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Changes in gene expression following long-term in vitro exposure of Macaca mulatta trophoblast stem cells to biologically relevant levels of endocrine disruptors

ABSTRACT: Trophoblast stem cells (TSCs) are key for embryo implantation and placentation. Environmental toxicants that compromise trophoblast function could compromise fetal viability, pregnancy outcome, and progeny health. Endocrine disrupting chemicals (EDCs) can epigenetically modify cells and alter their developmental properties. Understanding the effects of low, chronic EDC exposures on TSCs and pregnancy is a priority in developmental toxicology. Differences in placentation between primates and other mammals make a nonhuman primate model ideal for this. We examined effects of chronic low-level exposure to five EDCs on rhesus monkey TSCs in vitro. Two of the toxicants, ATR and TBT, exerted the strongest effects, with substantial overlap. Affected genes included some with obvious relevance to placentation and implantation (WNT7A, INHBA, and cytokines and their receptors). Pathway analysis revealed significant reductions in the expression of genes related to cytokine signaling, a feature shared across all five EDCs tested. Low-level chronic exposure of primate TSCs to EDCs may thus compromise trophoblast development in vivo, modify responses to pathogens and other challenges, and negatively affect embryo implantation and pregnancy rate.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE103033 | GEO | 2018/03/06

REPOSITORIES: GEO

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Project description:Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein–Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein (CREBBP) or E1A-binding protein p300 (EP300). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein–Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.

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Changes in gene expression following long-term in vitro exposure of Macaca mulatta trophoblast stem cells to biologically relevant levels of endocrine disruptors

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