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2.
Trauma Violence Abuse ; 24(4): 2772-2788, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-35993405

RESUMO

Child sexual abuse (CSA) has been recognized as a risk factor for sexual dysfunction and has attracted increasing attention. However, controversies remain regarding related research. The aim is to calculate the pooled effect size estimate for the correlation between CSA and sexual dysfunction in adults by meta-analysis. Five bibliographic databases (PubMed, Cochrane Library, Web of Science, Embase, and PsycINFO) were comprehensively searched to clarify the association between CSA and sexual dysfunction in adults. We used a fixed-effects model to determine the total pooled effect size estimate and reported odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Subgroup analysis, publication bias analysis, and sensitivity analysis were conducted. Adults who had a history of CSA experienced a higher proportion of sexual dysfunction than adults with no history of CSA (OR = 1.68, 95% CI [1.49, 1.87]). Subgroup analysis showed that women with a history of CSA reported a higher proportion of sexual dysfunction than men with a history of CSA (men: OR = 1.45, 95% CI [1.05, 1.84]; women: OR = 1.62, 95% CI [1.42, 1.83]). The estimates of the effect sizes differed substantially depending on the CSA and sexual dysfunction instruments that were used in each study and the region of each sample. This meta-analysis provides conclusive evidence of an association between CSA and sexual dysfunction in adults. Currently known interventions for the treatment of sexual dysfunction after CSA have only been evaluated in women, so specific interventions should be designed for men CSA survivors who experience sexual impairment.


Assuntos
Abuso Sexual na Infância , Maus-Tratos Infantis , Masculino , Criança , Humanos , Adulto , Feminino , Comportamento Sexual , Fatores de Risco , Sobreviventes
3.
Front Psychiatry ; 13: 857087, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419982

RESUMO

Epigenetic research in post-traumatic stress disorder (PTSD) is essential, given that environmental stressors and fear play such a crucial role in its development. As such, it may provide a framework for understanding individual differences in the prevalence of the disorder and in treatment response. This paper reviews the epigenetic markers associated with PTSD and its treatment, including candidate genes and epigenome-wide studies. Because the etiopathogenesis of PTSD rests heavily on learning and memory, we also draw upon animal neuroepigenetic research on the acquisition, update and erasure of fear memory, focusing on the mechanisms associated with memory reconsolidation. Reconsolidation blockade (or impairment) treatment in PTSD has been studied in clinical trials and, from a neurological perspective, may hold promise for identifying epigenetic markers of successful therapy. We conclude this paper by discussing several key considerations and challenges in epigenetic research on PTSD in humans.

4.
Artigo em Inglês | MEDLINE | ID: mdl-36445604

RESUMO

Self-harm (SH) increases significantly in early adolescence with great variability, and childhood maltreatment (CM) contributes to this increase. Understanding the developmental pathway from CM to SH could provide clues for SH prevention. This study used latent class analysis (LCA) to detect the phenotype of SH and explored the role of psychological resilience in the pathway from the CM to SH phenotype among 5724 early adolescents (52.5% male). Three interpretable phenotypes of SH were identified: low SH (57.8%), medium SH (29.0%), and high SH (13.2%). Furthermore, CM was positively associated with the SH phenotype, psychological resilience mediated the association between CM and the SH phenotype (all ps < 0.001), and a larger mediating effect was observed in the medium SH (22.41%). Our findings offer new perspectives that improving psychological resilience can be used as an efficient intervention to reduce the risk of SH among early adolescents who have experienced CM.

5.
Asian J Androl ; 24(5): 549-557, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915543

RESUMO

The incidence of infertility has recently risen. Semen quality is an important male fertility indicator, and dietary factors can affect semen quality. We conducted this systematic review and meta-analysis to determine the effects of healthy dietary patterns on semen quality. A literature search was conducted in 3 databases (Embase, Web of Science and PubMed) on August 21, 2021. The included cross-sectional studies examined the influence of the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and prudent diet patterns on semen quality parameters; six studies (1244 subjects) were included. By comparing high consumption with low consumption of healthy dietary patterns, the results of the meta-analysis showed significantly higher sperm concentrations (mean difference [MD] = 6.88 × 106 ml-1, 95% confidence interval [CI]: 1.26 × 106 ml-1-12.49 × 106 ml-1; P < 0.05), a significant increase in total sperm count (MD = 16.70 × 106, 95% CI: 2.37 × 106-31.03 × 106; P < 0.05), and a significant increase in progressive sperm motility (MD = 5.85%, 95% CI: 2.59%-9.12%; P < 0.01). The sperm concentration, progressive sperm motility, and total sperm count were significantly higher in men with higher versus lower consumption of healthy dietary patterns. However, the results must be interpreted with caution.


Assuntos
Infertilidade Masculina , Análise do Sêmen , Estudos Transversais , Humanos , Masculino , Sêmen , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatozoides
6.
J Affect Disord ; 314: 249-252, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35878835

RESUMO

BACKGROUND: A strong link between childhood maltreatment (CM) and borderline personality features (BPF) has been consistently demonstrated. However, little is known about the role of psychological adjustment (PA) as a mediator of this relationship. The purpose of the study was to explore the mediating role of PA in the CM-BPF linkage in a large sample of early adolescents. METHODS: A total of 5724 students (mean age = 13.5, SD = 1.0) were recruited from three middle schools by using the multistage random cluster sampling method in Anhui Province, China. Participants were required to complete self-report questionnaires regarding CM experience, self-perceived PA and BPF. Mediation analyses were computed via structural equation modelling. RESULTS: CM victimization was positively associated with BPF, and individuals with lower levels of PA were more likely to present with BPF. Mediation analysis showed a significant indirect effect of CM on BPF via PA (effect = 0.047, 95 % CI: 0.035, 0.058). LIMITATION: The cross-sectional design of this study did not allow testing causality. The retrospective investigation of CM history could cause recall bias. CONCLUSIONS: PA partially mediates the relationship between CM and BPF. These findings have important implications for considering PA as a protective factor in this relationship.


Assuntos
Transtorno da Personalidade Borderline , Maus-Tratos Infantis , Adolescente , Transtorno da Personalidade Borderline/psicologia , Criança , Maus-Tratos Infantis/psicologia , Estudos Transversais , Ajustamento Emocional , Humanos , Estudos Retrospectivos
7.
Front Behav Neurosci ; 15: 706660, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34566593

RESUMO

Gene-by-environment interactions influence brain development from conception to adulthood. In particular, the prenatal period is a window of vulnerability for the interplay between environmental and genetic factors to influence brain development. Rodent and human research demonstrates that prenatal maternal stress (PNMS) alters hippocampal volumes. Although PNMS affects hippocampal size on average, similar degrees of PNMS lead to different effects in different individuals. This differential susceptibility to the effects of PNMS may be due to genetic variants. Hence, we investigated the role of genetic variants of two SNPs that are candidates to moderate the effects of PNMS on hippocampal volume: COMT (rs4680) and BDNF (rs6265). To investigate this, we assessed 53 children who were in utero during the January 1998 Quebec ice storm. In June 1998 their mothers responded to questionnaires about their objective, cognitive, and subjective levels of stress from the ice storm. When children were 11 1/2 years old, T1-weighted structural magnetic resonance imaging (MRI) scans were obtained using a 3T scanner and analyzed to determine hippocampal volumes. We collected and genotyped the children's saliva DNA. Moderation analyses were conducted to determine whether either or both of the SNPs moderate the effect of PNMS on hippocampal volumes. We found that objective hardship was associated with right hippocampal volume in girls, and that the BDNF and COMT genotypes were associated with left hippocampal volume in boys and girls. In addition, SNPs located on COMT moderated the effect of maternal objective distress in boys, and subjective distress in girls, on both right hippocampal volume. Thus, we conclude that an individual's genotype alters their susceptibility to the effects of PNMS.

8.
Cells ; 10(9)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34572069

RESUMO

Epigenetic changes are associated with altered behavior and neuropsychiatric disorders and they modify the trajectory of aging. Maternal anxiety during pregnancy is a common environmental challenge for the fetus, causing changes in DNA methylation. Here, we determined the mediating role of DNA methylation and the moderating role of offspring sex on the association between maternal anxiety and children's behavioral measures. In 83 mother-child dyads, maternal anxiety was assessed in each trimester of pregnancy when the child was four years of age. Children's behavioral measures and children's buccal DNA methylation levels (NR3C1, IGF2/H19 ICR, and LINE1) were examined. Higher maternal anxiety during the third trimester was associated with more methylation levels of the NR3C1. Moderating effects of sex on the association between maternal anxiety and methylation were found for IGF2/H19 and LINE1 CpGs. Mediation analysis showed that methylation of NR3C1 could buffer the effects of maternal anxiety on children's behavioral measures, but this effect did not remain significant after controlling for covariates. In conclusion, our data support an association between maternal anxiety during pregnancy and DNA methylation. The results also underscore the importance of sex differences and timing effects. However, DNA methylation as underlying mechanism of the effect of maternal anxiety during pregnancy on offspring's behavioral measures was not supported.


Assuntos
Ansiedade/fisiopatologia , Metilação de DNA , Epigênese Genética , Mães/psicologia , Mucosa Bucal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Comportamento Problema/psicologia , Pré-Escolar , Depressão/fisiopatologia , Feminino , Humanos , Lactente , Fator de Crescimento Insulin-Like II/genética , Elementos Nucleotídeos Longos e Dispersos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , RNA Longo não Codificante/genética , Fatores Sexuais
9.
Child Neurol Open ; 8: 2329048X211027438, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368388

RESUMO

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

10.
Toxics ; 9(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800341

RESUMO

The potent neurotoxicity of benzo[a]pyrene (B[a]P) has been suggested to be a susceptibility factor accelerating the onset of brain tumours and the emergence of neurobehavioural disturbances. B[a]P has been shown to be neurotoxic, acting directly on both the central and peripheral nervous systems, as well as indirectly via peripheral organs like liver and gut. By using a realistic B[a]P exposure scenario (0.02-200 mg/kg/day, 10 days) in mice, we elucidated brain-specific B[a]P metabolism and at identified hydroxylated B[a]P metabolites in serum which could be used as markers of cognitive impairment. Repeated oral administration of B[a]P led to, at the doses of 20 and 200 mg/kg/day, significant overexpression of Cyp1a1/Cyp1b1 in 2 out of the 3 brain regions considered, thereby suggesting the ability of the brain to metabolize B[a]P itself. At the same doses, mice exhibited a reduction in anxiety in both the elevated plus maze and the hole board apparatus. Concomitantly, B[a]P triggered dose-dependent changes in Nmda subunit expression (Nr1 and Nr2a/Nr2b) in areas involved in cognition. We detected 9-OH-B[a]P and 7,8-diol-B[a]P in serum at the level for which cognitive impairment was observed. We suggest that these metabolites may, in the future be exploited as potent biomarkers of B[a]P-induced cognitive impairments.

11.
BMC Res Notes ; 12(1): 174, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909978

RESUMO

OBJECTIVE: Exposure to stress during pregnancy may program susceptibility to the development of obesity in offspring. Our goal was to determine whether prenatal maternal stress (PNMS) due to a natural disaster was associated with child obesity, and to compare the DNA methylation profiles in obese versus non-obese children at age 13½ years. Women and their children were involved in the longitudinal natural disaster study-Project Ice Strom, which served as a human model to study PNMS. Blood was collected from 31 children (including five obese children). Infinium HumanMethylation450 BeadChip Array was performed for genome-wide DNA methylation analyses. RESULTS: Results demonstrated a well-defined obesity-associated genome-wide DNA methylation pattern. There were 277 CpGs, corresponding to 143 genes, were differentially-methylated. IPA analyses revealed 51 canonical pathways, and enrichment of pathways was involved in immune function. Although no significant association was found between PNMS and child obesity, the preliminary data in the study revealed obesity-associated methylation patterns on a genome-wide level in children.


Assuntos
Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Obesidade Infantil/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/complicações , Adolescente , Adulto , Ilhas de CpG , Feminino , Humanos , Estudos Longitudinais , Masculino , Mães , Desastres Naturais , Obesidade Infantil/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia
12.
Dev Psychopathol ; 31(4): 1395-1409, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30394245

RESUMO

The 5-HTTLPR polymorphism of the serotonin transporter has been shown to play a role in autism spectrum disorders (ASD). Moreover, disaster-related prenatal maternal stress (PNMS) has also been shown to be associated with ASD. However, no study to date has examined whether these two factors, either individually or in combination, are predictive of ASD traits in the same sample. We hypothesized that children, particularly boys, with the LL genotype exposed to high levels of disaster-related PNMS would exhibit higher levels of ASD traits compared to boys with the LS or SS genotypes and girls regardless of genotype. Genotype and ASD levels obtained using the Australian normed Autism Spectrum Rating Scales - Short Form were available for 105 30-month-old children exposed to varying levels of PNMS following the 2011 Queensland Flood. For boys, higher ASD traits were associated with the 5-HTTLPR LL genotype in combination with either a negative maternal appraisal of the flood, or high levels of maternal composite subjective stress, PSTD-like or peritraumatic dissociation symptoms. For girls, maternal peritraumatic dissociation levels in combination with the 5-HTTLPR LS or SS genotype were associated with higher ASD traits. The present findings are the first to demonstrate that children's genotype moderates effects of disaster-related PNMS on ASD traits, with different pattern according to child sex.


Assuntos
Transtorno do Espectro Autista/etiologia , Desastres , Inundações , Polimorfismo de Nucleotídeo Único , Efeitos Tardios da Exposição Pré-Natal/etiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/complicações , Austrália , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Pré-Escolar , Família , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/psicologia , Queensland , Fatores Sexuais , Estresse Psicológico/psicologia
13.
PLoS One ; 13(2): e0192199, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29401509

RESUMO

Animal and human studies suggest that prenatal exposure to stress is associated with adverse health outcomes such as type 2 diabetes. Epigenetic modification, such as DNA methylation, is considered one possible underlying mechanism. The 1998 Quebec ice storm provides a unique opportunity to study an independent prenatal stressor on child outcomes. C-peptide is the best measure of endogenous insulin secretion and is widely used in the clinical management of patients with diabetes. The objectives of this study are to determine 1) the extent to which prenatal exposure to disaster-related stress (maternal objective hardship and maternal cognitive appraisal) influences children's C-peptide secretion, and 2) whether DNA methylation of diabetes-related genes mediates the effects of prenatal stress on C-peptide secretion. Children's (n = 30) C-peptide secretion in response to an oral glucose tolerance test were assessed in blood at 13½ years. DNA methylation levels of selected type 1 and 2 diabetes-related genes were chosen based upon the genes associated with prenatal maternal objective hardship and/or cognitive appraisal levels. Bootstrapping analyses were performed to determine the mediation effect of DNA methylation. We found that children whose mothers experienced higher objective hardship exhibited higher C-peptide secretion. Cognitive appraisal was not directly associated with C-peptide secretion. DNA methylation of diabetes-related genes had a positive mediation effect of objective hardship on C-peptide secretion: higher objective hardship predicted higher C-peptide secretion through DNA methylation. Negative mediation effects of cognitive appraisal were observed: negative cognitive appraisal predicted higher C-peptide secretion through DNA methylation. However, only one gene, LTA, remained a significant mediator of cognitive appraisal on C-peptide secretion after the conservative Bonferroni multiple corrections. Our findings suggest that DNA methylation could act as an intervening variable between prenatal stress and metabolic outcomes, highlighting the importance of epigenetic mechanisms in response to environmental factors.


Assuntos
Peptídeo C/metabolismo , Cognição , Metilação de DNA , Desastres , Mães/psicologia , Adolescente , Criança , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal
14.
Early Hum Dev ; 103: 189-192, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27718477

RESUMO

We determined the extent to which DNA methylation mediates the effects of maternal cognitive appraisal of a natural disaster during pregnancy on offspring growth at age 13. Negative maternal cognitive appraisal predicted both lower BMI and central adiposity via DNA methylation of diabetes-related genes, suggesting a protective role of epigenetics.


Assuntos
Adiposidade , Atitude , Índice de Massa Corporal , Metilação de DNA , Desastres , Complicações na Gravidez/psicologia , Estresse Psicológico/epidemiologia , Cognição , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Estresse Psicológico/genética
15.
Clin Epigenetics ; 8: 54, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27182285

RESUMO

BACKGROUND: Prenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effect of objective PNMS on Th1 and Th2 cytokine production in blood from 13½ year olds who were exposed in utero to the 1998 Quebec ice storm. RESULTS: Bootstrapping analyses were performed with 47 CpGs across a selection of 20 genes for Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-4 and IL-13). Six CpGs in six different NF-κB signaling genes (PIK3CD, PIK3R2, NFKBIA, TRAF5, TNFRSF1B, and LTBR) remained as significant negative mediators of objective PNMS on IFN-γ secretion after correcting for multiple comparisons. However, no mediation effects on IL-2, IL-4 and IL-13 survived Bonferroni correction. CONCLUSIONS: The present study provides preliminary evidence supporting the mediating role of DNA methylation in the association between objective aspects of PNMS and child immune states, favoring a Th2 shift.


Assuntos
Citocinas/genética , Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/psicologia , Adolescente , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Exposição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Transdução de Sinais
16.
Epigenetics ; 10(8): 749-61, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26098974

RESUMO

Prenatal maternal stress (PNMS) in animals and humans predicts obesity and metabolic dysfunction in the offspring. Epigenetic modification of gene function is considered one possible mechanism by which PNMS results in poor outcomes in offspring. Our goal was to determine the role of maternal objective exposure and subjective distress on child BMI and central adiposity at 13½ years of age, and to test the hypothesis that DNA methylation mediates the effect of PNMS on growth. Mothers were pregnant during the January 1998 Quebec ice storm. We assessed their objective exposure and subjective distress in June 1998. At age 13½ their children were weighed and measured (n = 66); a subsample provided blood samples for epigenetic studies (n = 31). Objective and subjective PNMS correlated with central adiposity (waist-to-height ratio); only objective PNMS predicted body mass index (BMI). Bootstrapping analyses showed that the methylation level of genes from established Type-1 and -2 diabetes mellitus pathways showed significant mediation of the effect of objective PNMS on both central adiposity and BMI. However, the negative mediating effects indicate that, although greater objective PNMS predicts greater BMI and adiposity, this effect is dampened by the effects of objective PNMS on DNA methylation, suggesting a protective role of the selected genes from Type-1 and -2 diabetes mellitus pathways. We provide data supporting that DNA methylation is a potential mechanism involved in the long-term adaptation and programming of the genome in response to early adverse environmental factors.


Assuntos
Metilação de DNA/genética , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/genética , Adiposidade/genética , Adolescente , Índice de Massa Corporal , Feminino , Humanos , Masculino , Exposição Materna , Obesidade/sangue , Obesidade/etiologia , Obesidade/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Quebeque , Estresse Psicológico/sangue , Estresse Psicológico/patologia
17.
PLoS One ; 9(9): e107653, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25238154

RESUMO

BACKGROUND: Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is hampered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress. METHODS: Five months after the 1998 Quebec ice storm we recruited women who had been pregnant during the disaster and assessed their degrees of objective hardship and subjective distress. Thirteen years later, we investigated DNA methylation profiling in T cells obtained from 36 of the children, and compared selected results with those from saliva samples obtained from the same children at age 8. RESULTS: Prenatal maternal objective hardship was correlated with DNA methylation levels in 1675 CGs affiliated with 957 genes predominantly related to immune function; maternal subjective distress was uncorrelated. DNA methylation changes in SCG5 and LTA, both highly correlated with maternal objective stress, were comparable in T cells, peripheral blood mononuclear cells (PBMCs) and saliva cells. CONCLUSIONS: These data provide first evidence in humans supporting the conclusion that PNMS results in a lasting, broad, and functionally organized DNA methylation signature in several tissues in offspring. By using a natural disaster model, we can infer that the epigenetic effects found in Project Ice Storm are due to objective levels of hardship experienced by the pregnant woman rather than to her level of sustained distress.


Assuntos
Metilação de DNA , Desastres , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Criança , Epigênese Genética , Feminino , Humanos , Masculino , Gravidez
18.
J Psychiatr Res ; 47(11): 1597-607, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23948638

RESUMO

Glucocorticoids and the glucocorticoid (GR) and mineralocorticoid (MR) receptors have been implicated in many processes, particularly in negative feedback regulation of the hypothalamic-pituitary-adrenal axis. Epigenetically programmed GR alternative promoter usage underlies transcriptional control of GR levels, generation of GR 3' splice variants, and the overall GC response in the brain. No detailed analysis of GR first exons or GR transcript variants throughout the human brain has been reported. Therefore we investigated post mortem tissues from 28 brain regions of 5 individuals. GR first exons were expressed throughout the healthy human brain with no region-specific usage patterns. First exon levels were highly inter-correlated suggesting that they are co-regulated. GR 3' splice variants (GRα and GR-P) were equally distributed in all regions, and GRß expression was always low. GR/MR ratios showed significant differences between the 28 tissues with the highest ratio in the pituitary gland. Modification levels of individual CpG dinucleotides, including 5-mC and 5-hmC, in promoters 1D, 1E, 1F, and 1H were low, and diffusely clustered; despite significant heterogeneity between the donors. In agreement with this clustering, sum modification levels rather than individual CpG modifications correlated with GR expression. Two-way ANOVA showed that this sum modification was both promoter and brain region specific, but that there was however no promoter*tissue interaction. The heterogeneity between donors may however hide such an interaction. In both promoters 1F and 1H modification levels correlated with GRα expression suggesting that 5-mC and 5-hmC play an important role in fine tuning GR expression levels throughout the brain.


Assuntos
Encéfalo/metabolismo , Fosfatos de Dinucleosídeos/genética , Expressão Gênica/fisiologia , Regiões Promotoras Genéticas/fisiologia , Receptores de Glucocorticoides/metabolismo , Adulto , Análise de Variância , Encéfalo/anatomia & histologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Adulto Jovem
19.
Hum Genet ; 129(5): 533-43, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21234764

RESUMO

Glucocorticoid receptor levels are thought to be controlled by multiple alternative first exons. Seven of these exons are located in an upstream CpG island. In this study, we investigated the promoter activity of the intronic regions between these exons, and their susceptibility to CpG methylation and sequence variability. The seven promoters were cloned into luciferase reporter genes, and their activity measured in ten cell lines. CpG islands of 221 donors were genotyped and the effects of these SNPs were investigated in a reporter gene assay. We showed that each of the first exons was independently controlled by a unique promoter located directly upstream. Promoter activities were cell type-specific, and varied considerably between cell types. Irrespective of the cell type, in vitro methylation effectively silenced all reporter constructs. Eleven SNPs were observed within the CpG island of 221 donors, and a new promoter-specific haplotype was revealed. Four of the minor alleles reduced the reporter gene activity, with cell type specific effects. This complexity within the CpG island helps to explain the variable, tissue-specific transcriptional control of the GR, and provides insight into the mechanisms underlying tissue specific deregulation of GR levels.


Assuntos
Regiões Promotoras Genéticas/genética , Receptores de Glucocorticoides/genética , Transcrição Gênica/genética , Sequência de Bases , Linhagem Celular , Ilhas de CpG/genética , Éxons , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único
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