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1.
Artigo em Inglês | MEDLINE | ID: mdl-31611402

RESUMO

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

2.
Neuroimage ; 203: 116108, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31472249

RESUMO

Disentangling age-related changes from developmental variations in hippocampal volume has proven challenging. This article presents a manual segmentation protocol for the hippocampal-to-ventricle ratio (HVR), a measure combining the assessment of hippocampal volume with surrounding ventricular volume. By providing in a single measure both a standard volumetric assessment of the hippocampus and an approximation of volume loss, based on ventricular enlargement, we believe the HVR provides a superior cross-sectional estimation of hippocampal structural integrity. In a first attempt to validate this measure, we contrasted the HVR and standard hippocampal volume in their associations with age and memory performance in two independent cohorts of healthy aging individuals. The first cohort consisted in 50 cognitively normal subjects (mean age: 66.8 years, SD: 4.96, range: 60-75 years), while the second cohort included 88 cognitively normal subjects (mean age: 65.06 years, SD: 6.42, range: 55-80 years). We showed that the manual segmentation protocol for the HVR can be implemented with high reliability. In both cohorts, the HVR showed stronger negative associations with age than standard hippocampal volume. Correlations with memory performance were also numerically superior with the HVR than standard hippocampal volume, across the two cohorts. These findings support an added benefit of using the HVR over standard hippocampal volume when examining relationships with age or memory function in aging individuals. Although further validation is required, we propose that the computation of the HVR is a promising method to improve the evaluation of hippocampal integrity from cross-sectional MR images.

3.
Nat Commun ; 10(1): 2548, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186427

RESUMO

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.


Assuntos
Metilação de DNA/genética , DNA/sangue , Interação Gene-Ambiente , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Genótipo , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
4.
Brain Behav Immun ; 80: 419-426, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30974172

RESUMO

INTRODUCTION: Telomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth. METHODS AND MATERIALS: Participants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth. RESULTS: After adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (ß = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy. DISCUSSION: These findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30858011

RESUMO

OBJECTIVE: Women exposed to childhood maltreatment (CM) are more likely to exhibit insensitive parenting, which may have consequences for their offspring's development. Variation in the oxytocin-receptor gene (OXTR) moderates risk of CM-associated long-term sequelae associated with mother-child attachment, although functionality of previously investigated single nucleotide polymorphisms (SNPs) remained elusive. Here, we investigated the role of OXTR rs237895, a brain tissue expression quantitative trait locus (eQTL), as a moderator of the relationship between CM and maternal behavior (MB) and the association between MB and offspring attachment security. METHOD: Of 110 women with information on rs237895 genotype (T-allele = 64, CC = 46), 107 had information on CM (CTQ) and 99 on standardized observer-based ratings of MB at 6 months postpartum (responsivity and detachment), which were used in principal component analysis to obtain a latent factor representing MB. Offspring (n = 86) attachment was evaluated at 12 months of age. Analyses predicting MB were adjusted for socioeconomic status, age, postpartum depression, and genotype-based ethnicity. Analyses predicting child attachment were adjusted for infant sex, socioeconomic status, and postpartum depression. RESULTS: rs237895 significantly moderated the relationship between CM and MB (F1;66 = 7.99, p < .01), indicating that CM was associated with maternal insensitivity only in high-OXTR-expressing T-allele carriers but not in low-OXTR-expressing CC homozygotes. Moreover, maternal insensitivity predicted offspring insecure attachment (B = -0.551; p < .05). CONCLUSION: Women with a high OXTR expressing genotype are more susceptible to CM-related impairments in MB that, in turn, predict attachment security in their children, supporting the role of the OT system in the intergenerational transmission of risk associated with maternal CM.

6.
Psychoneuroendocrinology ; 103: 156-162, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30690225

RESUMO

Maternal behavior (MB) is observable across mammals and represents an important feature of environmental variation during early postnatal development. Oxytocin (OT) plays a crucial role in MB. Even prior to childbirth, pregnancy induces epigenetic and other downstream changes in the maternal OT-system, likely mediated by the actions of steroid hormones. However, little is known about the nature and consequences of epigenetic modifications in the maternal OT-encoding gene (OXT) during pregnancy. Our study aims to investigate temporal dynamics of OXT promoter DNA methylation (DNAm) throughout pregnancy in predicting MB in humans. In 107 mother-child dyads, maternal OXT DNAm was serially analyzed in whole blood in early, mid and late pregnancy. MB was coded based on standardized mother-child interactions at six months postpartum. After controlling for cellular heterogeneity, race/ethnicity, age, and socioeconomic status, OXT-promoter DNAm exhibited a dynamic profile during pregnancy (b = 0.026, t=-3.37, p < .001), with decreases in DNAm from early to mid-pregnancy and no further change until late pregnancy. Moreover, dynamic DNAm trajectories of the OXT-promoter region predicted MB (intrusiveness) at six months postpartum (b = 0.006, t = 2.0, p < 0.05), with 6% higher OXT DNAm in late pregnancy in intrusive compared to non-intrusive mothers. We here demonstrate that OXT promoter DNAm changes significantly throughout gestation in peripheral blood and that these changes are associated with variability in MB, providing a novel potential biomarker predicting postnatal MB.

7.
Neuroimage ; 185: 825-835, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29654875

RESUMO

Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL-6 concentrations in early (12.6 ±â€¯2.8 weeks [S.D.]), mid (20.4 ±â€¯1.5 weeks [S.D.]) and late (30.3 ±â€¯1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ±â€¯1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ±â€¯3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL-6 concentration was positively associated with rate of FA increase across the first year of life (bi-lateral, p < 0.05), resulting in a null association between maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated with offspring cognition at 12-mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context.


Assuntos
Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Interleucina-6/sangue , Rede Nervosa/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Anisotropia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação/complicações , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Substância Branca/crescimento & desenvolvimento
8.
Dev Cogn Neurosci ; 37: 100604, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30581123

RESUMO

Connectivity between the amygdala, insula (Amygdala-aI) and ventral medial prefrontal cortex (Amygdala-vmPFC) have been implicated in individual variability in fear and vulnerability to psychiatric disorders. However, it is currently unknown to what extent connectivity between these regions in the newborn period is relevant for the development of fear and other aspects of negative emotionality (NE), such as sadness. Here, we investigate newborn Am-Ins and Am-vmPFC resting state functional connectivity in relation to developmental trajectories of fear and sadness over the first two years of life using data from the Infant Behavior Questionnaire Revised (IBQ-R) and Early Childhood Behavior Questionnaire (ECBQ) (N=62). Stronger newborn amygdala connectivity predicts higher fear and sadness at 6-months-of-age and less change from 6 to 24-months-of-age. Interestingly, Am-Ins connectivity was specifically relevant for fear and not sadness, while Am-vmPFC was associated only with sadness. Associations remained consistent after considering variation in maternal sensitivity and maternal postnatal depressive symptomology. Already by the time of birth, individual differences in amygdala connectivity are relevant for the expression of fear over the first two-years-of-life. Additionally, specificity is observed, such that connections relevant for fear development are distinct from those predicting sadness trajectories.

9.
Psychoneuroendocrinology ; 105: 123-137, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30578047

RESUMO

This review integrates scientific knowledge obtained over the past few decades on the biological mechanisms that contribute to the profound association between exposure to early adversity, including childhood trauma and prenatal stress, and the lifelong elevated risk to develop a broad range of diseases. We further discuss insights into gene-environment interactions moderating the association between early adversity and disease manifestation and we discuss the role of epigenetic and other molecular processes in the biological embedding of early adversity. Based on these findings, we propose potential mechanisms that may contribute to the intergenerational transmission of risk related to early adversity from the mother to the fetus. Finally, we argue that basic research knowledge on the biological embedding of early adversity must now be translated into novel intervention strategies that are mechanism-driven and sensitive to developmental timing. Indeed, to date, there are no diagnostic biomarkers of risk or mechanism-informed interventions that we can offer to victims of early adversity in order to efficiently prevent or reverse adverse health outcomes. Such translational efforts can be expected to have significant impact on both clinical practice and the public health system, and will promote precision medicine in pediatrics and across the lifespan.

10.
Front Immunol ; 9: 2186, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319639

RESUMO

Milestones of brain development in mammals are completed before birth, which provide the prerequisite for cognitive and intellectual performances of the offspring. Prenatal challenges, such as maternal stress experience or infections, have been linked to impaired cognitive development, poor intellectual performances as well as neurodevelopmental and psychiatric disorders in the offspring later in life. Fetal microglial cells may be the target of such challenges and could be functionally modified by maternal markers. Maternal markers can cross the placenta and reach the fetus, a phenomenon commonly referred to as "vertical transfer." These maternal markers include hormones, such as glucocorticoids, and also maternal immune cells and cytokines, all of which can be altered in response to prenatal challenges. Whilst it is difficult to discriminate between the maternal or fetal origin of glucocorticoids and cytokines in the offspring, immune cells of maternal origin-although low in frequency-can be clearly set apart from offspring's cells in the fetal and adult brain. To date, insights into the functional role of these cells are limited, but it is emergingly recognized that these maternal microchimeric cells may affect fetal brain development, as well as post-natal cognitive performances and behavior. Moreover, the inheritance of vertically transferred cells across generations has been proposed, yielding to the presence of a microchiome in individuals. Hence, it will be one of the scientific challenges in the field of neuroimmunology to identify the functional role of maternal microchimeric cells as well as the brain microchiome. Maternal microchimeric cells, along with hormones and cytokines, may induce epigenetic changes in the fetal brain. Recent data underpin that brain development in response to prenatal stress challenges can be altered across several generations, independent of a genetic predisposition, supporting an epigenetic inheritance. We here discuss how fetal brain development and offspring's cognitive functions later in life is modulated in the turnstile of prenatal challenges by introducing novel and recently emerging pathway, involving maternal hormones and immune markers.

11.
Nutrients ; 10(9)2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30200631

RESUMO

Maternal inflammation during pregnancy is known to adversely impact fetal development, birth outcomes, and offspring physical and mental health. Diet and stress have been identified as important determinants of inflammation, yet their combined effects have not been examined in the context of pregnancy. The aim of this study was to examine the relationship between maternal diet with inflammatory potential and psychological stress, and to determine their interaction effect on concentrations of tumor necrosis factor (TNF)-α across pregnancy. We conducted a prospective longitudinal study of n = 202 women with three assessments during pregnancy, which included: ecological momentary assessment (EMA) of maternal stress using the perceived stress scale (PSS) short version; 24-h dietary recalls from which the dietary inflammatory index (DII) was computed; and serum measurements of TNF-α. Across pregnancy, higher perceived stress was associated with consumption of a more pro-inflammatory diet (r = 0.137; p < 0.05). In a linear regression model adjusted for covariates, DII was positively associated with TNF-α (B = 0.093, p = 0.010). The effect of the pro-inflammatory diet on concentrations of TNF-α was more pronounced in women reporting higher levels of stress (B = 0.134, p = 0.018 for DII*PSS interaction). These results highlight the need to consider nutrition and stress concurrently in the context of inflammation during pregnancy.

12.
Biol Psychiatry ; 2018 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-30122286

RESUMO

BACKGROUND: Maternal cortisol during pregnancy has the potential to influence rapidly developing fetal brain systems that are commonly altered in neurodevelopmental and psychiatric disorders. Research examining maternal cortisol concentrations across pregnancy and offspring neurodevelopment proximal to birth is needed to advance understanding in this area and lead to insight into the etiology of these disorders. METHODS: Participants were 70 adult women recruited during early pregnancy and their infants born after 34 weeks gestation. Maternal cortisol concentrations were assessed serially over 4 days in early, mid, and late gestation. Resting state functional connectivity magnetic resonance imaging of the neonatal amygdala was examined. Mothers reported on children's internalizing behavior problems at 24 months of age. RESULTS: Maternal cortisol concentrations during pregnancy were significantly associated with neonatal amygdala connectivity in a sex-specific manner. Elevated maternal cortisol was associated with stronger amygdala connectivity to brain regions involved in sensory processing and integration, as well as the default mode network in girls, and with weaker connectivity to these brain regions in boys. Elevated maternal cortisol was associated with higher internalizing symptoms in girls only, and this association was mediated by stronger neonatal amygdala connectivity. CONCLUSIONS: Normative variation in maternal cortisol during pregnancy is associated with the coordinated functioning of the amygdala soon after birth in a sex-specific manner. The identified pathway from maternal cortisol to higher internalizing symptoms in girls via alterations in neonatal amygdala connectivity may be relevant for the etiology of sex differences in internalizing psychiatric disorders, which are more prevalent in women.

13.
Brain Behav Immun ; 73: 731-735, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30086398

RESUMO

BACKGROUND: The process of acculturation (post-migration acquisition of host culture and/or loss of heritage culture) likely represents a key mediator of the observed post-migration decline in health that is evident among immigrant populations such as Mexican Americans. The observations that migrant health declines progressively as not only a function of length of stay in the U.S. but also across generations, and that this inter-generational decline in health is evident as early as at the time of birth itself, supports the concept of fetal programming of acculturation's effects. However, the underlying mechanisms remain to be elucidated. Inflammation during pregnancy represents a candidate pathway of particular interest for 2 reasons: it represents a key biological mediator of the psychosocial and/or behavioral sequelae of acculturation on health, and it represents a key pathway by which maternal states and conditions during pregnancy may influence fetal development and subsequent birth and child developmental and health outcomes. Therefore, the aim of this study was to examine the relationship between acculturation and inflammation across pregnancy in a population of Mexican-American women. Specifically, we tested the hypothesis that a higher level of acculturation is associated with higher circulating concentrations across pregnancy of the pro-inflammatory cytokine interleukin-6 (IL-6). METHODS: 75 pregnant first- or second-generation Mexican-American women constituted the study population. Acculturation was quantified using a commonly-used and previously validated measure - the Acculturation Rating Scale for Mexican Americans (ARSMA). Maternal blood samples were collected during early, mid and late pregnancy for analysis of circulating IL-6 concentrations. RESULTS: Hierarchical linear models indicated a significantly and positive main effect of acculturation on IL-6 concentrations across pregnancy after adjusting for key covariates including gestational age(s) at blood sampling, socioeconomic status, pre-pregnancy BMI, and presence of obstetric risk conditions. CONCLUSIONS: Maternal inflammation during pregnancy may represent a biological pathway of interest in the context of the inter-generational effects of acculturation from a mother to her as-yet-unborn child.

14.
Biol Psychiatry ; 2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30057177

RESUMO

Growing evidence supports an important role for the intrauterine environment in shaping fetal development and subsequent child health and disease risk. The fetal brain is particularly plastic, whereby even subtle changes in structure and function produced by in utero conditions can have long-term implications. Based on the consideration that conditions related to energy substrate and likelihood of survival to reproductive age are particularly salient drivers of fetal programming, maternal nutrition and stress represent the most commonly, but independently, studied factors in this context. However, the effects of maternal nutrition and stress are context dependent and may be moderated by one another. Studies examining the effects of the bidirectional nutrition-stress interplay in pregnancy on fetal programming of brain development are beginning to emerge in the literature. This review incorporates all currently available animal and human studies of this interplay and provides a synthesis and critical discussion of findings. Nine of the 10 studies included here assessed nutrition-stress interactions and offspring neurodevelopmental or brain development outcomes. Despite significant heterogeneity in study design and methodology, two broad patterns of results emerge to suggest that the effects of prenatal stress on various aspects of brain development may be mitigated by 1) higher fat diets or increased intake and/or status of specific dietary fats and 2) higher dietary intake or supplementation of targeted nutrients. The limitations of these studies are discussed, and recommendations are provided for future research to expand on this important area of fetal programming of brain development.

15.
Arch Womens Ment Health ; 21(6): 785-790, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29862416

RESUMO

To evaluate the association between psychotropic medication and inflammatory biomarkers in women with antenatal depressive symptoms (ADS). In this cross-sectional secondary analysis of a prospective multicenter observational study, 723 pregnant women underwent a depression screen using the Center for Epidemiologic Studies Depression Scale (CES-D) between 12 and 21 weeks gestation. Self-reported use of medications for depression and/or anxiety was corroborated with the medical record to document exposure to pharmacotherapy. Serum was collected and inflammatory biomarkers (IFNγ, IL13, IL6, IL8, TNFα, CRP) were measured concomitantly. Women were included if they fell into one of three categories: ADS responsive to treatment (CES-D < 16 with medication), ADS not responsive to medication (CES-D ≥ 23 despite medication), and untreated ADS (CES-D ≥ 23 with no medication). Levels of inflammatory biomarkers were compared among groups and multivariable regressions performed. Of the 85 women studied, 16 (19%) had ADS responsive to treatment, 12 (14%) had ADS not responsive to medication, and 57 (67%) had untreated ADS. TNFα concentrations significantly differed (P = 0.016) across the cohorts. Post hoc bivariate analyses demonstrated that women with ADS responsive to treatment had lower serum TNFα than non-responders (p = 0.02) and women with untreated ADS (p = 0.01). There were no differences in IFNγ, IL13, IL6, IL8, or CRP among the groups. Regressions demonstrated that, compared to women with ADS responsive to treatment, non-responders or women with untreated ADS had higher TNFα levels (ß = 0.27, 95% CI 0.02-0.52 and ß = 0.23, 95% CI 0.02-0.44, respectively). Pregnant women on pharmacotherapy who respond to treatment for ADS have lower TNFα compared to women not responsive to medication or women with untreated ADS. These data suggest the possibility that either the therapeutic response in the context of pharmacotherapy is accompanied by modulation of the immune system or that pre-existing higher levels of TNFα may be associated with a poorer response to traditional pharmacotherapy.

16.
Mol Nutr Food Res ; : e1700889, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29714050

RESUMO

SCOPE: The fetal programming paradigm posits that the origins of obesity can be traced, in part, to the intrauterine period of life. However, the mechanisms underlying fetal programming are not well understood, and few studies have measured offspring adiposity in the neonatal period. The aim of this study is to identify maternal metabolites, and their determinants, that are associated with neonatal adiposity. METHODS AND RESULTS: A targeted metabolomics approach is applied to analyze plasma samples collected across gestation from a well-characterized cohort of 253 pregnant women participating in a prospective study at the University of California, Irvine. Whole-body dual X-ray absorptiometry (DXA) imaging of body composition is obtained in N = 121 newborns. Statistical models are adjusted for potential confounders and multiple testing. The authors identify six alkyl-linked phosphatidylcholines (PCae), containing fatty acid 20:4, that are significantly and negatively associated with neonatal body fat percentage. Factors indicating higher socioeconomic status, non-Hispanic ethnicity, and higher nonesterified fatty acid percentages are positively associated with these PCae. CONCLUSIONS: The polyunsaturated fatty acid 20:4 contained in PCae may exert a beneficial effect with respect to future propensity for obesity development. Prepregnancy and early pregnancy factors are determinants of these PCae, highlighting the importance of addressing preconceptional conditions for fetal programming of newborn adiposity.

17.
Nat Neurosci ; 21(5): 765-772, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29632361

RESUMO

Several lines of evidence support the link between maternal inflammation during pregnancy and increased likelihood of neurodevelopmental and psychiatric disorders in offspring. This longitudinal study seeks to advance understanding regarding implications of systemic maternal inflammation during pregnancy, indexed by plasma interleukin-6 (IL-6) concentrations, for large-scale brain system development and emerging executive function skills in offspring. We assessed maternal IL-6 during pregnancy, functional magnetic resonance imaging acquired in neonates, and working memory (an important component of executive function) at 2 years of age. Functional connectivity within and between multiple neonatal brain networks can be modeled to estimate maternal IL-6 concentrations during pregnancy. Brain regions heavily weighted in these models overlap substantially with those supporting working memory in a large meta-analysis. Maternal IL-6 also directly accounts for a portion of the variance of working memory at 2 years of age. Findings highlight the association of maternal inflammation during pregnancy with the developing functional architecture of the brain and emerging executive function.

19.
Artigo em Inglês | MEDLINE | ID: mdl-29335381

RESUMO

Research on mechanisms underlying fetal programming of health and disease risk has focused primarily on processes that are specific to cell types, organs or phenotypes of interest. However, the observation that developmental conditions concomitantly influence a diverse set of phenotypes, the majority of which are implicated in age-related disorders, raises the possibility that such developmental conditions may additionally exert effects via a common underlying mechanism that involves cellular/molecular ageing-related processes. In this context, we submit that telomere biology represents a process of particular interest in humans because, firstly, this system represents among the most salient antecedent cellular phenotypes for common age-related disorders; secondly, its initial (newborn) setting appears to be particularly important for its long-term effects; and thirdly, its initial setting appears to be plastic and under developmental regulation. We propose that the effects of suboptimal intrauterine conditions on the initial setting of telomere length and telomerase expression/activity capacity may be mediated by the programming actions of stress-related maternal-placental-fetal oxidative, immune, endocrine and metabolic pathways in a manner that may ultimately accelerate cellular dysfunction, ageing and disease susceptibility over the lifespan. This perspectives paper provides an overview of each of the elements underlying this hypothesis, with an emphasis on recent developments, findings and future directions.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.

20.
J Perinatol ; 38(5): 462-467, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29379158

RESUMO

OBJECTIVE: To evaluate the association between prenatal stress and gestational weight gain (GWG). STUDY DESIGN: This was an analysis of women recruited between 2013-2015 from four sites in the US. We tested associations between responses at 32-35 weeks to the Life Experiences Survey (LES), a 37-item measure of events and perceived stress, and GWG categories. Bivariable comparisons and logistic regression were used to estimate the association between the total LES score and the odds of achieving adequate GWG. RESULT: Among the 725 women, those with adequate GWG had lower median LES scores (5) compared to women with inadequate (7) and excessive (7) GWG, p = 0.02. After adjusting for age, initial BMI, income, education, marital status and gestational diabetes, lower LES scores (multiples of the median) were associated with adequate GWG (aOR 0.81, 95% CI 0.67-0.98). CONCLUSION: Lower reported stress, as measured by the LES, was associated with a greater chance of women achieving adequate GWG. This relationship highlights the potential for interventions directed toward psychosocial support to have salutary effects upon GWG.

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