Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of the Igf axis in lungs of mouse offspring

Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels of Igf1 and its receptor ( Igf1: P = 0.05; Igf1r: P = 0.03). Furthermore, CpG-site-specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development.

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Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

International Journal of Molecular Sciences ◽

10.3390/ijms22010164 ◽

2020 ◽

Vol 22 (1) ◽

pp. 164

Author(s):

Khosbayar Lkhagvadorj ◽

Zhijun Zeng ◽

Karolin F. Meyer ◽

Laura P. Verweij ◽

Wierd Kooistra ◽

...

Keyword(s):

Dna Methylation ◽

Mrna Expression ◽

Nicotine Dependence ◽

Susceptibility Gene ◽

Smoke Exposure ◽

Adverse Outcomes ◽

Male Offspring ◽

Adult Offspring ◽

Mrna Levels ◽

Nicotine Metabolism

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.

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Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Nutrients ◽

10.3390/nu13010041 ◽

2020 ◽

Vol 13 (1) ◽

pp. 41

Author(s):

Nouf Aljobaily ◽

Michael J. Viereckl ◽

David S. Hydock ◽

Hend Aljobaily ◽

Tsung-Yen Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Methylation ◽

Body Weight ◽

Liver Fibrosis ◽

Liver Damage ◽

Cellular Senescence ◽

Weight Ratio ◽

Mrna Levels ◽

Body Weight Ratio ◽

Chromosomal Stability

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

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SH2B1 CpG-SNP Is Associated with Body Weight Reduction in Obese Subjects Following a Dietary Restriction Program

Annals of Nutrition and Metabolism ◽

10.1159/000368425 ◽

2014 ◽

Vol 66 (1) ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Maria Luisa Mansego ◽

Fermin Ignacio Milagro ◽

Maria Angeles Zulet ◽

José Alfredo Martinez

Keyword(s):

Dna Methylation ◽

Body Weight ◽

Weight Reduction ◽

Molecular Mechanisms ◽

White Blood Cells ◽

The Body ◽

Mrna Levels ◽

Bdnf Mrna ◽

Body Weight Reduction ◽

Obese Subjects

The objective of this study was to examine whether 7 SNPs previously associated with obesity-related traits that add or remove potential sites of DNA methylation are accompanied by differential DNA methylation and subsequently affect adiposity variables or body weight reduction in WBC from obese subjects under an energy-restricted program. Material and Methods: Anthropometric measurements were assessed in 47 volunteers recruited within the RESMENA study (Spain). At baseline, DNA from white blood cells was isolated and 7 obesity-related trait CpG-SNPs were genotyped by TaqMan-PCR. Then, methylation levels of CpG-SNP sites were quantified by MassArray® EpiTyper™ or MS-HRM approaches. Results: Differential DNA methylation levels were observed by genotypes in all of the CpG-SNPs analyzed. The FTO and BDNF methylation levels were further correlated with baseline body weight and, BDNF mRNA levels and body weight change, respectively. Moreover, the rs7359397 (SH2B1) was associated with the body weight, body mass index, and truncal fat mass reduction. Conclusions: Our results reveal the interaction of epigenetic and genetic variations in CpG-SNPs, especially in BDNF and SH2B1 genes, and how allele-specific methylation may contribute to elucidate the possible molecular mechanisms as these SNPs are affecting the decrease of mRNA levels and contributing to a lower body weight reduction. © 2014 S. Karger AG, Basel

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Intensity-Specific Differential Leukocyte DNA Methylation in Physical (In)Activity: An Exploratory Approach

Twin Research and Human Genetics ◽

10.1017/thg.2018.10 ◽

2018 ◽

Vol 21 (2) ◽

pp. 101-111 ◽

Cited By ~ 3

Author(s):

Maarten Caspers ◽

Sara Blocquiaux ◽

Ruben Charlier ◽

Sara Knaeps ◽

Johan Lefevre ◽

...

Keyword(s):

Dna Methylation ◽

Correlation Coefficients ◽

Global Dna Methylation ◽

Site Specific ◽

Cpg Sites ◽

Cpg Site ◽

Biological Pathway Analysis ◽

Exploratory Approach ◽

Health Related ◽

Related Pathway

The aim of this exploratory study was to investigate how sedentary behavior (SB) and physical activity (PA) influence DNA methylation at a global, gene-specific, and health-related pathway level. SB, light PA (LPA), and moderate-to-vigorous PA (MVPA) were assessed objectively for 41 Flemish men using the SenseWear Pro 3 Armband. CpG site-specific methylation in leukocytes was determined using the Illumina HumanMethylation 450 BeadChip. Correlations were calculated between time spent on the three PA intensity levels and global DNA methylation, using a z-score-based method to determine global DNA methylation levels. To determine whether CpG site-specific methylation can be predicted by these three PA intensity levels, linear regression analyses were performed. Based on the significantly associated CpG sites at α = 0.005, lists were created including all genes with a promoter region overlapping these CpG sites. A biological pathway analysis determined to what extent these genes are overrepresented within several pathways. No significant associations were observed between global DNA methylation and SB (r = 0.084), LPA (r = -0.168), or MVPA (r = -0.125), although the direction of the correlation coefficients is opposite to what is generally reported in literature. SB has a different impact on global and gene-specific methylation than PA, but also LPA and MVPA affect separate genes and pathways. Furthermore, the function of a pathway seems to determine its association with SB, LPA, or MVPA. Multiple PA intensity levels, including SB, should be taken into account in future studies investigating the effect of physical (in)activity on human health through epigenetic mechanisms.

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Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus

Neuropsychopharmacology ◽

10.1038/s41386-020-0780-2 ◽

2020 ◽

Vol 45 (12) ◽

pp. 2120-2130 ◽

Cited By ~ 1

Author(s):

Gonca Bayraktar ◽

PingAn Yuanxiang ◽

Alessandro D. Confettura ◽

Guilherme M. Gomes ◽

Syed A. Raza ◽

...

Keyword(s):

Dna Methylation ◽

Synaptic Plasticity ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

De Novo ◽

Memory Formation ◽

Epigenetic Mark ◽

Dependent Manner ◽

Synaptic Control ◽

Activity Dependent

Abstract DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.

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Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level

Clinical Science ◽

10.1042/cs20140688 ◽

2015 ◽

Vol 129 (4) ◽

pp. 385-394 ◽

Cited By ~ 20

Author(s):

Xuemei Xie ◽

Hongjie Gao ◽

Wanjiang Zeng ◽

Suhua Chen ◽

Ling Feng ◽

...

Keyword(s):

Dna Methylation ◽

Gestational Diabetes ◽

Glucose Level ◽

Peroxisome Proliferator ◽

Diabetes Group ◽

Peroxisome Proliferator Activated Receptor ◽

Site Specific ◽

Cpg Site

Among all the participants, the maternal gestational glucose level was positively correlated with placental DNA methylation. The correlation between gestational 2-h post-OGTT glycaemia and CpG site-specific methylation in placenta was stronger in the gestational diabetes group.

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Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner

PLoS ONE ◽

10.1371/journal.pone.0132136 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0132136 ◽

Cited By ~ 23

Author(s):

Julien Prados ◽

Ludwig Stenz ◽

Emmanuel Somm ◽

Christelle Stouder ◽

Alexandre Dayer ◽

...

Keyword(s):

Dna Methylation ◽

Prenatal Exposure ◽

Dependent Manner ◽

Sperm Dna ◽

Strain Dependent ◽

Sperm Dna Methylation

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Antiobesity Effects of UnripeRubus coreanusMiquel and Its Constituents: AnIn VitroandIn VivoCharacterization of the Underlying Mechanism

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4357656 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 10

Author(s):

Dool-Ri Oh ◽

Yujin Kim ◽

Eun-jin Choi ◽

Hunmi-Lee ◽

Myung-A Jung ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Bioactive Compounds ◽

Lipid Accumulation ◽

Weight Control ◽

Underlying Mechanism ◽

Serum Glucose ◽

Mrna Levels ◽

Dependent Manner

Background. The objective of the present study was to perform a bioguided fractionation of unripeRubus coreanusMiquel (uRC) and evaluate the lipid accumulation system involvement in its antiobesity activity as well as study the uRC mechanism of action.Results. After the fractionation, the BuOH fraction of uRC (uRCB) was the most active fraction, suppressing the differentiation of 3T3-L1 adipocytes in a dose-dependent manner. Moreover, after an oral administration for 8 weeks in HFD-induced obese mice, uRCB (10 and 50 mg/kg/day) produced a significant decrease in body weight, food efficiency ratio, adipose tissue weight and LDL-cholesterol, serum glucose, TC, and TG levels. Similarly, uRCB significantly suppressed the elevated mRNA levels of PPARγin the adipose tissuein vivo. Next, we investigated the antiobesity effects of ellagic acid, erycibelline, 5-hydroxy-2-pyridinemethanol, m-hydroxyphenylglycine, and 4-hydroxycoumarin isolated from uRCB. Without affecting cell viability, five bioactive compounds decreased the lipid accumulation in the 3T3-L1 cells and the mRNA expression levels of key adipogenic genes such as PPARγ, C/EBPα, SREBP-1c, ACC, and FAS.Conclusion. These results suggest that uRC and its five bioactive compounds may be a useful therapeutic agent for body weight control by downregulating adipogenesis and lipogenesis.

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Metabolic programming of sirtuin 1 (SIRT1) expression by moderate energy restriction during gestation in rats may be related to obesity susceptibility in later life

British Journal Of Nutrition ◽

10.1017/s0007114512001961 ◽

2012 ◽

Vol 109 (4) ◽

pp. 757-764 ◽

Cited By ~ 3

Author(s):

Mariona Palou ◽

Teresa Priego ◽

Juana Sánchez ◽

Andreu Palou ◽

Catalina Picó

Keyword(s):

Body Weight ◽

Mrna Expression ◽

Energy Restriction ◽

Metabolic Programming ◽

Sirtuin 1 ◽

Mrna Levels ◽

Dependent Manner ◽

Peripheral Tissues ◽

Moderate Energy ◽

Obesity Susceptibility

In rats, 20 % gestational energy restriction programmes offspring for higher food intake, which in adulthood results in higher body weight in males but not in females. Here, we aimed to assess whether the effects of moderate energy restriction during gestation and the sex-related outcomes on adult body weight may be related to the metabolic programming of sirtuin expression in different tissues. For this purpose, 25-d-old offspring of control and 20 % energy-restricted (ER) rats (from days 1–12 of pregnancy) were studied. Body weight and the weight of white adipose tissue (WAT) depots and liver were recorded and mRNA expression of sirtuin 1 (SIRT1) and selected genes in the WAT, liver, muscle and hypothalamus were analysed. No differences were found in body weight or the weight of WAT and liver between the control and ER animals. A similar pattern of SIRT1 mRNA expression was found in the WAT, liver and skeletal muscle of ER animals, but in a sex-dependent manner: ER males showed lower SIRT1 mRNA levels than the controls, while no differences were found in females. A sex-different pattern was also observed in the hypothalamus. ER males, but not females, also showed lower mRNA levels of adipose TAG lipase (ATGL) and uncoupling protein 2 in WAT and of sterol response element binding protein 1c and stearoyl-CoA desaturase-1 in the liver. Both sexes of ER animals showed lower mRNA levels of 5′ adenosine monophosphate-activated protein kinase and ATGL in the liver. In conclusion, moderate maternal energy restriction during gestation programmes a particular, sex-dependent gene expression profile of SIRT1 in different peripheral tissues, which may be related to obesity predisposition in adulthood; therefore SIRT1 expression emerges as a potential early biomarker of obesity susceptibility.

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Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

10.1101/602151 ◽

2019 ◽

Cited By ~ 1

Author(s):

Gonca Bayraktar ◽

PingAn Yuanxiang ◽

Guilherme M Gomes ◽

Aessandro D Confettura ◽

Syed A Raza ◽

...

Keyword(s):

Dna Methylation ◽

Synaptic Plasticity ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

De Novo ◽

Memory Formation ◽

Epigenetic Mark ◽

Dependent Manner ◽

Synaptic Control ◽

Activity Dependent

AbstractDNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation.

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