Research Article Advance Publication
Effects of the Endocrine-Disrupting Chemical DDT on Self-Renewal and Differentiation of Human Mesenchymal Stem Cells
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Citation: Strong AL, Shi Z, Strong MJ, Miller DF, Rusch DB, Buechlein AM, Flemington EK, McLachlan JA, Nephew KP, Burow ME, Bunnell BA. Effects of the Endocrine-Disrupting Chemical DDT on Self-Renewal and Differentiation of Human Mesenchymal Stem Cells. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1408188.
Received: 28 January 2014
Accepted: 10 July 2014
Advance Publication: 11 July 2014
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.
Objectives: Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology.
Methods: DDT-treated MSCs were assessed 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 the adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor (PPAR)-gamma, 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 estrogen-treated MSCs, suggesting that DDT may function via the estrogen receptor (ER)-mediated pathway. The co-administration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and non-coding RNAs to be differentially expressed in DDT-treated MSCs compared to controls cells.
Conclusion: 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.
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