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1.
Med Sci Monit ; 25: 3354-3365, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061382

RESUMO

BACKGROUND Maternal folate deficiency-mediated metabolic disruption is considered to be associated with the risk of intrauterine growth retardation (IUGR), but the exact mechanism remains unclear. The retrotransposon long interspersed nucleotide element-1 (LINE-1), which can induce birth defects via RNA intermediates, plays crucial roles during embryonic development. We investigated potential relationships between maternal folate and DNA methylation, and possible roles of LINE-1 in IUGR. MATERIAL AND METHODS The IUGR model was established by feeding female mice 1 of 3 diets - control diet (CD), folate-deficient diet for 2 weeks (FD2w), and folate-deficient diet for 4 weeks (FD4w) - prior to mating. Maternal serum folate, 5-methyltetrahydrofolate (5-MeTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) concentrations and global DNA methylation were assessed by LC/MS/MS method. LINE-1 methylation levels in fetuses were examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LINE-1 expression levels were validated by real-time PCR. RESULTS Maternal folate deficiency caused plasma folate and 5-MeTHF levels to decrease and SAH level to increase in the FD4w group. Compared with the CD group, methylation levels of genomic DNA and LINE-1 decreased significantly in placenta and fetal tissues from the FD4w group. Expression of LINE-1 open reading frame 1 (ORF1) protein was elevated in fetal liver tissues. Furthermore, a strong correlation was found between methylation and disrupted one-carbon metabolism, implying that dietary folate plays important roles during embryogenesis. CONCLUSIONS Maternal dietary folate deficiency impaired one-carbon metabolism, leading to global DNA and LINE-1 hypomethylation, and then increased retrotransposition in fetuses, which can lead to IUGR.


Assuntos
Retardo do Crescimento Fetal/genética , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Animais , Metilação de DNA/genética , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Elementos Nucleotídeos Longos e Dispersos/genética , Elementos Nucleotídeos Longos e Dispersos/fisiologia , Masculino , Troca Materno-Fetal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Gravidez , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Tetra-Hidrofolatos/metabolismo
2.
PLoS One ; 14(5): e0214307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31063509

RESUMO

The DOHaD (developmental origins of health and disease) hypothesis claims that fetal malnutrition or exposure to environmental pollutants may affect their lifelong health. Epigenetic changes may play significant roles in DOHaD; however, access to human fetuses for research has ethical and technical hurdles. Umbilical cord blood (CB) has been commonly used as an epigenetic surrogate of fetuses, but it does not provide direct evidence of fetal exposure to pollutants. Here, we propose umbilical cord tissue (UC), which accumulates substances delivered to fetuses during gestation, as an alternative surrogate for epigenetic studies on fetuses. To explore the feasibility to examine UC epigenome by deep sequencing, we determined CpG methylation profiles of human postnatal UC by reduced representation bisulfite sequencing. Principal component analysis clearly separated the DNA methylomes of UC and CB pairs isolated from the same newborn (n = 10). Although all UC chromosomes were modestly hypomethylated compared to CB chromosomes, GO analysis revealed strong enrichment of differentially methylated regions (DMRs) at promoter-associated CpG islands in the HOX gene clusters and other genes encoding transcription factors involved in determination of the body pattern. DNA methylomes of UC autosomes were largely comparable between males and females. Deficiency of folate during pregnancy has been suggested to affect fetal DNA methylation to cause congenital anomalies. Whereas DNA methylome of UC was not significantly affected by early-gestational (12 weeks) low levels of maternal plasma folate (< 8 ng/ml, n = 10) compared to controls (>19 ng/mL, n = 10), two specific loci of LTR12C endogenous retroviruses in chromosome 12 were significantly hypermethylated in the low-folate group. Our study suggests that UC is useful as an alternative surrogate for studying environmental effects on DNA methylation in human fetuses, compensating CB by providing additional information about epigenetic regulation of genes involved in developmental body patterning and endogenous retroviruses.


Assuntos
Padronização Corporal/genética , Metilação de DNA , Sangue Fetal , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Processos de Determinação Sexual/genética , Fatores de Transcrição/genética , Biologia Computacional/métodos , Epigênese Genética , Feminino , Ontologia Genética , Idade Gestacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Gravidez
3.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836646

RESUMO

Supplementation of micronutrients like folate is a double-edged sword in terms of their ambivalent role in cell metabolism. Although several epidemiological studies support a protective role of folate in carcinogenesis, there are also data arguing for an opposite effect. To address this issue in the context of human papillomavirus (HPV)-induced transformation, the molecular events of different folate availability on human keratinocytes immortalized by HPV16 E6 and E7 oncoproteins were examined. Several sublines were established: Control (4.5 µM folate), folate deficient (0.002 µM folate), and repleted cells (4.5 µM folate). Cells were analyzed in terms of oncogene expression, DNA damage and repair, karyotype changes, whole-genome sequencing, and transcriptomics. Here we show that folate depletion irreversibly induces DNA damage, impairment of DNA repair fidelity, and unique chromosomal alterations. Repleted cells additionally underwent growth advantage and enhanced clonogenicity, while the above mentioned impaired molecular properties became even more pronounced. Overall, it appears that a period of folate deficiency followed by repletion can shape immortalized cells toward an anomalous phenotype, thereby potentially contributing to carcinogenesis. These observations should elicit questions and inquiries for broader additional studies regarding folate fortification programs, especially in developing countries with micronutrient deficiencies and high HPV prevalence.


Assuntos
Deficiência de Ácido Fólico/genética , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/genética , Transcrição Genética , Carcinogênese/genética , Dano ao DNA/ética , Reparo do DNA/genética , Ácido Fólico/genética , Deficiência de Ácido Fólico/patologia , Deficiência de Ácido Fólico/virologia , Genômica , Papillomavirus Humano 16/patogenicidade , Humanos , Queratinócitos/virologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética
4.
Ital J Pediatr ; 45(1): 37, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30867013

RESUMO

BACKGROUND: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring. METHODS: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones. RESULTS: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308). CONCLUSION: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.


Assuntos
Deficiência de Ácido Fólico/genética , Predisposição Genética para Doença/epidemiologia , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Carbono/metabolismo , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Feminino , Ferredoxina-NADP Redutase/genética , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/epidemiologia , Marcadores Genéticos/genética , Genótipo , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Antígenos de Histocompatibilidade Menor/genética , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/fisiopatologia , Razão de Chances , Gravidez , Valores de Referência
5.
J Clin Neurosci ; 59: 341-344, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30420205

RESUMO

INTRODUCTION: Folate is essential for production of DNA, neurotransmitters and myelin and regulation of genetic activity. A specific transporter protein is required to transport folate from blood to CSF. Various inherited brain-specific folate transport defects have been recognized due to mutation in Folate Receptor alpha (FOLR1). FOLR1 mutation is one of the vitamin responsive encephalopathies and is inherited as an autosomal recessive condition. It has a wide spectrum of phenotype, commonly presenting as epileptic encephalopathy. Less frequently the condition may manifest with subtle hypotonia, movement disorder as tremors, ataxia or intellectual disability and autistic spectrum disorder. We present a case of folate transporter deficiency with non-epileptic manifestations, presenting with tremors, speech delay and stable white matter changes in MRI brain. OBJECTIVE: We present a case of Folate transporter defect with Non-epileptic presentation. CONCLUSION: Folate transporter deficiency has a wide range of presenting symptoms. Presentation with slowly progressive atypical symptoms, stable white matter changes in brain MRI that does not fit a specific diagnosis, should raise a high suspicion of FOLR1 mutation, even in absence of seizures. Since folate transporter deficiency is a treatable neurodegenerative disorder, early diagnosis and supplementation with folinic acid is vital.


Assuntos
Deficiência de Ácido Fólico/patologia , Síndromes de Malabsorção/patologia , Fenótipo , Encéfalo/metabolismo , Criança , Feminino , Receptor 1 de Folato/genética , Deficiência de Ácido Fólico/diagnóstico por imagem , Deficiência de Ácido Fólico/genética , Humanos , Síndromes de Malabsorção/diagnóstico por imagem , Síndromes de Malabsorção/genética , Mutação
6.
J Neurol Sci ; 396: 112-118, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448717

RESUMO

OBJECTIVE: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases. METHODS: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data. RESULTS: 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement. CONCLUSION: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.


Assuntos
Doenças Cerebelares/complicações , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Mutação/genética , Proteínas/genética , Adolescente , Adulto , Idoso , Calcinose/diagnóstico por imagem , Calcinose/etiologia , Calcinose/genética , Doenças Cerebelares/líquido cefalorraquidiano , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/genética , Criança , Pré-Escolar , Feminino , Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/diagnóstico por imagem , Seguimentos , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/etiologia , Estudos Retrospectivos , Tetra-Hidrofolatos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
7.
Vopr Pitan ; 87(2): 17-23, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30592864

RESUMO

The results of assessing the sufficiency of folic acid of the residents of the Moscow region have been presented depending on rs1801133 MTHFR gene polymorphism and rs9939609 FTO gene polymorphism. A total of 326 people were examined, including 74 men and 252 women aged 20 to 65 years. The results of determining the level of folic acid in blood serum showed insufficiency of this vitamin among the population of the Moscow region of the Russian Federation. The expressed vitamin deficit (level <3,0 ng/ml) was detected in 24.2% of the surveyed residents, in 22.8% folic acid level was at the lower bound of the norm (3.0-4.5 ng/ml). The results of genotyping showed a statistically significant association of low folic acid level with rs1801133 MTHFR gene polymorphism in carriers of A allele of rs9939609 FTO gene polymorphism both in the homozygous state (genotype AA) and in the heterozygous (genotype AT) state, OR=4.26; CI (1.40-12.9), p=0.008, as well as with rs9939609 FTO gene polymorphism in carriers of the T allele of rs1801133 MTHFR gene polymorphism both in the homozygous (genotype TT) and heterozygous (CT genotype) state, OR=3.29; CI (1.07-10.1), p=0.03. In carriers of 3 alleles of risk of folic acid deficiency [rs9939609 FTO gene polymorphism and rs1801133 MTHFR gene polymorphism (genotypes CT/AA and TT/AT)] blood serum level of folic acid was below the norm, that indicated folate deficiency in this category of persons.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Ácido Fólico/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Feminino , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Moscou
8.
Physiol Genomics ; 50(12): 1015-1025, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30240347

RESUMO

Folate plays an important role in DNA and RNA synthesis by donating methyl groups. To investigate the effects of maternal folate deficiency (FD) on the abdominal adipose transcriptome and on the accumulation of lipid droplets in the liver tissue of chicken offspring, differentially expressed genes (DEGs) of FD were identified with digital gene expression tag profiling. Ultramicroscopy suggested that the size of lipid droplets in hepatocytes increased with FD, while the lipid droplets population number was largely not affected. The serum parameters assay showed that the concentrations of MTHFR (476.57 vs. 395.27), DHFR (45.056 vs. 38.952), LPL (50.408 vs. 48.677), HCY (4.354 vs. 3.836), LEP (9.951 vs. 8.673), and IGF2 (1209.4 vs. 1027.7) in offspring serum of the FD group were significantly higher than those of the normal folate (NF) group ( P < 0.01). The 442 DEGs between NF and FD groups were identified by digital gene expression profiling. Considering the DEGs in the FD groups vs. NF groups, 179 genes were upregulated while 263 downregulated, and in particular, 145 upregulated and 214 downregulated DEGs were successfully annotated with the nonredundant database. Gene Ontology analysis showed that FD mainly affected cellular processes, cell part and binding, cell killing, virions, and receptor regulator activity. With pathway analysis, it indicated that 123 unigenes were assigned to 115 KEGG pathways, but only five of 115 these pathways were significantly enriched with P values ≤ 0.05. Taken together, these results provide a foundation for further studying the responses of offspring to maternal FD in breeding chickens.


Assuntos
Deficiência de Ácido Fólico/genética , Ácido Fólico/genética , Expressão Gênica/genética , Animais , Galinhas , Regulação para Baixo/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Hepatócitos/fisiologia , Fígado/fisiologia , Transcriptoma/genética , Regulação para Cima/genética
9.
Physiol Res ; 67(3): 417-422, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30036071

RESUMO

Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60+/-6 vs. 42+/-2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies.


Assuntos
Receptor 1 de Folato/genética , Deficiência de Ácido Fólico/sangue , Ácido Fólico/sangue , Fígado/metabolismo , Ratos Endogâmicos SHR/genética , Animais , Fígado Gorduroso/metabolismo , Deficiência de Ácido Fólico/genética , Masculino
10.
J Physiol ; 596(18): 4341-4360, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30024025

RESUMO

KEY POINTS: Folate (folic acid) deficiency and mutations in folate-related genes in humans result in megaloblastic anaemia. Folate metabolism, which requires the enzyme methionine synthase reductase (MTRR), is necessary for DNA synthesis and the transmission of one-carbon methyl groups for cellular methylation. In this study, we show that the hypomorphic Mtrrgt/gt mutation in mice results in late-onset and sex-specific blood defects, including macrocytic anaemia, extramedullary haematopoiesis and lymphopenia. Notably, when either parent carries an Mtrrgt allele, blood phenotypes result in their genetically wildtype adult daughters, the effects of which are parent specific. Our data establish a new model for studying the mechanism of folate metabolism in macrocytic anaemia aetiology and suggest that assessing parental folate status might be important when diagnosing adult patients with unexplained anaemia. ABSTRACT: The importance of the vitamin folate (also known as folic acid) in erythrocyte formation, maturation and/or longevity is apparent since folate deficiency in humans causes megaloblastic anaemia. Megaloblastic anaemia is a type of macrocytic anaemia whereby erythrocytes are enlarged and fewer in number. Folate metabolism is required for thymidine synthesis and one-carbon metabolism, though its specific role in erythropoiesis is not well understood. Methionine synthase reductase (MTRR) is a key enzyme necessary for the progression of folate metabolism since knocking down the Mtrr gene in mice results in hyperhomocysteinaemia and global DNA hypomethylation. We demonstrate here that abnormal folate metabolism in mice caused by Mtrrgt/gt homozygosity leads to haematopoietic phenotypes that are sex and age dependent. Specifically, Mtrrgt/gt female mice displayed macrocytic anaemia, which might be due to defective erythroid differentiation at the exclusion of haemolysis. This was associated with increased renal Epo mRNA expression, hypercellular bone marrow, and splenic extramedullary haematopoiesis. In contrast, the male response differed since Mtrrgt/gt male mice were not anaemic but did display erythrocytic macrocytosis and lymphopenia. Regardless of sex, these phenotypes were late onset. Remarkably, we also show that when either parent carries an Mtrrgt allele, a haematological defect results in their adult wildtype daughters. However, the specific phenotype was dependent upon the sex of the parent. For instance, wildtype daughters of Mtrr+/gt females displayed normocytic anaemia. In contrast, wildtype daughters of Mtrr+/gt males exhibited erythrocytic microcytosis not associated with anaemia. Therefore, abnormal folate metabolism affects adult haematopoiesis in an age-, sex- and parent-specific manner.


Assuntos
Anemia Megaloblástica/genética , Ferredoxina-NADP Redutase/genética , Deficiência de Ácido Fólico/genética , Hematopoese , Fatores Etários , Anemia Megaloblástica/sangue , Animais , Células Cultivadas , Feminino , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/sangue , Homozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais
11.
Nihon Eiseigaku Zasshi ; 73(2): 101-104, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29848858

RESUMO

X-chromosome inactivation (XCI) occurs during the gestation period to compensate for the dosage of X-linked genes in female mammals. Xist RNA is a long noncoding RNA with a global epigenetic function and is indispensable for XCI from the initiation to establishment and maintenance phases. The X chromosome contains over 1,000 genes that are essential for proper development, especially that of the brain, immune system, metabolism and reproductive functions. We found that exposure to bisphenol A or folate deficiency during the fetal period changes the expressions of Xist, Tsix (the antisense repressor of Xist), and many X chromosome linked genes widely in newborn mice. This finding suggests that this X-chromosome mediated effect is considered one of the mechanisms of various problems encountered in the fetal environment. The Developmental Origins of Health and Disease (DOHaD) hypothesis states that nutrition and other environmental stimuli during critical periods affect developmental pathways with epigenetics and induce metabolism and chronic disease susceptibility. The XCI process has some similarities to this hypothesis and it may become one of the approaches to reveal the DOHaD mechanisms.


Assuntos
Fenômenos Fisiológicos da Nutrição Pré-Natal , RNA Longo não Codificante , Inativação do Cromossomo X/genética , Cromossomo X/genética , Animais , Compostos Benzidrílicos/efeitos adversos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Epigênese Genética , Feminino , Deficiência de Ácido Fólico/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Ligados ao Cromossomo X , Humanos , Sistema Imunitário/embriologia , Sistema Imunitário/crescimento & desenvolvimento , Metabolismo/genética , Fenóis/efeitos adversos , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Reprodução/genética
12.
Microbiology ; 164(7): 982-991, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29799386

RESUMO

Dihydrofolate reductase (DHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (PurH) play key roles in maintaining folate pools in cells, and are targets of antimicrobial and anticancer drugs. While the activities of bacterial DHFR and PurH on their classical substrates (DHF and 10-CHO-THF, respectively) are known, their activities and kinetic properties of utilisation of 10-CHO-DHF are unknown. We have determined the kinetic properties (k cat/K m) of conversion of 10-CHO-DHF to 10-CHO-THF by DHFR, and to DHF by PurH. We show that DHFR utilises 10-CHO-DHF about one third as efficiently as it utilises DHF. The 10-CHO-DHF is also utilised (as a formyl group donor) by PurH albeit slightly less efficiently than 10-CHO-THF. The utilisation of 10-CHO-DHF by DHFR is ~50 fold more efficient than its utilisation by PurH. A folate deficient Escherichia coli (∆pabA) grows well when supplemented with adenine, glycine, thymine and methionine, the metabolites that arise from the one-carbon metabolic pathway. Notably, when the ∆pabA strain harboured a folate transporter, it grew in the presence of 10-CHO-DHF alone, suggesting that it (10-CHO-DHF) can enter one-carbon metabolic pathway to provide the required metabolites. Thus, our studies reveal that both DHFR and PurH could utilise 10-CHO-DHF for folate homeostasis in E. coli.


Assuntos
Escherichia coli/metabolismo , Ácido Fólico/análogos & derivados , Nucleotídeo Desaminases/metabolismo , Fosforribosilaminoimidazolcarboxamida Formiltransferase/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Ácido 4-Aminobenzoico , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/genética , Homeostase , Cinética , Redes e Vias Metabólicas , Nucleotídeo Desaminases/genética , Fosforribosilaminoimidazolcarboxamida Formiltransferase/genética , Tetra-Hidrofolato Desidrogenase/genética
13.
Mol Genet Metab ; 124(1): 87-93, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29661558

RESUMO

INTRODUCTION: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. STUDY AIMS AND METHODS: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. RESULTS: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. DISCUSSION: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions.


Assuntos
Autoanticorpos/sangue , Encefalopatias Metabólicas Congênitas/genética , Receptor 1 de Folato/imunologia , Deficiência de Ácido Fólico/genética , Adolescente , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/diagnóstico , Criança , Pré-Escolar , Consanguinidade , Enzimas Reparadoras do DNA/genética , Diagnóstico Diferencial , Família , Feminino , Receptor 1 de Folato/genética , Receptor 2 de Folato/genética , Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/diagnóstico , Humanos , Lactente , Masculino , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polineuropatias/etiologia , Sequenciamento Completo do Exoma , Adulto Jovem
14.
J Nutr ; 148(4): 501-509, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659962

RESUMO

Background: Suboptimal folate intake, a risk factor for birth defects, is common even in areas with folate fortification. A polymorphism in methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), R653Q (MTHFD1 c.1958 G > A), has also been associated with increased birth defect risk, likely through reduced purine synthesis. Objective: We aimed to determine if the interaction of MTHFD1 synthetase deficiency and low folate intake increases developmental abnormalities in a mouse model for MTHFD1 R653Q. Methods: Female Mthfd1S+/+ and Mthfd1S+/- mice were fed control or low-folate diets (2 and 0.3 mg folic acid/kg diet, respectively) before mating and during pregnancy. Embryos and placentas were examined for anomalies at embryonic day 10.5. Maternal 1-carbon metabolites were measured in plasma and liver. Results: Delays and defects doubled in litters of Mthfd1S+/- females fed low-folate diets compared to wild-type females fed either diet, or Mthfd1S+/- females fed control diets [P values (defects): diet 0.003, maternal genotype 0.012, diet × maternal genotype 0.014]. These adverse outcomes were associated with placental dysmorphology. Intrauterine growth restriction was increased by embryonic Mthfd1S+/- genotype, folate deficiency, and interaction of maternal Mthfd1S+/- genotype with folate deficiency (P values: embryonic genotype 0.045, diet 0.0081, diet × maternal genotype 0.0019). Despite a 50% increase in methylenetetrahydrofolate reductase expression in low-folate maternal liver (P diet = 0.0007), methyltetrahydrofolate concentration decreased 70% (P diet <0.0001) and homocysteine concentration doubled in plasma (P diet = 0.0001); S-adenosylmethionine decreased 40% and S-adenosylhomocysteine increased 20% in low-folate maternal liver (P diet = 0.002 and 0.0002, respectively). Conclusions: MTHFD1 synthetase-deficient mice are more sensitive to low folate intake than wild-type mice during pregnancy. Reduced purine synthesis due to synthetase deficiency and altered methylation potential due to low folate may increase pregnancy complications. Further studies and individualized intake recommendations may be required for women homozygous for the MTHFD1 R653Q variant.


Assuntos
Anormalidades Congênitas/etiologia , Deficiência de Ácido Fólico/complicações , Ácido Fólico/administração & dosagem , Formiato-Tetra-Hidrofolato Ligase/deficiência , Genótipo , Meteniltetra-Hidrofolato Cicloidrolase/deficiência , Metilenotetra-Hidrofolato Desidrogenase (NADP)/deficiência , Enzimas Multifuncionais/deficiência , Polimorfismo Genético , Complicações na Gravidez/etiologia , Animais , Metilação de DNA , Dieta , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/etiologia , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Formiato-Tetra-Hidrofolato Ligase/genética , Formiato-Tetra-Hidrofolato Ligase/metabolismo , Ligases , Fígado/metabolismo , Meteniltetra-Hidrofolato Cicloidrolase/genética , Meteniltetra-Hidrofolato Cicloidrolase/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Camundongos , Enzimas Multifuncionais/genética , Enzimas Multifuncionais/metabolismo , Placenta , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Prenhez , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Tetra-Hidrofolatos/sangue
15.
Environ Mol Mutagen ; 59(5): 366-374, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29668043

RESUMO

Folate deficiency causes megaloblastic anemia and neural tube defects, and is also associated with some cancers. In vitro, folate deficiency increases mutation frequency and genome instability, as well as exacerbates the mutagenic potential of known environmental mutagens. Conversely, it remains unclear whether or not elevated folic acid (FA) intakes are beneficial or detrimental to the induction of DNA mutations and by proxy human health. We used the MutaMouse transgenic model to examine the in vivo effects of FA deficient, control, and supplemented diets on somatic DNA mutant frequency (MF) and genome instability in hematopoietic cells. We also examined the interaction between FA intake and exposure to the known mutagen N-ethyl-N-nitrosourea (ENU) on MF. Male mice were fed the experimental diets for 20 weeks from weaning. Half of the mice from each diet group were gavaged with 50 mg/kg body weight ENU after 10 weeks on diet and remained on their respective diet for an additional 10 weeks. Mice fed a FA-deficient diet had a 1.3-fold increase in normochromatic erythrocyte micronucleus (MN) frequency (P = 0.034), and a doubling of bone marrow lacZ MF (P = 0.035), compared to control-fed mice. Mice exposed to ENU showed significantly higher bone marrow lacZ and Pig-a MF, but there was no effect of FA intake on ENU-induced MF. These data indicate that FA deficiency increases mutations and MN formation in highly proliferative somatic cells, but that FA intake does not mitigate ENU-induced mutations. Also, FA intake above adequacy had no beneficial or detrimental effect on mutations or MN formation. Environ. Mol. Mutagen. 59:366-374, 2018. © 2018 Her Majesty the Queen in Right of Canada 2018.


Assuntos
Anemia Megaloblástica/genética , Deficiência de Ácido Fólico/genética , Ácido Fólico/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Anemia Megaloblástica/induzido quimicamente , Anemia Megaloblástica/metabolismo , Anemia Megaloblástica/patologia , Animais , Dano ao DNA/efeitos dos fármacos , Suplementos Nutricionais , Etilnitrosoureia/toxicidade , Feminino , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/patologia , Instabilidade Genômica/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Óperon Lac/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Mutagênese/efeitos dos fármacos , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/patologia
16.
J Cell Physiol ; 233(9): 7333-7342, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29574721

RESUMO

Folate deficiency results in abnormal embryonic development, but the underlying mechanisms remain to be comprehensively investigated. Mutation of Vangl genes belonging to the planar cell polarity (PCP) pathway is associated with abnormal embryonic development, but the effect of folate deficiency on the PCP pathway is unclear. In this study, we found that folate deficiency inhibited Vangl gene expression and Vangl protein binding to the ligand Dvl. As a methyl donor, folate can chemically alter the DNA methylation levels of genomic sequences. Here, reduced representation bisulfite sequencing (RRBS) was employed to detect the methylation profiles of mouse embryos. The results confirmed that folate deficiency affected the genomic methylation levels of mouse embryos, which resulted in down-regulation of key genes involved in embryonic development. Gene ontology (GO) analysis suggested that the genes located in the differentially methylated regions (DMRs) are primarily involved in biological regulation, cellular processes, development, metabolism, and signaling pathways. The data revealed that folate deficiency inhibits the PCP pathway and alters genomic methylation profiles, which may be the underlying mechanisms through which folate deficiency impairs embryonic development.


Assuntos
Polaridade Celular/genética , Metilação de DNA/genética , Desenvolvimento Embrionário/genética , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/patologia , Genoma , Animais , Regulação para Baixo/genética , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Infertilidade/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos
17.
Blood Adv ; 2(1): 61-68, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29344585

RESUMO

Hereditary folate malabsorption (HFM) is an autosomal recessive disorder characterized by impaired intestinal folate absorption and impaired folate transport across the choroid plexus due to loss of function of the proton-coupled folate transporter (PCFT-SLC46A1). We report a novel mutation, causing HFM, affecting a residue located in the 11th transmembrane helix within the external gate. The mutant N411K-PCFT was stable, trafficked to the cell membrane, and had sufficient residual activity to characterize the transport defect and the structural requirements at this site for gate function. The influx Vmax of the N411K mutant was markedly decreased, as was the affinity for most, but not all, folate/antifolate substrates. The greatest loss of activity was for 5-methyltetrahydrofolate. Substitutions with positive charged residues resulted in a loss of activity (arginine > lysine > histidine). Function was retained for the negative charged aspartate, but not the larger glutamate substitutions, whereas the bulky hydrophobic (leucine), or polar (glutamine) substitutions, were tolerated. Homology models of PCFT, in the inward and outward open conformations, based upon the mammalian Glut5 fructose transporter structures, localize Asn411 protruding into the aqueous pathway. This is most prominent when the carrier is in the inward open conformation when the external gate is closed. Mutations at this site likely result in highly specific steric and electrostatic interactions between the Asn411-substituted, and other, residues in the gate region that impede carrier function. The substrate specificity of the N411K mutant may be due to alterations of substrate flows through the external gate, downstream allosteric alterations in the folate-binding pocket, or both.


Assuntos
Deficiência de Ácido Fólico/genética , Síndromes de Malabsorção/genética , Mutação de Sentido Incorreto , Transportador de Folato Acoplado a Próton/genética , Substituição de Aminoácidos , Linhagem Celular , Deficiência de Ácido Fólico/etiologia , Células HeLa , Humanos , Lactente , Síndromes de Malabsorção/etiologia , Masculino , Modelos Moleculares , Mutagênese Sítio-Dirigida , Transporte Proteico/genética , Especificidade por Substrato , Tetra-Hidrofolatos/metabolismo , Transfecção
18.
Asian J Psychiatr ; 32: 29-33, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29202425

RESUMO

The purpose of the research was to investigate the association of methylenetetrahydrofolate reductase (hereinafter MTHFR) genetic polymorphism 677C>T with schizophrenia in the Russian population in comparison with the control group of healthy blood donors. Also some characteristics of schizophrenia were examined in patients with/without defective T-allele of MTHFR677C>T polymorphism. 500 patients with schizophrenia and 499 blood donors were examined for T-allele carriage of polymorphism MTHFR677C>T by PCR method. 150 archival medical records were studied (in the first patients included in the study). The carriage of T-allele of genetic polymorphism MTHFR677C>T was significantly more common in patients than in healthy donors: 255/500 versus 219/499 (p=0,0287, χ2=4,79; OR=1,33, 95%CI [1037; 1707]). The number of patients with chronic type of schizophrenia onset was significantly more among T-allele carriers (n=77) than among normal CC-genotype carriers (n=73): р=0.038. The number of "incapacitated" persons in the group of patients with defective T-allele (n=77) was significantly higher than in patients with normal genotype (n=73, p=0.0439; OR=2.878, 95%CI=1.111-7.456). The results suggest that T-allele of genetic polymorphism MTHFR677C>T in the population of European Russia may increase the risk of developing schizophrenia and its unfavorable prognosis, which requires further investigation.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Deficiência de Ácido Fólico/genética , Estudos de Associação Genética , Hospitais Psiquiátricos/estatística & dados numéricos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Federação Russa/epidemiologia , Esquizofrenia/epidemiologia , Esquizofrenia/terapia
19.
Eur J Nutr ; 57(2): 751-760, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28004270

RESUMO

PURPOSE: Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. METHODS: A total of 988 women aged 40-65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson's partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. RESULTS: The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value <0.001) and 0.08 (p value = 0.008) for vitamin B12. Dietary scores were the main determinant of B vitamin plasma concentrations with a percent change per unit increase of 12.64% (p value <0.001) for folate and 7.6% (p value <0.001) for vitamin B12. Homozygous (T/T) or heterozygous (C/T) women for MTHFR-C677T had lower plasma folate concentrations [C/T: -6.48% (p value = 0.038) and T/T: -15.89% (p value <0.001)] compared to women carrying the C/C genotype. Other determinants of B vitamin plasma concentration include: smoking status for folate, and age and hormone replacement therapy for vitamin B12. CONCLUSIONS: We confirmed previous findings on the role of diet as main determinant of folate and vitamin B12 plasma concentrations. However, the impact of genetic polymorphisms and lifestyle factors on plasma B vitamin concentrations should not be neglected.


Assuntos
Dieta/efeitos adversos , Deficiência de Ácido Fólico/etiologia , Ácido Fólico/sangue , Estado Nutricional , Deficiência de Vitamina B 12/etiologia , Vitamina B 12/sangue , Substituição de Aminoácidos , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/prevenção & controle , França/epidemiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Cooperação do Paciente , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Autorrelato , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/prevenção & controle
20.
Am J Med Genet A ; 173(11): 3042-3057, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944587

RESUMO

Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 to 200 per 10,000 births with the United States of American NTD incidence at around 3-6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35-50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.


Assuntos
Deficiência de Ácido Fólico/epidemiologia , Ácido Fólico/genética , Defeitos do Tubo Neural/epidemiologia , Feminino , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/patologia , Humanos , Tubo Neural/crescimento & desenvolvimento , Tubo Neural/metabolismo , Tubo Neural/patologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Gravidez , Fatores Socioeconômicos , Estados Unidos
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