Actions of endocrine-disrupting chemicals on stem/progenitor cells during development and disease

Abstract

Development and fate of the stem cell are regulated by extrinsic signals from the environment. Endocrine-disrupting chemicals which perturb hormonal signaling in utero and during early childhood may cause deregulation of multiple developmental processes, ranging from breakdown of stem cell niche architecture, developmental reprograming and altered stem cell fate to impaired organ and gonad development and sexual differentiation. Therefore, study of the environmental effects on stem cell integrity and normal development is a new and emerging focus for developmental biologists and cell toxicologists. When combined with new human and mouse stem cell-based models, stem cell differentiation dynamics can be studied in more biologically relevant ways. In this study, we review the current status of our understanding of the molecular mechanisms by which endocrine disruptors alter embryonic stem cell and adult stem/progenitor cell fate, organ development, cancer stem cell activity, and tumorigenesis.

Keywords: cancer stem cell; endocrine disruptors; organ development; stem cell/progenitor cell; steroid hormone receptors.

Figure 1

Schematic representation of stem, progenitor, and cancer stem cells and the primary organ systems which are susceptible to EDC exposure. Abbreviations for the specific endocrine disruptors modulating each cell type and organ system are listed as indicated. The chemical names for these abbreviations are provided in the text of the manuscript.

Figure 2

EDCs which disrupt germ cell niche homeostasis. Production of androgens by Leydig cells is downregulated by plasticizers (DEHP) (Zhang et al. 2008). The process of spermatogenesis is disrupted by estrogenic compounds (BPA, E₂), preservatives (paraben), and organophosphates (TOCP, SCOTP) (Ahn et al. 2012, Aoki & Takada 2012, Chen et al. 2012). The physical contacts between Sertoli cells and germ cells are broken by exposure to plasticizers (DEHP, MEHP), resulting in premature loss of germ cells (Yao et al. 2010, Erkekoglu et al. 2012). The dicarboximide fungicide Vinclozolin is reported to induce epigenetic transgenerational changes in the sperm epigenome and to cause Leydig cell tumors in rats (Kavlock & Cummings 2005, Guerrero-Bosagna et al. 2012).