Inhibitory effects of cigarette smoke extract on neural crest migration occur through suppression of R-spondin1 expression via aryl hydrocarbon receptor (original) (raw)
Related papers
2012
While the pathologies associated with in utero smoke exposure are well established, their underlying molecular mechanisms are incompletely understood. We differentiated human embryonic stem cells in the presence of physiological concentrations of tobacco smoke and nicotine. Using post hoc microarray analysis, quantitative PCR, and immunoblot analysis, we demonstrated that tobacco smoke has lineage-and stage-specific effects on human embryonic stem cell differentiation, through both nicotine-dependent and -independent pathways. We show that three major stem cell pluripotency/differentiation pathways, Notch, canonical Wnt, and transforming growth factor-β, are affected by smoke exposure, and that Nodal signaling through SMAD2 is specifically impacted by effects on Lefty1, Nodal, and FoxH1. These events are associated with upregulation of microRNA-302a, a post-transcriptional silencer of Lefty1. The described studies provide insight into the mechanisms by which tobacco smoke influences fetal development at the cellular level, and identify specific transcriptional, post-transcriptional, and signaling pathways by which this likely occurs.
Malaysian Journal of Medical Sciences, 2018
Background and aim: This study aimed to determine the effect of gestational nicotine exposure before neurodevelopment on the morphology and histology of the prefrontal cortex (PFC) in rats. Methodology: Adult female Wistar rats were time-mated and grouped into three categories: (a) control-given 0.1 mL of normal saline, (b) low-dose nicotine-given 6.88 mg/ kg/d/0.05 mL, and (c) high-dose nicotine-given 13.76 mg/kg/d/0.1 mL in two divided doses. Treatment was given intraperitoneally from gestational days 2 to 6. On postnatal day 15 (P15), the pups were separated from their mothers, anaesthetised and sacrificed, followed by intracardial perfusion with 4% paraformaldehyde. PFC was excised from the brain and processed for tissue histology, histochemistry, and morphology of brain cells. Results: Gestational nicotine exposure during the first week of gestation in rats significantly reduced birth weights in nicotine-treated groups compared with control; it, however, accelerated body weights, altered neuronal morphology, and elevated astrocytic count significantly, while oligodendroglial count was slightly increased in the PFC of juvenile rats examined at P15. Conclusion: These alterations revealed that gestational nicotine exposure before the commencement of the cellular processes involved in brain development negatively affects neurodevelopment, and this could result in neurological dysfunctions in later life.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder (AD/HD), learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neuron...
Evidence of altered brain regulatory gene expression in tobacco-exposed fetuses
Journal of perinatal medicine, 2017
We sought to determine the association between prenatal smoking status and expression of fetal brain regulatory genes. At delivery, we collected information from parturient women on prenatal smoking habits and analyzed salivary cotinine levels. We obtained neonatal umbilical cord blood and extracted total RNA. We then employed the quantitative polymerase chain reaction (QPCR) analyses and the comparative CT method to calculate the relative gene expression of selected fetal brain regulatory genes responsible for (1) brain growth (brain-derived neutrotrophic factor, BDNF), (2) myelination (proteolipidic protein 1, PLP1 and myelin basic protein, MBP), and (3) neuronal migration and cell-cell interactions during fetal brain development or RLN. The χ2-test, analysis of variance (ANOVA), and the Grubb test were used to evaluate the relationship between prenatal smoking status and relative gene expression levels. Further analysis using bootstrapping was performed to assess the precision of...
2013
To examine the developmental exposure effect of nicotine (NIC) on hippocampal neurogenesis, pregnant Sprague–Dawley rats were treated with (−)-NIC hydrogen tartrate salt through drinking water at 2, 10 or 50 ppm from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, immunohistochemically doublecortin (Dcx)+ cells increased at ≥10 ppm in the dentate subgranular zone (SGZ) as examined in male offspring; however, dihydropyrimidinase-like 3 (TUC4)+ cells decreased at 2 ppm, and T box brain 2 (Tbr2)+ cells were unchanged at any dose. Double immunohistochemistry revealed decreases in TUC4+/Dcx+ and TUC4+/Dcx− cells, an increase in TUC4−/Dcx+ cells at 2 and 10 ppm and an increase in Tbr2−/Dcx+ cells at 50 ppm, suggesting an increase in type-3 progenitor cells at ≥2 ppm and decrease in immature granule cells at 2 and 10 ppm. The number of mature neuron-specific NeuN− progenitor cells expressing nicotinic acetylcholine receptor α7 in the SGZ and mRNA levels of Chrna7 and...
Neuropsychopharmacology, 2004
Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence. We evaluated neurotoxicant effects of prenatal and adolescent nicotine exposure in developing rats to evaluate whether these contribute to a biological basis for this relationship. Rats were given nicotine or vehicle throughout pregnancy and the offspring then again received nicotine or vehicle during adolescence (postnatal days PN30-47.5); this regimen reproduces the plasma nicotine levels found in smokers. Indices of neural cell number (DNA concentration and content), cell size (protein/DNA ratio), and cell membrane surface area (membrane/total protein) were then evaluated in brain regions during adolescent nicotine administration (PN45) and up to 1 month post-treatment. By itself, prenatal nicotine administration produced cellular alterations that persisted into adolescence, characterized by net cell losses in the midbrain and to a lesser extent, in the cerebral cortex, with corresponding elevations in the membrane/total protein ratio. The hippocampus showed a unique response, with increased DNA content and regional enlargement. Adolescent nicotine treatment alone had similar, albeit smaller effects, but also showed sex-dependence, with effects on protein biomarkers preferential to females. When animals exposed to nicotine prenatally were then given nicotine in adolescence, the net outcome was worsened, largely representing summation of the two individual effects. Our results indicate that prenatal nicotine exposure alters parameters of cell development lasting into adolescence, where the effects add to those elicited directly by adolescent nicotine; neurotoxicant actions may thus contribute to the association between maternal smoking and subsequent smoking in the offspring.
Reproductive Toxicology, 2008
Human embryonic stem cells (hESCs) share many characteristics including pluripotency with cells of the early embryo and so are potentially useful tools for studying the harmful effects of xenobiotics during early development. Here, we used hESCs as a model system to test the effects of nicotine on the pluripotent population of cells that forms the whole body. Specifically, we exposed hESCs (H7 and H9) to various concentrations of nicotine ranging from 0.1 to 6 M. We evaluated the effects in terms of cell adhesion, integrin expression, hESC colony morphology, markers of pluripotency and survival. The results revealed a significant negative impact of nicotine in the dose range between 1.8 and 3.7 M on all the endpoints analyzed. The observed effects were reversed by the addition of the nicotine antagonist d-tubocurarine, suggesting that the effects are receptor mediated. Together these results offer new explanations in terms of embryo toxicity for the large negative impact of cigarette smoke exposure on a woman's reproductive capacity.
Human Reproduction, 2009
background: Embryonic stem cells (ESC), which originate from the inner cell mass of blastocysts, are valuable models for testing the effects of toxicants on preimplantation development. In this study, mouse ESC (mESC) were used to compare the toxicity of mainstream (MS) and sidestream (SS) cigarette smoke on cell attachment, survival and proliferation. In addition, smoke from a traditional commercial cigarette was compared with smoke from three harm-reduction brands. methods: MS and SS smoke solutions were made using an analytical smoking machine and tested at three doses using D3 mESC plated on 0.2% gelatin. At 6 and 24 h, images were taken and the number of attached cells was evaluated.
Neuroscience, 2001
AbstractöThe nicotinic receptor proteins and gene transcripts for the di¡erent nicotinic receptor subunits exist in human prenatal brain already at 4^5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [ 3 H]epibatidine (labelling both the K3 and K4 subtype) and [ 3 H]cytisine (labelling the K4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5^11 weeks of gestation), the highest speci¢c binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The e¡ects of nicotine exposure were studied in primary cultures of prenatal brain (7.5^11 weeks of gestation). Treatment with nicotine (1^100 WM) for 3 days signi¢cantly increased the speci¢c binding of [ 3 H]epibatidine and [ 3 H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-speci¢c di¡erences in the sensitivity to nicotine exposure. Relative quan-ti¢cation of mRNA showed that the expression of the nicotinic receptor subunits K3 and K7, but not K4, was increased in cortical cells after nicotine treatment.
AJP: Lung Cellular and Molecular Physiology, 2006
Boros LW, Lee W-P, Torday JS. In utero nicotine exposure alters fetal rat lung alveolar type II cell proliferation, differentiation, and metabolism. We recently suggested that alveolar interstitial fibroblast-to-myofibroblast transdifferentiation may be a key mechanism underlying in utero nicotine-induced lung injury. However, the effects of in utero nicotine exposure on fetal alveolar type II (ATII) cells have not been fully determined. Placebo, nicotine (1 mg/kg), or nicotine (1 mg/kg) ϩ the peroxisome proliferatoractivated receptor (PPAR)-␥ agonist prostaglandin J2 (PGJ2, 0.3 mg/kg) was administered intraperitoneally once daily to time-mated pregnant Sprague-Dawley rats from embryonic day 6 until their death on embryonic day 20. Fetal ATII cells were isolated, and ATII cell proliferation, differentiation (surfactant synthesis), and metabolism (metabolic profiling with the stable isotope [1,2-13 C2]-D-glucose) were determined after nicotine exposure in utero or in vitro. In utero nicotine exposure significantly stimulated ATII cell proliferation, differentiation, and metabolism. Although the effects on ATII cell proliferation and metabolism were almost completely prevented by concomitant treatment with PGJ 2, the effects on surfactant synthesis were not. On the basis of in utero and in vitro data, we conclude that surfactant synthesis is stimulated by nicotine's direct effect on ATII cells, whereas cell proliferation and metabolism are affected via a paracrine mechanism(s) secondary to its effects on the adepithelial fibroblasts. These data provide evidence for direct and indirect effects of in utero nicotine exposure on fetal ATII cells that could permanently alter the "developmental program" of the developing lung. More importantly, concomitant administration of PPAR-␥ agonists can effectively attenuate many of the effects of in utero exposure to nicotine on ATII cells. chronic lung disease; smoking; surfactant; fibroblast; peroxisome proliferator-activated receptor-␥ THERE IS COMPELLING EVIDENCE to suggest that although maternal smoking during pregnancy causes accelerated alveolar type II (ATII) cell differentiation at birth, there are significant longterm deleterious effects on pulmonary outcome (5-7, 9, 10, 15, 35). However, the mechanism(s) underlying these paradoxical pulmonary effects remain(s) largely unknown (23, 24, 28). ATII cell growth and differentiation and, hence, alveolar integrity are regulated by a number of autocrine, paracrine, and endocrine factors. In particular, mesenchymal-epithelial interactions are critically important for normal lung development and injury/repair (29 -31, 33). We recently implicated the Address for reprint requests and other correspondence: