Abstract
Alterations in intrauterine programming occurring during critical periods of development have adverse consequences for whole-organ systems or individual tissue functions in later life. In this paper, we show that rat embryonic neural stem cells (NSCs) exposed to the synthetic glucocorticoid dexamethasone (Dex) undergo heritable alterations, possibly through epigenetic mechanisms. Exposure to Dex results in decreased NSC proliferation, with no effects on survival or differentiation, and changes in the expression of genes associated with cellular senescence and mitochondrial functions. Dex upregulates cell cycle-related genes p16 and p21 in a glucocorticoid receptor(GR)-dependent manner. The senescence-associated markers high mobility group (Hmg) A1 and heterochromatin protein 1 (HP1) are also upregulated in Dex-exposed NSCs, whereas Bmi1 (polycomb ring finger oncogene) and mitochondrial genes Nd3 (NADH dehydrogenase 3) and Cytb (cytochrome b) are downregulated. The concomitant decrease in global DNA methylation and DNA methyltransferases (Dnmts) suggests the occurrence of epigenetic changes. All these features are retained in daughter NSCs (never directly exposed to Dex) and are associated with a higher susceptibility to oxidative stress, as shown by the increased occurrence of apoptotic cell death on exposure to the redox-cycling reactive oxygen species (ROS) generator 2,3-dimethoxy-1-naphthoquinone (DMNQ). Our study provides novel evidence for programming effects induced by glucocorticoids (GCs) on NSCs and supports the idea that fetal exposure to endogenous or exogenous GCs is likely to result in long-term consequences that may predispose to neurodevelopmental and/or neurodegenerative disorders.
Highlights
Most of the prenatal challenges known to have programming effects have been associated with high levels of GCs in utero.[1]
GC-induced effects were investigated in parent NSCs (P1) exposed to 1 mM Dex for 48 h, and in daughter cells (D) from passage 2 (D2) and 3 (D3), which were never directly exposed to Dex
Live cell imaging revealed that Dex-exposed P1 had more processes and tended to grow disjointed, whereas control cells grew in clusters with tight cell–cell contacts (Figure 2a and b)
Summary
Most of the prenatal challenges known to have programming effects have been associated with high levels of GCs in utero.[1]. Fetal exposure to elevated GC levels can occur when exogenous GCs are administered for therapeutic purposes or in response to severe maternal stress. We observed that prenatal exposure to high levels of synthetic GC dexamethasone (Dex) induces long-lasting alterations in rat neuronal cells characterized by an increased susceptibility to oxidative stress,[16] which we observed in adult NSCs.[17] All together, the data pointed to a programming effect of Dex, which induced long-term changes in cells never directly exposed to it. In light of the central role that NSCs have in the developing and adult nervous system, we designed the present study to investigate the molecular mechanisms responsible for the long-lasting effects induced by GCs in primary cultures of embryonic cortical NSCs
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