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1.
Sci Rep ; 11(1): 3265, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547360

RESUMO

Glyphosate-based herbicides (GBHs) can disrupt the host microbiota and influence human health. In this study, we explored the potential effects of GBHs on urinary metabolites and their interactions with gut microbiome using a rodent model. Glyphosate and Roundup (equal molar for glyphosate) were administered at the USA glyphosate ADI guideline (1.75 mg/kg bw/day) to the dams and their pups. The urine metabolites were profiled using non-targeted liquid chromatography-high resolution mass spectrometry (LC-HRMS). Our results found that overall urine metabolite profiles significantly differed between dams and pups and between female and male pups. Specifically, we identified a significant increase of homocysteine, a known risk factor of cardiovascular disease in both Roundup and glyphosate exposed pups, but in males only. Correlation network analysis between gut microbiome and urine metabolome pointed to Prevotella to be negatively correlated with the level of homocysteine. Our study provides initial evidence that exposures to commonly used GBH, at a currently acceptable human exposure dose, is capable of modifying urine metabolites in both rat adults and pups. The link between Prevotella-homocysteine suggests the potential role of GBHs in modifying the susceptibility of homocysteine, which is a metabolite that has been dysregulated in related diseases like cardiovascular disease or inflammation, through commensal microbiome.

2.
Genet Epidemiol ; 44(8): 924-933, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32710482

RESUMO

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

3.
Environ Int ; 137: 105508, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007686

RESUMO

BACKGROUND/AIM: Selenium (Se) levels in pregnancy have been linked to neurobehavioral development of the offspring. DNA methylation is a potential mechanism underlying the impacts of environmental exposures on fetal development; however, very few studies have been done elucidating the role of DNA methylation linking prenatal Se and child neurobehavior. We aimed to investigate the associations between placental Se concentration and epigenome-wide DNA methylation in two U.S. cohorts, and to assess the association between Se-related DNA methylation modifications and newborns' neurobehavior. METHODS: We measured placental Se concentrations in 343 newborns enrolled in the New Hampshire Birth Cohort Study and in 141 newborns in the Rhode Island Child Health Study. Genome-wide placental DNA methylation was measured by HumanMethylation450 BeadChip, and newborn neurobehavioral development was assessed by the NICU Network Neurobehavioral Scales (NNNS). We meta-analyzed the associations between placental Se concentration and DNA methylation in each cohort, adjusting for covariates. We also fit multiple linear regression and ordinal logistic regression for methylation and newborn NNNS summary scores. RESULTS: We identified five Se-related differentially methylated CpG sites. Among them was cg09674502 (GFI1), where selenium concentration was positively associated with methylation (ß-coefficient = 1.11, FDR-adjusted p-value = 0.045), and where we observed that a one percent methylation level increase was associated with a 15% reduced odds of higher muscle tone in the arms, legs and trunk of newborns, (OR [95% Confidence Interval, CI] = 0.85 [0.77, 0.95]). We also observed for each interquartile range (IQR) increase in selenium concentration in the placenta, there was 1.76 times greater odds of higher hypotonicity (OR [95% CI] = 1.76 [1.12, 2.82]). CONCLUSIONS: Placental selenium concentration was inversely associated with muscle tone of newborns, and hypermethylation of GFI1 could be a potential mechanism underlying this association.


Assuntos
Metilação de DNA , Epigênese Genética , Comportamento do Lactente , Sistema Nervoso , Placenta , Selênio , Criança , Estudos de Coortes , Epigenoma , Feminino , Humanos , Comportamento do Lactente/efeitos dos fármacos , Recém-Nascido , Sistema Nervoso/efeitos dos fármacos , New Hampshire , Gravidez , Selênio/toxicidade
4.
Mol Cell Endocrinol ; 505: 110739, 2020 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004678

RESUMO

BACKGROUND: Maternal diet is an important factor in prenatal development that also has implications for disease risk later in life. The adipokine leptin is a key regulator of energy homeostasis and may be involved in the association between maternal nutrition, maternal obesity, and infant outcomes. DNA methylation of placenta genes may occur in response to exposures and may program subsequent infant development. This study examined maternal diet, placenta leptin gene DNA methylation, and neonatal growth in a sample of healthy neonates and their mothers. METHODS: Mothers and their healthy neonates (N = 135) were recruited within 1-2 days following delivery at Women and Infants Hospital in Providence, RI. A structured interview was conducted to assess maternal dietary intake. Maternal pre-pregnancy weight, weight gain during pregnancy, maternal health, medications, and vitamin use were obtained from medical records. Bisulfite pyrosequencing was used to measure methylation of CpG sites in the promoter region of the placenta leptin gene and determine genotype of the leptin single nucleotide polymorphism (SNP) rs2167270, which is known to influence leptin methylation. Bivariate analyses and linear regression models were used to evaluate associations of demographics, diet, and mean leptin methylation. RESULTS: Genotype was a significant predictor of placenta leptin DNA methylation (p < .01), and after controlling for this and other relevant maternal and infant covariates, lower levels of leptin methylation were significantly associated with greater intake of carbohydrates (p < .05), in particular added sugars (p < .05) and white/refined carbohydrates (p < .05). Total caloric intake was also associated with placenta leptin methylation (p < .05), however after controlling for relevant covariates, significance diminished to trend-level. There were no significant associations of placenta leptin methylation and intake of protein (p > .05) or fat (p > .05). CONCLUSION: These findings underline the importance of intake of carbohydrate consumption for methylation of the placenta leptin gene. Because methylation reduces gene transcription, lower methylation may indicate a placenta response to high caloric intake and carbohydrate food that would result in higher levels of this hormone during fetal development. Further investigation of the developmental ramifications of epigenetic changes to placenta leptin methylation should be pursued.

6.
Environ Int ; 132: 105012, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31402058

RESUMO

BACKGROUND: Hepato- and nephrotoxicity of fluoride have been demonstrated in animals, but few studies have examined potential effects in humans. This population-based study examines the relationship between chronic low-level fluoride exposure and kidney and liver function among United States (U.S.) adolescents. This study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver parameters among U.S. youth. METHODS: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2013-2016). We analyzed data from 1983 and 1742 adolescents who had plasma and water fluoride measures respectively and did not have kidney disease. Fluoride was measured in plasma and household tap water. Kidney parameters included estimated glomerular filtration rate (calculated by the original Schwartz formula), serum uric acid, and the urinary albumin to creatinine ratio. Liver parameters were assessed in serum and included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase, and albumin. Survey-weighted linear regression examined relationships between fluoride exposure and kidney and liver parameters after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons. RESULTS: The average age of adolescents was 15.4 years. Median water and plasma fluoride concentrations were 0.48 mg/L and 0.33 µmol/L respectively. A 1 µmol/L increase in plasma fluoride was associated with a 10.36 mL/min/1.73 m2 lower estimated glomerular filtration rate (95% CI: -17.50, -3.22; p = 0.05), a 0.29 mg/dL higher serum uric acid concentration (95% CI: 0.09, 0.50; p = 0.05), and a 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: -1.87, -0.70; p < 0.001). A 1 mg/L increase in water fluoride was associated with a 0.93 mg/dL lower blood urea nitrogen concentration (95% CI: -1.44, -0.42; p = 0.007). CONCLUSIONS: Fluoride exposure may contribute to complex changes in kidney and liver related parameters among U.S. adolescents. As the study is cross-sectional, reverse causality cannot be ruled out; therefore, altered kidney and/or liver function may impact bodily fluoride absorption and metabolic processes.


Assuntos
Fluoretos/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Adolescente , Aspartato Aminotransferases/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Feminino , Fluoretos/metabolismo , Taxa de Filtração Glomerular , Humanos , Lactente , Recém-Nascido , Rim/metabolismo , Testes de Função Renal , Modelos Lineares , Fígado/metabolismo , Masculino , Minerais , Inquéritos Nutricionais , Estados Unidos , Ácido Úrico/sangue , Adulto Jovem , gama-Glutamiltransferase/metabolismo
7.
Environ Health ; 18(1): 15, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30857531

RESUMO

BACKGROUND: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats. METHODS: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups. RESULTS: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure. CONCLUSIONS: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Canal Anal/anatomia & histologia , Canal Anal/efeitos dos fármacos , Animais , Sistema Endócrino/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Feminino , Genitália Feminina/anatomia & histologia , Genitália Feminina/efeitos dos fármacos , Genitália Masculina/anatomia & histologia , Genitália Masculina/efeitos dos fármacos , Glicina/toxicidade , Humanos , Masculino , Troca Materno-Fetal , Projetos Piloto , Gravidez , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacos , Testosterona/sangue , Tireotropina/sangue , Testes de Toxicidade Subcrônica
8.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
9.
Curr Environ Health Rep ; 5(4): 531-543, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30267228

RESUMO

PURPOSE OF REVIEW: Herein, we summarize existent epidemiological studies relating adverse maternal metabolic environments of maternal obesity and gestational diabetes and placental DNA methylation. RECENT FINDINGS: Multiple studies have evaluated associations between intrauterine exposure to gestational diabetes and/or maternal glucose levels and DNA methylation at candidate metabolic genes as well as in epigenome-wide studies. Some of the genomic regions more consistently associated include lipid-related genes (LPL and PPARGC1A), the major histocompatibility complex (MHC), and imprinted genes. Studies solely focused on maternal obesity influences on the placental epigenome are scarce. Understanding the placental mechanisms involved in fetal metabolic programming could lead to discovery of placental biomarkers at birth that predict later-life metabolic risk. Moving forward is important to standardize methods utilized in epigenetics research; consistent methodology can help interpret disparate findings. Larger studies with longitudinal follow-up are needed to address future challenges in fetal programming research.


Assuntos
Metilação de DNA/genética , Diabetes Gestacional/metabolismo , Desenvolvimento Fetal/genética , Placenta/metabolismo , Epigênese Genética , Epigenômica , Feminino , Humanos , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Gravidez
10.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
11.
Environ Health ; 17(1): 50, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29843725

RESUMO

BACKGROUND: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including its effects on microbiome. The present pilot study examines whether exposure to GBHs at doses of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero, may modify the composition of gut microbiome in Sprague Dawley (SD) rats. METHODS: Glyphosate alone and Roundup, a commercial brand of GBHs, were administered in drinking water at doses comparable to the US glyphosate ADI (1.75 mg/kg bw/day) to F0 dams starting from the gestational day (GD) 6 up to postnatal day (PND) 125. Animal feces were collected at multiple time points from both F0 dams and F1 pups. The gut microbiota of 433 fecal samples were profiled at V3-V4 region of 16S ribosomal RNA gene and further taxonomically assigned and assessed for diversity analysis. We tested the effect of exposure on overall microbiome diversity using PERMANOVA and on individual taxa by LEfSe analysis. RESULTS: Microbiome profiling revealed that low-dose exposure to Roundup and glyphosate resulted in significant and distinctive changes in overall bacterial composition in F1 pups only. Specifically, at PND31, corresponding to pre-pubertal age in humans, relative abundance for Bacteriodetes (Prevotella) was increased while the Firmicutes (Lactobacillus) was reduced in both Roundup and glyphosate exposed F1 pups compared to controls. CONCLUSIONS: This study provides initial evidence that exposures to commonly used GBHs, at doses considered safe, are capable of modifying the gut microbiota in early development, particularly before the onset of puberty. These findings warrant future studies on potential health effects of GBHs in early development such as childhood.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Glicina/análogos & derivados , Herbicidas/efeitos adversos , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Glicina/efeitos adversos , Masculino , Projetos Piloto , Ratos , Ratos Sprague-Dawley
12.
Clin Epigenetics ; 9: 56, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28572860

RESUMO

BACKGROUND: Numerous pulmonary diseases manifest with upper lobe predominance including cystic fibrosis, smoking-related chronic obstructive pulmonary disease, and tuberculosis. Zonal hypoxia, characteristic of these pulmonary maladies, and oxygen stress in general is known to exert profound effects on various important aspects of cell biology. Lung macrophages are major participants in the pulmonary innate immune response and regional differences in macrophage responsiveness to hypoxia may contribute in the development of lung disease. MicroRNAs are ubiquitous regulators of human biology and emerging evidence indicates altered microRNA expression modulates respiratory disease processes. The objective of this study is to gain insight into the epigenetic and cellular mechanisms influencing regional differences in lung disease by investigating effect of hypoxia on regional microRNA expression in the lung. All studies were performed using primary alveolar macrophages (n = 10) or bronchoalveolar lavage fluid (n = 16) isolated from human subjects. MicroRNA was assayed via the NanoString nCounter microRNA assay. RESULTS: Divergent molecular patterns of microRNA expression were observed in alternate lung lobes, specifically noted was disparate expression of miR-93 and miR-4454 in alveolar macrophages along with altered expression of miR-451a and miR-663a in bronchoalveolar lavage fluid. Gene ontology was used to identify potential downstream targets of divergent microRNAs. Targets include cytokines and matrix metalloproteinases, molecules that could have a significant impact on pulmonary inflammation and fibrosis. CONCLUSIONS: Our findings show variant regional microRNA expression associated with hypoxia in alveolar macrophages and BAL fluid in the lung-upper vs lower lobe. Future studies should address whether these specific microRNAs may act intracellularly, in a paracrine/endocrine manner to direct the innate immune response or may ultimately be involved in pulmonary host-to-pathogen trans-kingdom cross-talk.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Redes Reguladoras de Genes , Macrófagos Alveolares/imunologia , MicroRNAs/genética , Líquido da Lavagem Broncoalveolar/química , Hipóxia Celular , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Macrófagos Alveolares/química , Masculino , Adulto Jovem
13.
Nat Genet ; 48(12): 1544-1550, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749845

RESUMO

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.


Assuntos
Marcadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Neoplasias Bucais/genética , Infecções por Papillomavirus/genética , Neoplasias Faríngeas/genética , Idoso , Estudos de Casos e Controles , Feminino , Antígenos HLA , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Boca/metabolismo , Boca/patologia , Boca/virologia , Neoplasias Bucais/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Neoplasias Faríngeas/virologia
14.
Epigenetics ; 11(8): 603-13, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27366929

RESUMO

The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 × 10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.


Assuntos
Desenvolvimento Infantil , Metilação de DNA , Epigênese Genética , Placenta/metabolismo , Hidrolases Anidrido Ácido/genética , Adolescente , Adulto , Atenção , Ilhas de CpG , Feminino , Humanos , Recém-Nascido , Masculino , Movimento , Proteínas de Neoplasias/genética , Transtornos do Neurodesenvolvimento/genética , Gravidez , Proteínas Repressoras/genética
15.
Paediatr Perinat Epidemiol ; 30(4): 367-75, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27004434

RESUMO

BACKGROUND: Identifying the prenatal origins of mental conditions is of increasing interest, yet most studies have focused on high-risk populations and cannot disentangle prenatal and postnatal programming effects. Thus, we examined whether profiles of neurobehaviour indicative of future risk could be identified in healthy 1-3-day-old infants, and examined associations with perinatal risk factors. METHODS: Participants included 627 healthy mothers and term infants from a population-based US cohort. Neurobehaviour was assessed within 24-72 h after delivery with the NICU Network Neurobehavioural Scales (NNNS). A model-based clustering algorithm was used to derive neurobehavioural profiles from NNNS scores. Maternal health histories, pregnancy conditions and behaviours, labour/delivery factors, and infant attributes were examined in relation to the neurobehavioural profiles. RESULTS: Seven discrete neurobehavioural profiles were identified, including one average functioning profile, and two inversely patterned below and above average profiles. Higher pregnancy weight gain (OR 1.44, 95% CI 1.10, 1.88) and birthweight percentiles (OR 1.46, 95% CI 1.10, 1.95) were associated with greater odds of below average newborn neurobehaviour. Above average neurobehaviour was associated with experiencing longer gestations (OR 1.29, 95% CI 1.02, 1.64) and higher 5-min APGAR scores (OR 2.43, 95% CI 1.07, 5.52). Maternal pregnancy alcohol use (OR 0.54, 95% CI 0.33, 0.89), and fetal distress (OR 0.10, 95% CI 0.01, 0.72) were associated with lower likelihood of having average neurobehaviour. CONCLUSION: Distinct profiles of neurobehaviour can be derived in a healthy population of newborns, with different sets of perinatal factors predicting different patterns of neurobehaviour. These findings suggest a potential in utero origin for mental health risk.


Assuntos
Cognição/fisiologia , Saúde , Comportamento do Lactente/fisiologia , Exame Neurológico , Efeitos Tardios da Exposição Pré-Natal , Nascimento a Termo/fisiologia , Adulto , Algoritmos , Índice de Apgar , Peso ao Nascer , Feminino , Sofrimento Fetal , Idade Gestacional , Humanos , Recém-Nascido , Trabalho de Parto , Masculino , Idade Materna , Gravidez , Rhode Island , Ganho de Peso
16.
Epigenomics ; 7(5): 767-79, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26343289

RESUMO

AIM: To determine associations between methylation of NR3C1, HSD11B2, FKBP5 and ADCYAP1R1 and newborn neurobehavioral outcomes. METHODS: In 537 newborns, placental methylation was quantified using bisulfite pyrosequencing. Profiles of neurobehavior were derived via the Neonatal Intensive Care Unit Network Neurobehavioral Scales. Using exploratory factor analysis, the relationships between methylation factor scores and neurobehavioral profiles were examined. RESULTS: Increased scores of the factor characterized by NR3C1 methylation were associated with membership in a reactive, poorly regulated profile (odds ratio: 1.47; 95% CI: 1.00-2.18), while increased scores of the factor characterized by HSD11B2 methylation reduced this risk. CONCLUSION: These results suggest that coordinated regulation of these genes influences neurobehavior and demonstrates the importance of examining these alterations in a harmonized fashion.


Assuntos
Epigênese Genética/genética , Epigenômica/métodos , Glucocorticoides/metabolismo , Sistema Nervoso/metabolismo , Placenta/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Adolescente , Adulto , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética/efeitos dos fármacos , Feminino , Idade Gestacional , Glucocorticoides/farmacologia , Humanos , Comportamento do Lactente/efeitos dos fármacos , Comportamento do Lactente/fisiologia , Recém-Nascido , Masculino , Idade Materna , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/crescimento & desenvolvimento , Gravidez , Receptores de Glucocorticoides/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Análise de Regressão , Proteínas de Ligação a Tacrolimo/genética , Adulto Jovem
17.
Clin Epigenetics ; 7: 79, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26244062

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) affects approximately 10 % of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM. RESULTS: To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 BeadChips) and expression (Affymetrix transcriptome microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex (MHC) region, which were validated in an independent cohort, the Rhode Island Child Health Study. Gene ontology enrichment among gene regulation influenced by GDM revealed an over-representation of immune response pathways among differential expression, reflecting these coordinated changes in the MHC region. This differential methylation and expression may be capturing shifts in cellular composition, reflecting physiological changes in the placenta associated with GDM. CONCLUSIONS: Our study represents the largest investigation of transcriptomic and methylomic differences associated with GDM, providing comprehensive insight into how GDM shapes the intrauterine environment, which may have implications for fetal (re)programming.

18.
Dev Psychopathol ; 27(2): 577-85, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25997773

RESUMO

Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic-pituitary-adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1(D), 1(F), and 1(H) of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1(D) and 1(F) in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.


Assuntos
Maus-Tratos Infantis , Metilação de DNA , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/genética , Pré-Escolar , Epigênese Genética , Éxons , Feminino , Humanos , Masculino
19.
Biol Reprod ; 92(6): 149, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25788665

RESUMO

Maternal stress has been linked to infant birth weight outcomes, which itself may be associated with health later in life. The placenta acts as a master regulator for the fetal environment, mediating intrauterine exposures to stress through the activity of genes regulating glucocorticoids, including the 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1 and 2 genes, and so we hypothesized that variation in these genes will be associated with infant birth weight. We investigated DNA methylation levels at six sites across the two genes, as well as mRNA expression for each, and the relationship to infant birth weight. Logistic regressions correcting for potential confounding factors revealed a significant association between methylation at a single CpG site within HSD11B1 and being born large for gestational age. In addition, our analysis identified correlations between methylation and gene expression, including sex-specific transcriptional regulation of HSD11B2. Our work is one of the first comprehensive views of DNA methylation and expression in the placenta for both HSD11B types 1 and 2, linking epigenetic alterations with the regulation of fetal stress and birth weight outcomes.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Peso ao Nascer/genética , Metilação de DNA , Expressão Gênica , Placenta/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Adolescente , Adulto , Feminino , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Masculino , Gravidez , Regiões Promotoras Genéticas , Adulto Jovem
20.
Psychoneuroendocrinology ; 52: 32-42, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25459891

RESUMO

Infant neurobehavior, a potential sentinel of future mental and behavioral morbidity characterized in part by reflex symmetry, excitability and habituation to stimuli, is influenced by aspects of the intrauterine environment partially through epigenetic alterations of genes involved in the stress response. DNA methylation of two related cortisol response genes, the glucocorticoid receptor (NR3C1), a nuclear receptor to which cortisol binds, and 11-beta hydroxysteroid dehydrogenase (HSD11B2), the enzyme responsible for conversion of cortisol into inactive cortisone, independently associate with infant neurobehavior. Although these factors are part of a common cortisol regulation pathway, the combined effect of DNA methylation of these factors on infant neurobehavior has not been characterized. Therefore, we conducted an examination of the joint contribution of NR3C1 and HSD11B2 DNA methylation on infant neurobehavior. Among 372 healthy term newborns, we tested the interaction between placental NR3C1 and HSD11B2 DNA methylation in association with neurobehavior as assessed with the validated NICU Network Neurobehavioral Scales. Controlling for confounders, interactions between DNA methylation of these genes were detected for distinct domains of neurobehavior (habituation, excitability, asymmetrical reflexes). Moreover, different patterns of DNA methylation across the cortisol regulation pathway associated with different neurobehavioral phenotypes. Those with low NR3C1 methylation but high HSD11B2 methylation had lower excitability scores; those with high NR3C1 methylation but low HSD11B2 methylation had more asymmetrical reflexes; those with high DNA methylation across the entire pathway had higher habituation scores. These results suggest that epigenetic alterations across the cortisol regulation pathway may contribute to different neurobehavioral phenotypes, likely though varying degrees of glucocorticoid exposure during gestation. While the postnatal environment may continue to affect neurobehavioral risk, this study provides novel insights into the molecular basis for fetal origins of mental conditions.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Metilação de DNA , Epigênese Genética/fisiologia , Regulação da Expressão Gênica , Comportamento do Lactente/fisiologia , Placenta/metabolismo , Receptores de Glucocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Epigênese Genética/genética , Feminino , Humanos , Comportamento do Lactente/classificação , Recém-Nascido , Masculino , Fenótipo , Gravidez , Receptores de Glucocorticoides/genética
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