23 research outputs found
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Environmental and epigenetic determinants of child adipokines in a Mexican-American population.
In the last 30 years there has been a sharp increase in obesity among children, and minority populations are particularly vulnerable. Although etiology of obesity is thought to be multifactorial with causes stemming from diet, environment, genetics and their interaction, no clear molecular pathways have been identified. Underlying obesity development are changes in critical energy balance hormones, adiponectin and leptin (adipokines), however their development and determinants over the childhood period remain poorly understood. Previous studies indicate that certain features of the early life environment may have lasting effects on future child metabolic health and highlight the potential obesogenic role of Bisphenol A (BPA) - a high volume production chemical detectable in 93% of the United States population. Mechanisms of BPA action remain uncertain however a leading hypothesis argues that BPA exposure may result in epigenetic changes, such as altered deoxyribonucleic acid (DNA) methylation, affecting expression of adipogenic genes. To address these data gaps, we proposed the following specific aims: (1) To measure plasma adiponectin and leptin in Mexican-American children from the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort at birth and again at 2, 5, and 9 years, examining heterogeneity in adipokine growth patterns and their association with candidate perinatal factors.(2) To determine whether maternal or concurrent urinary BPA concentrations are associated with adiponectin and/or leptin levels in children.(3) To characterize DNA methylation structure of peroxisome proliferator-activated receptor gamma (PPARy) - the master regulator gene in adipogenesis, determine whether PPARy methylation is associated with child adipokines and/or body size and whether prenatal or concurrent BPA may influence PPARy methylation.Our results highlight several developmental differences in adiponectin vs. leptin over the childhood period. While leptin levels closely and positively correlated with child body size at all ages, adiponectin had inverse and weaker associations with body mass index (BMI) at 2, 5, and 9 years. Further, adjusting for BMI, adiponectin reflected an improved lipid profile while leptin was directly related to systolic and diastolic blood pressure in 9-year-old children. Of the candidate perinatal factors examined, we identified maternal consumption of sugar-sweetened beverages (SSB) during pregnancy and increased rate of growth during the first 6 months of life as significant risk factors for altered adiponectin levels during childhood. Further, children with greater birth weight had rapidly-rising leptin levels over the birth to 9-year period and highest BMI and waist circumference at 9 years. Our BPA analyses indicated sexually dimorphic responses similar to those previously reported in animal studies. While BPA concentrations during early pregnancy were directly associated with adiponectin levels in 9-year-old girls (b=3.71, P=0.03, N=131), BPA concentrations during late pregnancy were associated with increased plasma leptin in 9-year-old boys (b=0.06, P=0.01, N=179), controlling for sociodemographics, dietary variables and child BMI. Finally, using the Infinium Illumina 450K Array, we examined DNA methylation in 23 sites spanning the PPARy promoter and gene body region in discovery (N=117 at birth, N=108 at 9 years) and validation (N=116 at birth, N=131 at 9 years) sets of children. We report that methylation in site 1 was significantly and negatively associated with child size at birth (b=-2.5, P=0.04) and at 9 years (b=-4.8, P<0.001) in the discovery set, and these relationships were replicated in the validation set. Overall our research adds evidence in support of the hypothesis the children's metabolic health may be programmed during early life and suggests that epigenetic mechanisms may play an important role in determining child size
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Environmental and epigenetic determinants of child adipokines in a Mexican-American population.
In the last 30 years there has been a sharp increase in obesity among children, and minority populations are particularly vulnerable. Although etiology of obesity is thought to be multifactorial with causes stemming from diet, environment, genetics and their interaction, no clear molecular pathways have been identified. Underlying obesity development are changes in critical energy balance hormones, adiponectin and leptin (adipokines), however their development and determinants over the childhood period remain poorly understood. Previous studies indicate that certain features of the early life environment may have lasting effects on future child metabolic health and highlight the potential obesogenic role of Bisphenol A (BPA) - a high volume production chemical detectable in 93% of the United States population. Mechanisms of BPA action remain uncertain however a leading hypothesis argues that BPA exposure may result in epigenetic changes, such as altered deoxyribonucleic acid (DNA) methylation, affecting expression of adipogenic genes. To address these data gaps, we proposed the following specific aims: (1) To measure plasma adiponectin and leptin in Mexican-American children from the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort at birth and again at 2, 5, and 9 years, examining heterogeneity in adipokine growth patterns and their association with candidate perinatal factors.(2) To determine whether maternal or concurrent urinary BPA concentrations are associated with adiponectin and/or leptin levels in children.(3) To characterize DNA methylation structure of peroxisome proliferator-activated receptor gamma (PPARy) - the master regulator gene in adipogenesis, determine whether PPARy methylation is associated with child adipokines and/or body size and whether prenatal or concurrent BPA may influence PPARy methylation.Our results highlight several developmental differences in adiponectin vs. leptin over the childhood period. While leptin levels closely and positively correlated with child body size at all ages, adiponectin had inverse and weaker associations with body mass index (BMI) at 2, 5, and 9 years. Further, adjusting for BMI, adiponectin reflected an improved lipid profile while leptin was directly related to systolic and diastolic blood pressure in 9-year-old children. Of the candidate perinatal factors examined, we identified maternal consumption of sugar-sweetened beverages (SSB) during pregnancy and increased rate of growth during the first 6 months of life as significant risk factors for altered adiponectin levels during childhood. Further, children with greater birth weight had rapidly-rising leptin levels over the birth to 9-year period and highest BMI and waist circumference at 9 years. Our BPA analyses indicated sexually dimorphic responses similar to those previously reported in animal studies. While BPA concentrations during early pregnancy were directly associated with adiponectin levels in 9-year-old girls (b=3.71, P=0.03, N=131), BPA concentrations during late pregnancy were associated with increased plasma leptin in 9-year-old boys (b=0.06, P=0.01, N=179), controlling for sociodemographics, dietary variables and child BMI. Finally, using the Infinium Illumina 450K Array, we examined DNA methylation in 23 sites spanning the PPARy promoter and gene body region in discovery (N=117 at birth, N=108 at 9 years) and validation (N=116 at birth, N=131 at 9 years) sets of children. We report that methylation in site 1 was significantly and negatively associated with child size at birth (b=-2.5, P=0.04) and at 9 years (b=-4.8, P<0.001) in the discovery set, and these relationships were replicated in the validation set. Overall our research adds evidence in support of the hypothesis the children's metabolic health may be programmed during early life and suggests that epigenetic mechanisms may play an important role in determining child size
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Relationship between expression and methylation of obesity-related genes in children
Epigenetic control of gene expression in children remains poorly understood, but new technologies can help elucidate the relationship between expression and DNA methylation. Here, we utilized the nCounter Analysis System to characterise the expression of 60 genes in 69 9-year-old children from a cohort with a high prevalence of obesity. nCounter expression levels ranged broadly (from 3 to over 10000 messenger RNA counts) and were divided into four categories: high (>2000 counts), moderate (200-1000 counts), low (100-200 counts) and marginal (<100 counts). For a subset of five genes (ADIPOR1, PPARG1, GSTM1, PON1 and ACACA) from different expression level categories, we validated nCounter data using reverse transcription-polymerase chain reaction (RT-PCR), and expanded RT-PCR analysis of ADIPOR1 to include 180 children. Expression data from the two methodologies were correlated for all five genes included in the validation experiment, with estimates ranging from r s = 0.26 (P = 0.02) to r s = 0.88 (P < 5×10(-6)). ADIPOR1 and PPARG1 nCounter expression levels were negatively correlated (r = -0.60, P < 5×10(-5)), and this relationship was stronger in overweight children (r = -0.73, P < 5×10(-5)) than in normal weight children (r = -0.42, P = 0.016). Using methylation data from the Infinium HumanMethylation450 BeadChip (n = 180), we found eight CpG sites in ADIPOR1 and PPARG where methylation level was associated with expression by RT-PCR (P < 0.05). Hypomethylation of PPARG gene body site cg10499651 was associated with increased expression as measured by both RT-PCR and nCounter (P < 0.05). We found no statistically significant relationships between either expression or methylation of ADIPOR1 and PPARG and body mass index or waist circumference. In addition to demonstrating the validity of expression data derived from nCounter, our results illustrate the use of new technologies in assessing epigenetic effects on expression in children
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CpG Methylation across the adipogenic PPARγ gene and its relationship with birthweight and child BMI at 9 years.
BackgroundTo examine methylation of the peroxisome proliferator-activated receptor γ (PPARγ) gene and its relationship with child weight status, at birth and 9 years.MethodsWe measured PPARγ methylation across 23 CpG sites using the Infinium Illumina 450 k array for children from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort at birth (N = 373) and 9 years (N = 245).ResultsMethylation level correlation patterns across the 23 PPARγ CpG sites were conserved between birth and 9-year ages. We found high inter-CpG correlations between sites 1-3 (methylation block 1) and also between sites 18-23 (methylation block 2) for both time points, although these patterns were less pronounced at 9 years. Additionally, sites 1-3 (north shore) had the highest intra-CpG correlations over time (r = 0.24, 0.42, and 0.3; P = 0.002, P < 0.001, P < 0.001, respectively). PPARγ methylation levels tended to increase with age, and the largest differences were observed for north shore sites (7.4%). Adjusting for sex, both site 1 and site 20 (gene body) methylation at birth was significantly and inversely associated with birth weight (β = -0.13, P = 0.033; β = -0.09, P = 0.025, respectively). Similarly, we found that site 1 and site 20 methylation at 9 years was significantly and inversely associated with 9-year BMI z-score (β = -0.41, P = 0.015; β = -0.23, P = 0.045, respectively).ConclusionOur results indicate that PPARγ methylation is highly organized and conserved over time, and highlight the potential functional importance of north shore sites, adding to a better understanding of regional human methylome patterns. Overall, our results suggest that PPARγ methylation may be associated with child body size