The plasticizer BBP selectively inhibits epigenetic regulator sirtuin during differentiation of C3H10T1/2 stem cell line

Toxicol In Vitro. 2017 Mar;39:75-83. doi: 10.1016/j.tiv.2016.11.016. Epub 2016 Dec 5.

Abstract

Exposure to environmental chemicals can perturb an individual's metabolic set point, especially during critical periods of development, and as a result increase his or her propensity towards obesity that is manifested later in life and possibly in successive generations. We hypothesized that benzyl butyl phthalate (BBP), a widespread endocrine disruptor, may impair one important epigenetic regulator, sirtuin, in mesenchymal stem cells and induce adipogenesis. Our results showed that gene expression of two well-known adipogenic markers, aP2 and PPARγ, were significantly increased from day 2 to day 8 under 50μM BBP exposure when compared to control in C3H10T1/2 stem cells (p<0.05) and induced adipogenesis. Sirt1 gene expression was also significantly decreased at day 2, 4, 6, and 8 (p<0.05). However, Sirt7 gene expression was decreased only at day 2 and 8 (p<0.05) while other sirtuin transcriptional levels remained unaltered throughout. Furthermore, Sirt1 and Sirt3 protein expression was decreased (p<0.05) and overall protein hyperacetylation was observed at day 8. Furthermore, FOXO1 and β-catenin, Sirt1 targets and adipogenesis regulators, were hyperacetylated at day 8. PGC1α, NRF1, NRF2, and Tfam, were also significantly decreased (p<0.05). In conclusion, our study suggests for the first time that BBP, a potential epigenetic disruptor, can lead to increased adipogenesis and metabolic dysregulation by impairing vital epigenetic regulators.

Keywords: Adipogenesis; Benzyl butyl phthalate (BBP); Endocrine disruptor; Hyperacetylation; Mesenchymal stem cell; Sirtuins.

MeSH terms

  • Adipogenesis / drug effects*
  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic*
  • Forkhead Box Protein O1 / metabolism
  • Gene Expression / drug effects
  • High Mobility Group Proteins / genetics
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • Nuclear Respiratory Factor 1 / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Phthalic Acids / toxicity*
  • Plasticizers / toxicity*
  • Sirtuins / antagonists & inhibitors*
  • Sirtuins / genetics
  • Sirtuins / metabolism
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Stem Cells / physiology
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, mouse
  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • High Mobility Group Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phthalic Acids
  • Plasticizers
  • Ppargc1a protein, mouse
  • Tfam protein, mouse
  • beta Catenin
  • Sirtuins
  • butylbenzyl phthalate