Comparative microarray analyses of mono(2-ethylhexyl)phthalate impacts on fat cell bioenergetics and adipokine network

Cell Biol Toxicol. 2017 Dec;33(6):511-526. doi: 10.1007/s10565-016-9380-7. Epub 2017 Jan 12.

Abstract

Cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) has been recently demonstrated to disturb fat cell energy metabolism; however, the underlying mechanism remained unclear. The study aimed to determine how MEHP influenced fat cell transcriptome and how the changes might contribute to bioenergetics. Because of the pivotal role of PPARγ in energy metabolism of fat cells, comparative microarray analysis of gene expression in 3T3-L1 adipocytes treated with both MEHP and rosiglitazone was performed. Pathway enrichment analysis and gene ontology (GO) enrichment analysis revealed that both treatments caused up-regulation of genes involved in PPAR signaling/energy metabolism-related pathways and down-regulation of genes related to adipokine/inflammation signals. MEHP/rosiglitazone-treated adipocytes exhibited increased levels of lipolysis, glucose uptake, and glycolysis; the gene expression profiles provided molecular basis for the functional changes. Moreover, MEHP was shown to induce nuclear translocation and activation of PPARγ. The similarity in gene expression and functional changes in response to MEHP and rosiglitazone suggested that MEHP influenced bioenergetics and adipokine network mainly via PPARγ. Importantly, adipokine levels in C57BL/6J mice with di(2-ethylhexyl)phthalate (DEHP) treatments provided in vivo evidence for microarray results. On the basis of correlation between gene expression and functional assays, possible involvements of genes in bioenergetics of MEHP-treated adipocytes were proposed.

Keywords: Adipocytes; Endocrine disruptor; Energy metabolism; PPARγ; Phthalates.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Adipokines / genetics
  • Adipokines / metabolism*
  • Animals
  • Diethylhexyl Phthalate / analogs & derivatives*
  • Diethylhexyl Phthalate / pharmacology
  • Energy Metabolism / drug effects
  • Fatty Acids / metabolism
  • Gene Expression / drug effects
  • Gene Expression Profiling / methods
  • Glucose / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microarray Analysis
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Rosiglitazone
  • Thiazolidinediones / pharmacology

Substances

  • Adipokines
  • Fatty Acids
  • PPAR gamma
  • Thiazolidinediones
  • Rosiglitazone
  • Diethylhexyl Phthalate
  • mono-(2-ethylhexyl)phthalate
  • Glucose