title: Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells.
abstract: BACKGROUND
  Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear.
  
  
  OBJECTIVE
  Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology.
  
  
  METHODS
  We assessed DDT-treated MSCs for self-renewal, proliferation, and differentiation potential. Whole genome RNA sequencing was performed to assess gene expression in DDT-treated MSCs.
  
  
  RESULTS
  MSCs exposed to DDT formed fewer colonies, suggesting a reduction in self-renewal potential. DDT enhanced both adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor gamma (PPARγ), leptin, osteonectin, core binding factor 1 (CBFA1), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Expression of factors in DDT-treated cells was similar to that in estrogen-treated MSCs, suggesting that DDT may function via the estrogen receptor (ER)-mediated pathway. The coadministration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and noncoding RNAs to be differentially expressed in DDT-treated MSCs compared with controls cells.
  
  
  CONCLUSIONS
  Human MSCs provide a powerful biological system to investigate and identify the molecular mechanisms underlying the effects of environmental agents on stem cells and human health. MSCs exposed to DDT demonstrated profound alterations in self-renewal, proliferation, differentiation, and gene expression, which may partially explain the homeostatic imbalance and increased cancer incidence among those exposed to long-term EDCs.
authors.affiliation: Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Strong
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Shi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.forename: David F B
authors.initials: DF
authors.lastname: Miller
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Rusch
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Buechlein
authors.forename: Erik K
authors.initials: EK
authors.lastname: Flemington
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bunnell
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D003634:DDT / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D047628:Estrogen Receptor alpha; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma; D011960:Receptors, Estrogen; D017423:Sequence Analysis, RNA
chemical_list: C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D047495:PPAR gamma; D011960:Receptors, Estrogen; D003634:DDT