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.Objectives: 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.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.Citation: Strong AL, Shi Z, Strong MJ, Miller DF, Rusch DB, Buechlein AM, Flemington EK, McLachlan JA, Nephew KP, Burow ME, Bunnell BA. 2015. Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells. Environ Health Perspect 123:42–48; http://dx.doi.org/10.1289/ehp.1408188

Exposure top,p′-DDE Induces Morphological Changes and Activation of the PKCα-p38-C/EBPβPathway in Human Promyelocytic HL-60 Cells

“…These observations agree with the ability of p , p ′ - DDT (at 20  μ M) to induce differentiation in adipocytes 3T3-L1 and preadipocytes 3T-F442A [40]. They are also consistent with a recent study in human mesenchymal stem cells (MSCs) from bone marrow, which showed that p , p ′ - DDT exposure enhanced osteogenic and adipogenic differentiation [39]. Our work suggests that p , p ′ - DDE exposure at the concentrations found in bone marrow of humans can induce intracellular molecular pathways (ROS, PKC α , p38, and C/EBP β ) that are involved in the myeloid differentiation and, consequently, induce morphological differentiation of this human myeloid cell line.…”

“…The few in vitro experiments that have been performed demonstrate that DDT induces adipogenic and osteogenic differentiation of mesenchymal stem cells [39] and adipocyte differentiation from preadipocyte 3T3-L1 cells and increases the nuclear levels of C/EBP α , β [40]. DDT negatively affects haematic cells and their immunocompetence, but its effect on differentiation of immune cells and the mechanisms underlying these effects remain to be defined.…”

The Effects of Endocrine Disruptors on Adipogenesis and Osteogenesis in Mesenchymal Stem Cells: A Review

“…Many endocrine disruptors target PPARγ by binding to it directly to activate downstream cascades that lead to enhanced adipogenesis or by increasing PPARγ expression to allow for a lower threshold for activation. These EDCs include DDT, dichlorodiphenyldichloroethylene or 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (81), 4-NP, OP, BPA, PCB-77, DEHP, MEHP, DBP, BBP, and MBzP (35, 37, 39, 43, 63, 66, 68–70, 75, 77–80, 82–85). Perinatal exposure to 4-NP has also been shown to increase PPARγ gene expression and sterol regulatory element-binding factor 1 (SREBF-1) expression in adipose tissue (83).…”

“…Thus, PPARγ and SREBF-1 are key transcriptional factors in adipogenesis. The expression of C/EBPα and expression of factors promoted by PPARγ, such as lipoprotein lipase and fatty acid binding protein 4/adipocyte protein 2 (aP2), have been shown to be increased in response to DDT, DDE, 4-NP, BPA, PCB-77, DEHP, MEHP, and BBP (37, 39, 42, 45, 46, 66, 68, 69, 73, 75, 76, 78, 82–84, 86–89). p , p ′-DDT has also been shown to increase binding of C/EBPα to its DNA response element, demonstrating that the promotion of adipogenesis may be occurring through both increased expression and activation of targeted receptors (66).…”

Toxic Effects of Organochlorine Pesticides: A Review

“…Different authors have proved DDT to be hazardous to humans by using different tests [50][51][52][53][54][55]. Shaw et al [56] presented data on pesticide residues in milk from Indonesian women which demonstrated general exposure to p,p'-DDT and hexachlorobenzene (HCB).…”