of genes involved in transporting calcium ions to the cytosol and ER decreased while the expression of those affecting the removal of calcium from the cytosol and ER increased. Depletion of calcium from the ER leads to ER stress and can induce insulin resistance. Insulin resistance is also confirmed by insulin-responsive gene, such as glucose transporter 4 (GLUT4) and IRS2, expression. Taken together, these results imply that disruption of calcium homeostasis by BPA and OP induces ER stress and leads to insulin resistance, especially in a streptozotocin (STZ) -induced type 1 diabetes mellitus model.

Keywords: Bisphenol A; Calcium homeostasis; Diabetes; ER stress; Octylphenol.

MeSH terms

  • Animals
  • Benzhydryl Compounds / toxicity*
  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Calcium / metabolism*
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism
  • Cell Death / drug effects
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / chemically induced*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / chemically induced*
  • Diabetes Mellitus, Type 1 / pathology
  • Endocrine Disruptors / toxicity*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / drug effects
  • Glucose Transporter Type 4 / metabolism
  • Homeostasis
  • Insulin / blood
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice, Inbred ICR
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Phenols / toxicity*
  • Plasma Membrane Calcium-Transporting ATPases / drug effects
  • Plasma Membrane Calcium-Transporting ATPases / metabolism
  • Streptozocin
  • TRPV Cation Channels / drug effects
  • TRPV Cation Channels / metabolism

Substances

  • Benzhydryl Compounds
  • Biomarkers
  • Blood Glucose
  • CACNA1C protein, mouse
  • Calcium Channels
  • Calcium Channels, L-Type
  • Endocrine Disruptors
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Phenols
  • Slc2a4 protein, mouse
  • TRPV Cation Channels
  • Trpv6 protein, mouse
  • octylphenol
  • Streptozocin
  • Plasma Membrane Calcium-Transporting ATPases
  • Atp2b1 protein, mouse
  • bisphenol A
  • Calcium