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1.
Environ Pollut ; 291: 118208, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34740291

RESUMO

Increasingly, studies suggest benefits of natural environments or greenness on children's health. However, little is known about cumulative exposure or windows of susceptibility to greenness exposure. Using inverse probability weighting of marginal structural models (IPW/MSM), we estimated effects of greenness exposure from birth through adolescence on executive function and behavior. We analyzed data of 908 children from Project Viva enrolled at birth in 1999-2002 and followed up until early adolescence. In mid-childhood (median 7.7 years) and early adolescence (13.1 years), executive function and behavior were assessed using the Behavior Rating Inventory of Executive Function and the Strengths and Difficulties Questionnaire (SDQ). Greenness was measured at birth, early childhood, mid-childhood, and early adolescence, using the Normalized Difference Vegetation Index. We used inverse probability weighting of marginal structural models to estimate effects of interventions that ensure maximum greenness exposure versus minimum through all intervals; and that ensure maximum greenness only in early childhood (vs. minimum through all intervals). Results of the effects of "maximum (vs. minimum) greenness at all timepoints" did not suggest associations with mid-childhood outcomes. Estimates of "maximum greenness only in early childhood (vs. minimum)" suggested a beneficial association with mid-childhood SDQ (-3.21, 99 %CI: -6.71,0.29 mother-rated; -4.02, 99 %CI: -7.87,-0.17 teacher-rated). No associations were observed with early adolescent outcomes. Our results for "persistent" maximum greenness exposure on behavior, were not conclusive with confidence intervals containing the null. The results for maximum greenness "only in early childhood" may shed light on sensitive periods of greenness exposure for behavior regulation.


Assuntos
Meio Ambiente , Função Executiva , Adolescente , Criança , Pré-Escolar , Humanos , Recém-Nascido , Modelos Estruturais , Probabilidade
2.
Hum Reprod ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34755186

RESUMO

STUDY QUESTION: Is cesarean delivery associated with earlier offspring pubertal development? SUMMARY ANSWER: We identified that boys born by cesarean delivery developed puberty earlier, evidenced by an earlier age at peak height velocity and earlier attainment of puberty score > 1, than boys born by vaginal delivery. WHAT IS KNOWN ALREADY: Cesarean delivery is posited to have long-term effects on health outcomes. However, few studies have examined whether mode of delivery is related to pubertal development. STUDY DESIGN, SIZE, DURATION: Prospective pre-birth cohort study consisting of 1485 mother-child pairs enrolled during pregnancy from obstetric practices and followed up until early adolescence (median age 12.9 years). Participant inclusion required data on mode of delivery and at least one measure of pubertal development. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants are children from the Project Viva study. We abstracted information on delivery mode from electronic medical records from children followed since birth (1999-2002) and examined the following markers of pubertal development: age at peak height velocity (APHV); age at menarche (girls only); parent-reported pubertal development score; and child-reported pictograph Tanner pubic hair staging. We used multivariable regression models to examine associations of delivery mode with these four pubertal indices, adjusting for the following confounders: demographic and socioeconomic factors; maternal height, pre-pregnancy BMI, total gestational weight gain, pregnancy conditions, parity, and maternal age at menarche; paternal height and BMI; gestational age at delivery and birthweight-for-gestational-age z-score. MAIN RESULTS AND THE ROLE OF CHANCE: In this study, 23.2% of children were born by cesarean delivery. Girls had an earlier APHV, had a higher pubertal score throughout childhood and in early adolescence, and were more likely to attain puberty score >1 and Tanner pubic hair Stage >1 earlier compared to boys. Mean (SD) age at menarche in girls was 12.4 (1.0) years. Boys born by cesarean delivery had significantly earlier APHV (ß -0.23 years; 95% CI -0.40, -0.05) and higher risk of earlier attainment of puberty score > 1 (hazard ratio 1.09; 95% CI 1.01, 1.19) than boys born by vaginal delivery, after adjusting for confounders. These associations were not mediated by pre-pubertal BMI and were similar for planned (no labor) and unplanned (labor) cesarean delivery. No associations were observed between delivery mode and time to attain Tanner pubic hair Stage > 1 in boys. In girls, mode of delivery was not associated with any of the measured pubertal development markers. LIMITATIONS, REASONS FOR CAUTION: This study used, as secondary outcomes, parent- and child-reported measures of pubertal development, which may be more prone to error and misclassification than information collected by trained observers or physicians during clinical examinations. The findings may also not be generalizable to populations from different settings, because all participants lived in one geographic area, were well educated, and had health care. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide support for cesarean delivery as a potential indicator of identifying children who are likely to experience earlier pubertal development; however, more studies are needed to confirm or refute these observations. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by grants from the National Institutes of Health. The authors have no financial relationships or competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

3.
Environ Health Perspect ; 129(11): 117007, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34797165

RESUMO

BACKGROUND: Metal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants. OBJECTIVES: We evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress. METHODS: We measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions. RESULTS: A 2-fold increase in maternal magnesium was associated with lower maternal [ß=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (ß=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (ß=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (ß=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (ß=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium. DISCUSSION: Maternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.

4.
Clin Epigenetics ; 13(1): 208, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798907

RESUMO

BACKGROUND: Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses. RESULTS: Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10-6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn. CONCLUSIONS: Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

5.
JAMA Netw Open ; 4(10): e2125161, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623410

RESUMO

Importance: Although the literature on the association between birth by cesarean delivery and children's anthropometry has continued to increase, only a few studies have examined the association of cesarean delivery with measures of body composition assessed using dual-energy x-ray absorptiometry (DXA), which allows the differentiation of fat and lean mass overall and in specific regions of the body. Objective: To investigate whether differences exist in DXA-measured body composition between children and adolescents born by cesarean delivery and those born by vaginal delivery. Design, Setting, and Participants: This prospective cohort study included singleton children of mothers enrolled between April 1999 and July 2002 in Project Viva, a longitudinal prebirth cohort of mother-child pairs in Massachusetts. The children had at least 1 DXA scan at a follow-up visit during middle childhood (2007-2010) and/or early adolescence (2013-2016). Data analysis was performed from October 16, 2020, to May 9, 2021. Exposures: Mode of delivery (cesarean vs vaginal). Main Outcomes and Measures: Total lean mass index, total and truncal fat mass indexes, visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue, and total abdominal adipose tissue (TAAT) were estimated using DXA. Multivariable linear regression models were used to estimate the association between mode of delivery and DXA-derived outcomes with adjustment for confounders. Stabilized inverse probability weights were used to control for potential selection bias owing to loss to follow-up. Results: A total of 975 mother-child pairs were included in the study. The mean (SD) maternal age at study entry was 32.0 (5.5) years, and the mean (SD) self-reported prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25.0 (5.4). Of the children included in the study, 491 (50%) were female; 212 (22%) were born by cesarean delivery and 763 (78%) by vaginal delivery. Body composition in middle childhood as measured by DXA did not differ by mode of delivery. In early adolescence, participants born by cesarean delivery had a significantly greater total lean mass index (ß, 0.4; 95% CI, 0.0-0.7), total fat mass index (ß, 0.6; 95% CI, 0.1-1.1), truncal fat mass index (ß, 0.3; 95% CI, 0.0-0.5), VAT area (ß, 4.7; 95% CI, 0.9-8.6), and TAAT area (ß, 23.8; 95% CI, 0.8-46.8) in a model adjusted for child sex and age at the time of DXA measurements; maternal age, educational level, race and ethnicity, total gestational weight gain, and smoking status during pregnancy; birth-weight-per-gestational-age z score; and paternal BMI. Associations between mode of delivery and measures of adiposity were found for cesarean deliveries performed in the absence of labor (total fat mass index: ß, 1.3; 95% CI, 0.3-2.3; truncal fat mass index: ß, 0.6; 95% CI, 0.1-1.0; VAT area: ß, 10.7; 95% CI, 3.1-18.3; TAAT area: ß, 47.3; 95% CI, 2.3-92.2). There were no associations after adjustment for maternal self-reported prepregnancy BMI (total lean mass index: ß, 0.2; 95% CI, -0.1 to 0.6; total fat mass index: ß, 0.4; 95% CI, -0.1 to 0.9; truncal fat mass index: ß, 0.2; 95% CI, -0.1 to 0.4; VAT area: ß, 3.0; 95% CI, -0.6 to 6.7; TAAT area: ß, 13.6; 95% CI, -8.2 to 35.3). Conclusions and Relevance: In this cohort study, adolescents born by cesarean delivery had significantly higher measures of lean mass, fat mass, and central adiposity compared with those born by vaginal delivery, but associations did not remain after adjustment for the mothers' self-reported prepregnancy BMI. The findings suggest that the association between birth by cesarean delivery and adolescent adiposity may partly be explained by maternal self-reported prepregnancy BMI.

6.
Epigenomics ; 13(18): 1459-1472, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34596421

RESUMO

Background: Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization. Methods: In the Gen3G study, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother-child pairs. Results: The first principal component was robustly associated with lower DNAm at cg26974062 (TXNIP; p = 9.9 × 10-9) in cord blood. TXNIP is a well-known DNAm marker for type 2 diabetes in adults. Conclusion: We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation of TXNIP across the life course.

7.
Int J Epidemiol ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34534313

RESUMO

BACKGROUND: Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages. METHODS: We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm). RESULTS: EAA was associated with paternal education in CARDIA [GEEs: ßsome college = -1.01 years (-1.91, -0.11) and ß

8.
Am J Clin Nutr ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523669

RESUMO

Food systems are at the center of a brewing storm consisting of a rapidly changing climate, rising hunger and malnutrition and significant social inequities. At the same time, there are vast opportunities to ensure that food systems produce healthy and safe food in equitable ways that promote environmental sustainability, especially if the world can come together at the UN Food Systems Summit in late 2021 and make strong and binding commitments towards food system transformation. The NIH-funded Nutrition Obesity Research Center at Harvard and the Harvard Medical School Division of Nutrition held their 22nd Annual Harvard Nutrition Obesity Symposium entitled "Global Food Systems and Sustainable Nutrition in the 21st Century" in June 2021. This paper presents a synthesis of this symposium and highlights the importance of food systems to address the burden of malnutrition and non-communicable diseases, climate change, and the economic and social inequities. Transformation of food systems is possible, and the nutrition and health communities have a significant role to play in this transformative process.

9.
Environ Res ; 204(Pt B): 112093, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34562483

RESUMO

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (ß = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (ß = 0.004, p-value = 4.97 × 10-5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (ß = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (ß = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.

10.
Obesity (Silver Spring) ; 29(11): 1882-1891, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34529343

RESUMO

OBJECTIVE: This study examined the associations of central adiposity gain from midchildhood to early adolescence with cardiometabolic health markers in early adolescence. METHODS: A total of 620 participants were studied in Project Viva. In midchildhood (mean age = 7.8 years) and early adolescence (12.9 years), waist circumference and dual-energy x-ray absorptiometry-measured visceral adipose tissue, subcutaneous abdominal adipose tissue, and trunk fat were obtained. Central adiposity gain was calculated as change per year between visits. Cardiometabolic health markers, including blood pressure, lipids, markers of insulin resistance, inflammation, and adipokines, were collected in early adolescence. RESULTS: Greater waist circumference gain was associated with higher log triglycerides (ß 0.07 mg/dL; 95% CI: 0.02-0.13), log alanine aminotransferase (0.07 U/L; 95% CI: 0.03-0.12), log high-sensitivity C-reactive protein (0.43 mg/L; 95% CI: 0.28-0.58), and other cardiometabolic markers in early adolescence. Directly measured central adiposity gains were associated with higher systolic blood pressure z score in early adolescence (visceral adipose tissue [0.13 SD units; 95% CI: 0.04-0.23], subcutaneous abdominal adipose tissue [0.18 SD units; 95% CI: 0.04-0.31], and trunk fat [0.21 SD units; 95% CI: 0.06-0.36]). These associations were independent of baseline and change in total adiposity from midchildhood to early adolescence. CONCLUSIONS: Monitoring central adiposity gain may enable identification and intervention in children vulnerable to developing cardiometabolic health risks.

11.
Am J Clin Nutr ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581769

RESUMO

BACKGROUND: It is unknown whether behavioral interventions to improve diet are effective in people with a genetic predisposition to obesity. OBJECTIVES: To examine associations between BMI genetic risk and changes in weight and workplace purchases by employees participating in a randomized controlled trial of an automated behavioral workplace intervention to promote healthy food choices. METHODS: Participants were hospital employees enrolled in a 12-mo intervention followed by a 12-mo follow-up. Hospital cafeterias utilized a traffic-light labeling system (e.g., green = healthy, red = unhealthy) that was used to calculate a validated Healthy Purchasing Score (HPS; higher = healthier). A weighted genome-wide BMI genetic score was generated by summing BMI-increasing alleles. RESULTS: The study included 397 adults of European ancestry (mean age, 44.9 y; 80.9% female). Participants in the highest genetic quartile (Q4) had a lower HPS and higher purchases of red-labeled items relative to participants in the lowest quartile (Q1) at baseline [Q4-Q1 Beta HPS, -4.66 (95% CI, -8.01 to -1.32); red-labeled items, 4.26% (95% CI, 1.45%-7.07%)] and at the 12-mo [HPS, -3.96 (95% CI, -7.5 to -0.41); red-labeled items, 3.20% (95% CI, 0.31%-6.09%)] and 24-mo [HPS, -3.70 (95% CI, -7.40 to 0.00); red-labeled items, 3.48% (95% CI, 0.54%-6.41%)] follow-up periods. In the intervention group, increases in HPS were similar in Q4 and Q1 at 12 mo (Q4-Q1 Beta, 1.04; 95% CI, -2.42 to 4.50). At the 24-mo follow-up, the change in BMI from baseline was similar between Q4 and Q1 (0.17 kg/m2; 95% CI, -0.55 to 0.89 kg/m2) in the intervention group, but higher in Q4 than Q1 (1.20 kg/m2; 95% CI, 0.26-2.13 kg/m2) in the control group. No interaction was evident between the treatment arm and genetic score for BMI or HPS. CONCLUSIONS: Having a high BMI genetic risk was associated with greater increases in BMI and lower quality purchases over 2 y. The 12-mo behavioral intervention improved employees' food choices, regardless of the genetic burden, and may have attenuated weight gain conferred by having the genetic risk.

12.
Environ Int ; 157: 106789, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34333293

RESUMO

BACKGROUND: Understanding the temporal trends and change of concentrations of per- and polyfluoroalkyl substances (PFAS) is important to evaluate the health impact of PFAS at both the individual- and population-level, however, limited information is available for pre-diabetic adults in the U.S. OBJECTIVES: Determine trends and rate of change of plasma PFAS concentrations in overweight or obese U.S. adults and evaluate variation by sex, race/ethnicity, and age. METHODS: We described temporal trends of plasma PFAS concentrations using samples collected in 1996-1998, 1999-2001, and 2011-2012 from 957 pre-diabetic adults enrolled in the Diabetes Prevention Program (DPP) trial and Outcomes Study (DPPOS) and compared to serum concentrations from the National Health and Nutrition Examination Survey (NHANES 1999-2000, 2003-2016, adults with BMI ≥ 24 kg/m2). We examined associations between participants' characteristics and PFAS concentrations and estimated the rate of change using repeated measures in DPP/DPPOS assuming a first-order elimination model. RESULTS: Longitudinal measures of PFAS concentrations in DPP/DPPOS individuals were comparable to NHANES cross-sectional populational means. Plasma concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorohexanesulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), and N-methylperfluorooctane sulfonamido acetic acid (MeFOSAA) started to decline after the year 2000 and concentrations of perfluorononanoic acid (PFNA) increased after 2000 and, for NHANES, decreased after 2012. We consistently observed higher PFOS, PFHxS and PFNA among male, compared to female, and higher PFOS and PFNA among Black, compared to white, participants. The estimated time for concentrations to decrease by half ranged from 3.39 years for EtFOSAA to 17.56 years for PFHxS. DISCUSSION: We observed a downward temporal trend in plasma PFOS concentrations that was consistent with the timing for U.S. manufacturers' phaseout. Male and Black participants consistently showed higher PFOS and PFNA than female and white participants, likely due to differences in exposure patterns, metabolism or elimination kinetics.


Assuntos
Ácidos Alcanossulfônicos , Diabetes Mellitus Tipo 2 , Poluentes Ambientais , Fluorcarbonetos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Obesidade/prevenção & controle , Sobrepeso , Estados Unidos
13.
Nat Commun ; 12(1): 5095, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429407

RESUMO

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.


Assuntos
Metilação de DNA , Desenvolvimento Fetal/efeitos dos fármacos , Desenvolvimento Fetal/genética , Placenta/metabolismo , Fumar/efeitos adversos , Epigênese Genética , Feminino , Heterogeneidade Genética , Humanos , Motivos de Nucleotídeos , Gravidez , Tabaco
14.
Artigo em Inglês | MEDLINE | ID: mdl-34333643

RESUMO

CONTEXT: An increase in maternal insulin resistance (IR) during pregnancy is essential for normal fetal growth. The mechanisms underlying this metabolic adaptation to pregnancy are poorly understood. Placenta factors are believed to instigate and maintain these metabolic changes, as IR decreases shortly after delivery. Methylation of placental gene loci that are common targets for miRNAs, are associated with maternal IR. OBJECTIVE: We hypothesized that placental miRNAs targeting methylated loci are associated with maternal IR during late pregnancy. METHODS: We collected placentas from 132 elective cesarean sections and fasting blood sample at delivery to estimate maternal HOMA-IR. Placental miRNA expression was measured via whole genome small RNA-sequencing in a subset of 40 placentas selected by maternal pre-gravid BMI and neonatal adiposity. Five miRNAs that correlated with maternal HOMA-IR and were previously identified as targeting methylated genes were selected for validation in all 132 placenta samples via RT-qPCR. Multiple regression was used to adjust for relevant clinical variables. RESULTS: Median maternal age was 27.5 years, with a median pre-pregnancy BMI of 24.7 kg/m 2, and median HOMA-IR of 2.9. Among the five selected miRNA, maternal HOMA-IR correlated with the placental expression of miRNA-371b-3p (r=0.25; p=0.008) and miRNA-3940-3p (r=0.32; p=0.0004) across the 132 individuals. After adjustment for confounding variables, placental miRNA-3940-3p expression remained significantly associated with HOMA-IR (ß=0.16; p=0.03). CONCLUSION: Placental miRNA-3940-3p was associated with maternal IR at delivery. This placental miRNA may have an autocrine or paracrine effect - regulating placental genes which play a role in modulating maternal IR.

15.
Am J Obstet Gynecol ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34419453

RESUMO

BACKGROUND: Women with gestational glucose intolerance, defined as an abnormal initial gestational diabetes mellitus screening test, are at risk of adverse pregnancy outcomes even if they do not have gestational diabetes mellitus. Previously, we defined the physiological subtypes of gestational diabetes mellitus based on the primary underlying physiology leading to hyperglycemia and found that women with different subtypes had differential risks of adverse outcomes. Physiological subclassification has not yet been applied to women with gestational glucose intolerance. OBJECTIVE: We defined the physiological subtypes of gestational glucose intolerance based on the presence of insulin resistance, insulin deficiency, or mixed pathophysiology and aimed to determine whether these subtypes are at differential risks of adverse outcomes. We hypothesized that women with the insulin-resistant subtype of gestational glucose intolerance would have the greatest risk of adverse pregnancy outcomes. STUDY DESIGN: In a hospital-based cohort study, we studied women with gestational glucose intolerance (glucose loading test 1-hour glucose, ≥140 mg/dL; n=236) and normal glucose tolerance (glucose loading test 1-hour glucose, <140 mg/dL; n=1472). We applied homeostasis model assessment to fasting glucose and insulin levels at 16 to 20 weeks' gestation to assess insulin resistance and deficiency and used these measures to classify women with gestational glucose intolerance into subtypes. We compared odds of adverse outcomes (large for gestational age birthweight, neonatal intensive care unit admission, pregnancy-related hypertension, and cesarean delivery) in each subtype to odds in women with normal glucose tolerance using logistic regression with adjustment for age, race and ethnicity, marital status, and body mass index. RESULTS: Of women with gestational glucose intolerance (12% with gestational diabetes mellitus), 115 (49%) had the insulin-resistant subtype, 70 (27%) had the insulin-deficient subtype, 40 (17%) had the mixed pathophysiology subtype, and 11 (5%) were uncategorized. We found increased odds of large for gestational age birthweight (primary outcome) in women with the insulin-resistant subtype compared with women with normal glucose tolerance (odds ratio, 2.35; 95% confidence interval, 1.43-3.88; P=.001; adjusted odds ratio, 1.74; 95% confidence interval, 1.02-3.48; P=.04). The odds of large for gestational age birthweight in women with the insulin-deficient subtype were increased only after adjustment for covariates (odds ratio, 1.69; 95% confidence interval, 0.84-3.38; P=.14; adjusted odds ratio, 2.05; 95% confidence interval, 1.01-4.19; P=.048). Among secondary outcomes, there was a trend toward increased odds of neonatal intensive care unit admission in the insulin-resistant subtype in an unadjusted model (odds ratio, 2.09; 95% confidence interval, 0.99-4.40; P=.05); this finding was driven by an increased risk of neonatal intensive care unit admission in women with the insulin-resistant subtype and a body mass index of <25 kg/m2. Infants of women with other subtypes did not have increased odds of neonatal intensive care unit admission. The odds of pregnancy-related hypertension in women with the insulin-resistant subtype were increased (odds ratio, 2.09; 95% confidence interval, 1.31-3.33; P=.002; adjusted odds ratio, 1.77; 95% confidence interval, 1.07-2.92; P=.03) compared with women with normal glucose tolerance; other subtypes did not have increased odds of pregnancy-related hypertension. There was no difference in cesarean delivery rates in nulliparous women across subtypes. CONCLUSION: Insulin-resistant gestational glucose intolerance is a high-risk subtype for adverse pregnancy outcomes. Delineating physiological subtypes may provide opportunities for a more personalized approach to gestational glucose intolerance.

16.
Epigenetics ; : 1-11, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384032

RESUMO

Women entering pregnancy with elevated body mass index (BMI) face greater risk of adverse outcomes during pregnancy, delivery, and for their offspring later in life, potentially via epigenetics. If epigenetic programming occurs early during in utero development, the differential marks should be detectable in multiple tissues despite the known unique epigenetic profile in each.We used early-pregnancy BMI as reflection of maternal metabolic milieu exposure in peri-conception and early-pregnancy period. We analysed DNA methylation in paired cord blood and placenta samples among 437 newborns from Gen3G, a pre-birth prospective cohort of primarily European descent. We measured DNA methylation in both tissues across the genome in >720,000 CpG sites using the Illumina MethylationEPIC array. At each site, we used linear mixed models (LMMs) with an unstructured variance-covariance matrix to test for an association between maternal early-pregnancy BMI and DNA methylation in both tissues (modelled as M-values). We adjusted for tissue-specific covariates, offspring sex, gestational age at delivery, and maternal smoking and age.Women had a mean (SD) BMI of 25.4 (5.7) kg/m2 measured at first trimester visit (mean=9.9 weeks). Early-pregnancy BMI was associated with differential DNA methylation levels in paired-tissue analyses at two sites: cg10593758 (ß=0.0126, SE=0.0025; P=4.07e-7), annotated to CRHBP, and cg0762168 (ß=-0.0094, SE=0.0018; P=2.78e-7), annotated to CCDC97.Application of LMMs in DNA methylation data from distinct fetal-origin tissues allowed us to identify CpG sites at which early-pregnancy BMI may have an epigenetic 'programming' effect on overall fetus development. One site (CRHBP) may play a role in hypothalamic-pituitary-adrenal axis regulation.

17.
Am J Epidemiol ; 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34308473

RESUMO

The association between early life greenness and child cognition is not well understood. Using prospective data from Project Viva (n=857) from 1999 to 2010, we examined associations of early life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1y), and mid-childhood (7.8y) using 30m resolution Landsat satellite imagery [Normalized Difference Vegetation Index]. In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness<0.6), greenness exposure at early childhood was associated with a 0.48% increase in non-verbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with non-verbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.

18.
Pediatr Rep ; 13(2): 279-288, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205853

RESUMO

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near LMX1B (interaction ß = 0.39; standard error (SE) = 0.17), rs17001654 near SCARB2 (ß = 0.53; SE = 0.22), and rs16951275 near MAP2K5 (ß = 0.37; SE = 0.17). BMI-associated genetic variants may enhance the association between exposure to in utero diabetes and higher childhood BMI, but larger studies of in utero exposures are necessary to confirm the observed nominally significant relationships.

19.
Cytokine ; 146: 155636, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34265640

RESUMO

BACKGROUND: Maternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin resistance and other glycemic markers with offspring inflammation at birth and at 5 years of age. METHODS: We included 653 mother-child pairs from the prospective pre-birth Gen3G cohort. We examined maternal insulin and glucose levels measured during the second trimester of pregnancy, from which we derived the homeostatic model of assessment of insulin resistance (HOMA-IR) and the Matsuda index. We assessed offspring inflammation at birth and at 5 years of age by measuring plasma tumor necrosis factor-α (TNFα) concentrations. We conducted multivariable regression models to evaluate associations of each insulin and glucose marker with offspring inflammation adjusting for confounding variables. RESULTS: Higher levels of fasting insulin were associated with lower TNFα levels at birth (-0.78, 95% CI [-1.45, -0.11]), in the fully adjusted model. We observed similar associations with the HOMA-IR and opposite direction with the Matsuda index. We did not find persistence of the association between maternal fasting insulin and offspring TNFα at 5 years of age. CONCLUSIONS: Greater maternal insulin resistance during pregnancy was associated with lower cord blood TNFα levels in newborns. The mechanisms by which maternal insulin resistance may promote lower inflammatory levels in newborns are not fully understood and more research is needed to deepen our understanding of these mechanisms.

20.
Environ Mol Mutagen ; 62(7): 388-398, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34288135

RESUMO

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m2 . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.

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