Assuntos
Arsênio/toxicidade , Dieta , Contaminação de Alimentos , Oryza , Adolescente , Arsênio/urina , Pesquisa Biomédica/tendências , Carcinógenos , Criança , Pré-Escolar , Exposição Ambiental , Pessoal de Saúde , Humanos , Lactente , Estados UnidosRESUMO
OBJECTIVE: To examine patterns of microbial colonization of the respiratory and intestinal tracts in early life in infants with cystic fibrosis (CF) and their associations with breastfeeding and clinical outcomes. STUDY DESIGN: A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis. RESULTS: Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. CONCLUSIONS: Our findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed.
Assuntos
Fibrose Cística/microbiologia , Intestinos/microbiologia , Microbiota , Sistema Respiratório/microbiologia , Aleitamento Materno , Pré-Escolar , Progressão da Doença , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Estudos Prospectivos , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosaRESUMO
Acute lymphoblastic leukemia (ALL) likely has a multistep etiology, with initial genetic aberrations occurring early in life. An abnormal immune response to common infections has emerged as a plausible candidate for triggering the proliferation of pre-leukemic clones and the fixation of secondary genetic mutations and epigenetic alterations. We investigated whether evidence of infection with a specific common myelotropic childhood virus, parvovirus B19 (PVB19), relates to patterns of gene promoter DNA methylation in ALL patients. We serologically tested bone marrow samples at diagnosis of B-cell ALL for PVB19 infection and DNA methylation using a high-throughput bead array and found that 4.2% and 36.7% of samples were seroreactive to PVB19 IgM and IgG, respectively. Leukemia samples were grouped by DNA methylation pattern. Controlling for age and immunophenotype, unsupervised modeling confirmed that the DNA methylation pattern was associated with history of PVB19 (assessed by IgG, p = 0.02), but not recent infection (assessed by IgM). Replication assays on single genes were consistent with the association. The data indicate that a common viral illness may drive specific DNA methylation patterns in susceptible B-precursor cells, contributing to the leukemogenic potential of such cells. Infections may impact childhood leukemia by altering DNA methylation patterns and specific key genes in susceptible cells; these changes may be retained even after the clearance of infection.
Assuntos
Metilação de DNA , Epigênese Genética , Infecções por Parvoviridae/complicações , Parvovirus B19 Humano , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Adolescente , Medula Óssea/patologia , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Infecções por Parvoviridae/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Regiões Promotoras GenéticasRESUMO
The mechanism(s) by which arsenic exposure contributes to human cancer risk is unknown ; however, several indirect cocarcinogenesis mechanisms have been proposed. Many studies support the role of As in altering one or more DNA repair processes. In the present study we used individual-level exposure data and biologic samples to investigate the effects of As exposure on nucleotide excision repair in two study populations, focusing on the excision repair cross-complement 1 (ERCC1) component. We measured drinking water, urinary, or toenail As levels and obtained cryopreserved lymphocytes of a subset of individuals enrolled in epidemiologic studies in New Hampshire (USA) and Sonora (Mexico). Additionally, in corroborative laboratory studies, we examined the effects of As on DNA repair in a cultured human cell model. Arsenic exposure was associated with decreased expression of ERCC1 in isolated lymphocytes at the mRNA and protein levels. In addition, lymphocytes from As-exposed individuals showed higher levels of DNA damage, as measured by a comet assay, both at baseline and after a 2-acetoxyacetylaminofluorene (2-AAAF) challenge. In support of the in vivo data, As exposure decreased ERCC1 mRNA expression and enhanced levels of DNA damage after a 2-AAAF challenge in cell culture. These data provide further evidence to support the ability of As to inhibit the DNA repair machinery, which is likely to enhance the genotoxicity and mutagenicity of other directly genotoxic compounds, as part of a cocarcinogenic mechanism of action.
Assuntos
Arsênio/efeitos adversos , Arsênio/análise , Reparo do DNA/efeitos dos fármacos , Abastecimento de Água/análise , Adulto , Western Blotting , Ensaio Cometa , Dano ao DNA , Proteínas de Ligação a DNA/genética , Eletroforese em Gel de Poliacrilamida , Endonucleases/genética , Exposição Ambiental , Feminino , Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Unhas/química , New Hampshire/epidemiologia , RNA/biossíntese , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Gold mining can release contaminants, including mercury, into the environment, and may increase exposure to naturally occurring elements such as arsenic. The authors investigated environmental and human tissue concentrations of arsenic and mercury in the gold mining town of Siuna, Nicaragua. The study involved 49 randomly selected households in Siuna, from whom a questionnaire along with environmental and fingernail samples were collected. Environmental samples indicated that mercury concentrations in drinking water, although generally low, were higher near the mine site. Arsenic concentrations were elevated in water and soil samples, but their distribution was unrelated to the mining site. Mercury concentrations in fingernail samples were correlated with residential proximity to the mine, drinking water concentrations, occupation, and, among children, with soil concentrations. Fingernail arsenic concentrations correlated with drinking water concentrations among adults who consumed higher levels, and with soil concentrations among children. Fingernail analysis helped to identify differential exposure pathways in children and adults. Mercury and arsenic uptake via soil exposure in children warrants further consideration.