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1.
Ideggyogy Sz ; 72(9-10): 325-336, 2019 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-31625699

RESUMO

With the acceptance of "The developmental origins of health and disease" concept in the 1990s, it became clear that epigenetic inheritance, which do not involve changes in the DNA sequence has important role in the pathogenesis of diseases. Epigenetic regulation serves the adaptation to the changing environment and maintains the reproductive fitness even on the drawback of increased risk of diseases in later life. The role of epigenetic mechanisms in chronic non-communicable diseases has been well established. Recent studies have revealed that epigenetic changes have also causal role in certain pediatric diseases. The review evaluates the recent epigenetic findings in the pathomechanism of common pediatric diseases. The wide range and long-lasting duration of epigenetic regulations give importance to the subject. Methods are already available to evaluate a part of the epigenetic changes in the clinical practice, presently aiming primarily the estimation of the disease risk or definition of diagnosis. Furthermore, there are already available limited means to influence the epigenetic regulation.


Assuntos
Metilação de DNA/fisiologia , Epigênese Genética , Cardiopatias , Infecção , Transtornos Mentais , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Cardiopatias/genética , Humanos , Infecção/genética , Transtornos Mentais/genética , Doenças Metabólicas/genética , Pediatria , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
2.
Environ Pollut ; 252(Pt A): 330-335, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158661

RESUMO

Aluminum is a widely distributed metal that has been reported to have embryotoxicity and fetotoxicity in animal studies. However, there has been no study of the association between prenatal aluminum exposure and newborn mitochondrial DNA copy number (mtDNAcn). We aimed to investigate the effect of prenatal aluminum exposure on newborn mtDNAcn. A total of 762 mother-newborn pairs were recruited between November 2013 and March 2015 in Wuhan city, China. We measured maternal urinary aluminum concentrations at three trimesters of pregnancy. Relative mtDNAcn was measured in DNA extracted from umbilical cord blood samples. We used generalized estimating equations to assess the relationship between prenatal aluminum exposure and newborn mtDNAcn. The geometric means of creatinine corrected aluminum concentrations were 31.0 µg/g Cr (95% CI: 27.6, 34.7), 40.9 µg/g Cr (95% CI: 35.7, 46.8) and 58.4 µg/g Cr (95% CI: 51.2, 67.4) for the first, second and third trimesters, respectively. After adjustment for potential confounding factors, a doubling of maternal urinary aluminum concentrations during the second and third trimesters was related to 3.16% (95% CI: 0.88, 5.49) and 4.20% (95% CI: 1.64, 6.81) increases in newborn mtDNAcn, respectively, while the association between maternal urinary aluminum concentration during the first trimester and newborn mtDNAcn was not significant (percent difference: 0.70%, 95% CI: -2.25, 3.73). Prenatal aluminum exposure during the second and third trimesters was positively associated with newborn mtDNAcn. Further studies are essential to elucidate on the potential health consequences of newborn mtDNAcn.


Assuntos
Alumínio/toxicidade , Variações do Número de Cópias de DNA/efeitos dos fármacos , DNA Mitocondrial/genética , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto , Alumínio/urina , China , Cidades , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mitocôndrias/genética , Gravidez , Primeiro Trimestre da Gravidez
3.
Chemosphere ; 230: 432-439, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31121507

RESUMO

This study was conducted to investigate the effects of maternal exposure to BPA on testicular development in offspring males. Pregnant Kunming mice were randomly divided into 7 groups with 20 mice in each group. Group A was the control group and the mice were given distilled water orally. Mice in groups B, C, D, E, F, G received BPA orally at a dose of 0.05 mg/kg/d, 0.5 mg/kg/d, 5 mg/kg/d, 10 mg/kg/d, 20 mg/kg/d, 50 mg/kg/d, respectively. F0 mice were exposed to BPA for 40 days from gestation day 0 to lactation day 21. F1 male mice were sacrificed at weaning (postnatal day 21). Histological observations revealed architectural damages in testis in BPA exposed groups. The testicular organ index increased significantly when the BPA oral exposure dose was above 20 mg/kg/d (P < 0.05). BPA contents in serum of F1 male mice increased significantly when BPA was above 5 mg/kg/d (P < 0.05), while the contents significant increased in maternal serum when BPA was higher than 0.5 mg/kg/d. The damage of cell nuclear DNA of testis was significantly aggravated when BPA was above 5 mg/kg/d. The expression of AR in the testis was significantly increased when BPA was above 20 mg/kg/d (P < 0.05). Transcriptome sequencing showed that the Snrnp 40 which encoding U5 snRNA subunit was significantly up-regulated in spliceosome pathway, and the Hnrnpu which encoding splicing universal protein component was significantly down-regulated. The blockage of spliceosome might be one of the reasons why BPA affects testicular development.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Processamento de RNA/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Lactação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Transcriptoma/efeitos dos fármacos
4.
Nord J Psychiatry ; 73(4-5): 257-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070508

RESUMO

Background: Prenatal maternal stress increases the risk of offspring developmental and psychological difficulties. The biological mechanisms behind these associations are mostly unknown. One explanation suggests that exposure of the fetus to maternal stress may influence DNA methylation. However, this hypothesis is largely based on animal studies, and human studies of candidate genes from single timepoints. Aim: The aim of this study was to investigate if prenatal maternal stress, in the form of maternal depressive symptoms, was associated with variation in genome-wide DNA methylation at two timepoints. Methods: One-hundred and eighty-four mother-child dyads were selected from a population of pregnant women in the Little-in-Norway study. The Edinburgh Postnatal Depression Scale (EPDS) measured maternal depressive symptoms. It was completed by the pregnant mothers between weeks 17 and 32 of gestation. DNA was obtained from infant saliva cells at two timepoints (age 6 weeks and 12 months). DNA methylation was measured in 274 samples from 6 weeks (n = 146) and 12 months (n = 128) using the Illumina Infinium HumanMethylation 450 BeadChip. Linear regression analyses of prenatal maternal depressive symptoms and infant methylation were performed at 6 weeks and 12 months separately, and for both timepoints together using a mixed model. Results: The analyses revealed no significant genome-wide association between maternal depressive symptoms and infant DNA methylation in the separate analyses and for both timepoints together. Conclusions: This sample of pregnant women and their infants living in Norway did not reveal associations between maternal depressive symptoms and infant DNA methylation.


Assuntos
Metilação de DNA/fisiologia , Depressão/psicologia , Epigenômica/métodos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Adulto , Animais , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Recém-Nascido , Estudos Longitudinais , Mães/psicologia , Noruega/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto Jovem
5.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
6.
BMC Med ; 17(1): 77, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971237

RESUMO

BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. METHOD: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3). RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.


Assuntos
Antioxidantes/administração & dosagem , Exposição Ambiental/análise , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Metais Pesados/toxicidade , Homeostase do Telômero/fisiologia , Telômero/fisiologia , Adolescente , Adulto , Argentina/epidemiologia , Criança , Estudos de Coortes , Dieta , Exposição Ambiental/prevenção & controle , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Exposição Materna/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/genética , Metais Pesados/análise , Metais Pesados/sangue , Metais Pesados/urina , Mães , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Adulto Jovem
7.
Part Fibre Toxicol ; 16(1): 17, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975218

RESUMO

BACKGROUND: Developmental exposure to particulate matter air pollution is harmful to cardiovascular health, but the mechanisms by which this exposure mediates susceptibility to heart disease is poorly understood. We have previously shown, in a mouse model, that gestational exposure to diesel exhaust (DE) results in increased cardiac hypertrophy, fibrosis and susceptibility to heart failure in the adult offspring following transverse aortic constriction. RESULTS: In this study, we have analyzed gene expression in neonatal cardiomyocytes after gestational exposure by RNA-sequencing and have identified 300 genes that are dysregulated, including many involved in cardiac metabolism. We subsequently determined that these cardiomyocytes exhibit reduced metabolic activity as measured by Seahorse extracellular flux analysis. We also surveyed for modifications in DNA methylation at global regulatory regions using reduced representation bisulfite sequencing and found hypomethylation of DNA in neonatal cardiomyocytes isolated from in utero DE exposed neonates. CONCLUSION: We have demonstrated that in utero exposure to diesel exhaust alters the neonatal cardiomyocyte transcriptional and epigenetic landscapes, as well as the metabolic capability of these cells. Understanding how exposure alters the developing heart through dysregulation of gene expression, metabolism and DNA methylation is vital for identifying therapeutic interventions for air pollution-related heart failure.


Assuntos
Metilação de DNA/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transcriptoma/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Animais Recém-Nascidos , Feminino , Exposição por Inalação/efeitos adversos , Exposição Materna/efeitos adversos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo
8.
Proc Natl Acad Sci U S A ; 116(14): 7083-7088, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30890645

RESUMO

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.


Assuntos
Epóxido Hidrolases/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Animais , Epóxido Hidrolases/genética , Feminino , Camundongos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/prevenção & controle , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/prevenção & controle
9.
Dev Psychol ; 55(6): 1164-1181, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843708

RESUMO

This study examines interactions of heritable influences, prenatal substance use, and postnatal parental warmth and hostility on the development of conduct problems in middle childhood for boys and girls. Participants are 561 linked families, collected in 2 cohorts, including birth parents, adoptive parents, and adopted children. Heritable influences on internalizing and externalizing (including substance use) problems were derived from birth mothers' and fathers' symptoms, diagnoses, and age of onset from diagnostic interviews, and the proportion of first-degree relatives with the same type of problems. Smoking during pregnancy (SDP) and alcohol use during pregnancy were assessed retrospectively from birth mothers at 5 months postpartum. Earlier externalizing problems and parental warmth and hostility and were assessed at 1 assessment prior to the outcome (Cohort II: 4.5 years; Cohort I: 7 years). Conduct problems were symptoms from a diagnostic interview assessed at age 6 (Cohort II) or 8 (Cohort I). Findings from regression analyses suggest that (a) SDP plays an important role for the development of conduct problems, (b) some relatively well-accepted effects (e.g., parental hostility) were less important when simultaneously considering multiple factors influencing the development of conduct problems, and (c) main effects of genetic risk and SDP, and interactions among genetic risk and postnatal warmth, SDP and postnatal warmth, and genetic risk, SDP, and postnatal hostility for conduct problems were important for boys' but not girls' conduct problems. Replication is needed, but the current results provide preliminary but empirically grounded hypotheses for future research testing complex developmental models of conduct problems. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Transtorno da Conduta/genética , Relações Pais-Filho , Poder Familiar/psicologia , Efeitos Tardios da Exposição Pré-Natal/genética , Alcoolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hostilidade , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Fatores de Risco
10.
Oxid Med Cell Longev ; 2019: 1472623, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915194

RESUMO

Early-life exposure (from postnatal day 6 to postnatal day 21) to permethrin has been associated with long-term development of dopaminergic neurodegeneration in rats. Here, we first investigated if the dopamine decrease observed following early postnatal exposure to permethrin, an oxidative stressor, can impair the dopamine level in the brain of their untreated offspring. Secondly, we evaluated whether this adverse event affects the epigenome of both directly exposed rats (F0) and their untreated offspring (F1). The results show that early-life exposure to the stressor is associated with changes in global DNA methylation and hydroxymethylation in adult age. Furthermore, parental exposure leads to a significant reduction in dopamine level in the offspring (F1) born from parents or just mothers early-life treated (72.72% and 47.35%, respectively). About 2/3 of pups from exposed mothers showed a significant reduction in dopamine level compared to controls. Global DNA methylation and hydroxymethylation impairment was associated with the F1 pups that showed reduced dopamine. This study provides pivotal evidences on intergenerational effects of postnatal exposure to permethrin emphasizing that this xenobiotic can influence the epigenetic memory of early-life parental perturbations disturbing offspring health.


Assuntos
Metilação de DNA/genética , Dopamina/metabolismo , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Cruzamentos Genéticos , Feminino , Humanos , Masculino , Neostriado/metabolismo , Gravidez , Ratos Wistar
11.
BMC Res Notes ; 12(1): 174, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909978

RESUMO

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


Assuntos
Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Obesidade Pediátrica/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/complicações , Adolescente , Adulto , Ilhas de CpG , Feminino , Humanos , Estudos Longitudinais , Masculino , Mães , Desastres Naturais , Obesidade Pediátrica/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia
12.
Subcell Biochem ; 91: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888647

RESUMO

The prevalence of age-associated disease is increasing at a striking rate globally and there is evidence to suggest that the ageing process may actually begin before birth. It has been well-established that the status of both the maternal and early postnatal environments into which an individual is exposed can have huge implications for the risk of developing age-associated disease, including cardiovascular disease (CVD), type-2 diabetes (T2D) and obesity in later life. Therefore, the dissection of underlying molecular mechanisms to explain this phenomenon, known as 'developmental programming' is a highly investigated area of research. This book chapter will examine the epidemiological evidence and the animal models of suboptimal maternal and early postnatal environments and will discuss the progress being made in the development of safe and effective intervention strategies which ultimately could target those 'programmed' individuals who are known to be at-risk of age-associated disease.


Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Obesidade/etiologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Envelhecimento/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Epigênese Genética , Feminino , Humanos , Modelos Animais , Obesidade/genética , Obesidade/prevenção & controle , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
13.
Gene ; 694: 97-101, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30738962

RESUMO

BACKGROUND: Previous studies indicate that low birth weight and exposure to maternal stress during pregnancy may result in shortened telomeres in infants. Shorter telomere length has in turn been linked with accelerated ageing and with age-related diseases. This study aimed to investigate the association between pregnancy and birth factors and relative telomere length in offspring at 11 years of age. METHODS: Participants were aged 11 years enrolled in the Auckland Birthweight Collaborative Study at birth (n = 380). Half of the children were born small for gestational age (SGA = birthweight ≤ 10th percentile) and half were appropriate for gestational age (AGA = birthweight > 10th percentile). Maternal stress during pregnancy was assessed using the Perceived Stress Scale. Relative leukocyte telomere length (RTL) in leukocytes was measured at 11 years of age using quantitative real-time PCR. RESULTS: RTL was normally distributed (mean = 3.78, SD = 1.05). There were no significant associations between RTL at age 11 years and birthweight, sex, maternal smoking, maternal stress during pregnancy or maternal pre-pregnancy body mass index. CONCLUSION: At age 11 years, RTL did not differ between children by birthweight or pregnancy-related stressors. Further telomere-related studies in newborns, children and adolescents are merited to increase knowledge of potential telomere modulating factors.


Assuntos
Peso ao Nascer/genética , Estresse Psicológico/genética , Homeostase do Telômero/genética , Adulto , Peso ao Nascer/fisiologia , Índice de Massa Corporal , Criança , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Leucócitos , Masculino , Herança Materna/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/metabolismo , Telômero/genética , Encurtamento do Telômero/genética
14.
Food Chem Toxicol ; 126: 142-151, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790712

RESUMO

The retinoid system controls essential cellular processes including mitosis, differentiation and metabolism among others. Although the retinoid-signalling pathway is a potential target for the action of several endocrine disrupting chemicals (EDCs), the information about the developmental effects of bisphenol-A (BPA) on the hepatic retinoid system is scarce. Herein, male mice were in utero exposed to BPA following maternal subcutaneous doses of 0, 10 and 100 µg/kg bw/day from gestational day 9-16 and they were sacrificed at post-natal day 30. Retinoid concentrations and gene expression of key elements involved in the retinoid system were determined in liver. BPA increased all-trans-retinoic acid concentration and expression of Adh1, Aox1 and Cyp1a2 (biosynthesis of retinoic acid), while reduced Mrp3 (efflux from hepatocyte to blood), increased Bcrp expression (biliary excretion) and changed the retinoid-dependent signalling system after reducing expression of Rxrß and increasing that of Fgf21. Furthermore, we found bivariate associations of Rarγ and Rxrγ expressions with all-trans-retinoic acid concentrations and of Fgf21 expression with that of Rarγ. Those findings occurred in animals which showed altered pancreatic function and impaired glucose metabolism during adulthood. The present information should be useful for enhancing testing methods for the identification of EDCs.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Exposição Materna/efeitos adversos , Fenóis/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Retinoides/metabolismo , Animais , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Útero/efeitos dos fármacos , Útero/metabolismo
15.
Reprod Biol Endocrinol ; 17(1): 13, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670046

RESUMO

BACKGROUND: Excessive gestational weight gain (GWG), which is associated with adverse long-term effects on the health of the offspring, has become a major clinical problem. Accumulating evidence indicates that the ovary kisspeptin/GPR54 system directly participates in a series of physiological activities. We used a model of high-fat diet (HFD) during gestational to investigate offspring's ovarian function and whether kisspeptin/GPR54 system is involved. METHODS: After introducing the male and confirmation of mating by checking a vaginal sperm plug, female rats were randomized into two groups: control diet called NCD group and high-fat diet called HFD group. After birth, all rats were changed into a control diet and litter size was adjusted to 12 pups per litter. Ovaries were collected for assessment at postnatal day (PND) 4 and PND 30. The timing of vaginal opening was recorded, and the estrous cyclicity was monitored for 2 consecutive weeks immediately. Primary granulosa cells and ovaries which were taken from PND 4 were collected for determination of the direct effect of kisspeptin-10 (kp-10) in vitro. RESULTS: Neonatal rats exposed to HFD during gestation had a lower number of secondary follicles in the ovary. The expression of follicle-stimulating hormone receptor (FSHR) and kisspeptin was not altered. At prepuberty, the number of antral follicles and preovulatory follicles was elevated with decreased type III follicles in the HFD group. While the expression of ovulation-related genes was decreased, the expression levels of follicular growth-related genes and steroidogenesis synthesis related genes were elevated. A significant increase in kiss1 mRNA and kisspeptin protein was detected without changes in kiss1r mRNA and GPR54. Maternal high-fat diet during gestation resulted in a significant advanced puberty onset and an irregular estrous cycle in offspring rats. In addition, the administration of kp-10 produced an increase in viability of primary granulosa cells and enlarged the size of oocytes. CONCLUSIONS: HFD exposure during maternal gestation had a long-term effect on reproductive function in the offspring and the increased ovarian kisspeptin/GPR54 system might be involved.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Kisspeptinas/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Receptores de Kisspeptina-1/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Kisspeptinas/genética , Masculino , Folículo Ovariano/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos Sprague-Dawley , Receptores de Kisspeptina-1/genética , Maturidade Sexual/genética
16.
Nutr Res ; 61: 41-52, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683438

RESUMO

Previous studies have shown that early life intake of high-fat diet or western-style diet (WD) enhances the development of mammary tumors in adult female rats. Thus, we hypothesized that maternal WD throughout pregnancy and the lactation period could speed up the development of MNU-induced mammary tumors and alter their gene expression. For this, the present study investigated the gene expression profile of chemically-induced mammary tumors in female rat offspring from dams fed a WD or a control diet. Pregnant female Sprague-Dawley rats received a WD (high-fat, low-fiber and oligoelements) or a control diet from gestational day 12 until post-natal day (PND) 21. At PND 21, female offspring received a single dose of N-Methyl-N-Nitrosourea (MNU, 50 mg/kg body weight) and were fed a control diet for 13 weeks. Tumor incidence, multiplicity, and latency were recorded and mammary gland samples were collected for histopathology and gene expression analysis. Tumor multiplicity and histological grade were significantly higher and tumor latency was lower in WD offspring compared to control offspring. Transcriptome profiling identified 57 differentially expressed genes in tumors from WD offspring as compared to control offspring. There was also an increase in mRNA expression of genes such as Emp3, Ccl7, Ets1, Abcc5, and Cyr61, indicative of more aggressive disease detected in tumors from WD offspring. Thus, maternal WD diet increased MNU-induced mammary carcinogenesis in adult female offspring through transcriptome changes that resulted in a more aggressive disease.


Assuntos
Dieta Hiperlipídica , Dieta Ocidental , Neoplasias Mamárias Animais/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Transcriptoma , Animais , Feminino , Perfilação da Expressão Gênica , Genes Neoplásicos , Lactação , Neoplasias Mamárias Animais/induzido quimicamente , Neoplasias Mamárias Animais/patologia , Metilnitrosoureia , Mães , Gradação de Tumores , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
17.
Nutr Res ; 61: 53-63, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683439

RESUMO

Recent studies point to the important role of in utero malnutrition in gene programming and in the development of vascular diseases. We hypothesize that maternal undernutrition affects vascular function in the offspring by promoting epigenetic changes that drive the differential expression of genes involved in endothelial function. To test this, we exposed mice to nutrient deprivation in utero and analyzed its effect on global DNA methylation and expression of endothelium-specific genes in the pulmonary endothelium of the adult progeny. Mice were kept either on ad libitum (AL) or energy-restricted (ER) diet during the second and third trimesters of gestation. Mice in the ER group received 65% of energy compared to mice in the AL diet group. Pulmonary endothelial cells were isolated from 6-week-old male offspring mice (AL-F1 and ER-F1). The expression of genes in the pulmonary endothelium was analyzed using quantitative reverse-transcription polymerase chain reaction array and confirmed by qRT-PCR. Several genes including fibronectin 1 and plasminogen activator inhibitor 1 were upregulated in the endothelium of male ER-F1 mice, whereas the expression of genes involved in regulation of histone acetylation was significantly attenuated. At the same time, the global DNA methylation did not change in pulmonary endothelial cells of ER-F1 mice compared to AL-F1 mice. Overall, we found that maternal undernutrition during pregnancy affects the expression of genes involved in regulation of endothelial cell function in the pulmonary vasculature of male progeny, which could potentially promote pulmonary vascular remodeling.


Assuntos
Dieta , Endotélio Vascular/fisiopatologia , Epigênese Genética , Desnutrição , Fenômenos Fisiológicos da Nutrição Materna , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Metilação de DNA , Ingestão de Energia , Feminino , Fibronectinas/metabolismo , Expressão Gênica , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/metabolismo , Masculino , Desnutrição/etiologia , Camundongos Endogâmicos C57BL , Mães , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Reação em Cadeia da Polimerase , Gravidez , Complicações na Gravidez/etiologia , Fatores Sexuais , Regulação para Cima , Remodelação Vascular
18.
Transl Psychiatry ; 9(1): 23, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655507

RESUMO

Prenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring. Consistent with this hypothesis, fetal Nr3c1 heterozygosity leads to altered DNA methylation landscape in fetal placenta in a sex-specific manner. There was a significant overlap of differentially methylated genes in fetal placenta and adult frontal cortex in Nr3c1 heterozygotes. Phenotypically, Nr3c1 heterozygotes show significantly more anxiety-like behavior than wildtype. DNA methylation status of fetal placental tissue is significantly correlated with anxiety-like behavior of the same animals in adulthood. Thus, placental DNA methylation might predict behavioral phenotypes in adulthood. Our data supports the hypothesis that Nr3c1 influences DNA methylation at birth and that DNA methylation in placenta correlates with adult frontal cortex DNA methylation and anxiety-like phenotypes.


Assuntos
Transtornos de Ansiedade/genética , Comportamento Animal , Metilação de DNA , Placenta , Receptores de Glucocorticoides/deficiência , Fatores Sexuais , Animais , Ilhas de CpG , Modelos Animais de Doenças , Epigênese Genética , Feminino , Feto , Masculino , Camundongos , Camundongos Knockout , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
19.
Nutrients ; 11(1)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641941

RESUMO

Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.


Assuntos
Dieta Hiperlipídica , Nefropatias/genética , Sirtuína 1/metabolismo , Albuminúria/urina , Animais , Biomarcadores/urina , Creatinina/urina , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Inflamação/genética , Inflamação/urina , Rim/metabolismo , Nefropatias/prevenção & controle , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Obesidade/genética , Obesidade/metabolismo , Tamanho do Órgão , Estresse Oxidativo/genética , Cuidado Pós-Natal , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Regulação para Cima
20.
Lipids Health Dis ; 18(1): 19, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658634

RESUMO

BACKGROUND: Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet. METHODS: Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age. RESULTS: Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet. CONCLUSION: Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/genética , Relógios Circadianos/genética , Dexametasona/efeitos adversos , Dieta Hiperlipídica , Gordura Intra-Abdominal/patologia , Obesidade/etiologia , Obesidade/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal , Feminino , Inflamação/genética , Inflamação/patologia , Gordura Intra-Abdominal/metabolismo , Leptina/metabolismo , Tamanho do Órgão , Gravidez , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
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