Background: Knowledge on the long-term development of adiposity throughout childhood/adolescence and its prenatal determinants and health sequelae is lacking. We sought to (1) identify trajectories of Body Mass Index (BMI) from 1 to 18 years of age, (2) examine associations of maternal gestational smoking and early pregnancy overweight with offspring BMI trajectories and (3) determine whether BMI trajectories predict health outcomes: asthma, lung function parameters (forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) ratio), and blood pressure, at 18 years. Methods: The Isle of Wight birth cohort, a population-based sample of 1456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10 and 18 years. Group-based trajectory modelling was applied to test for the presence of latent BMI trajectories. Associations were assessed using log-binomial and linear regression models. Results: Four trajectories of BMI were identified: ‘normal’, ‘early persistent obesity’, ‘delayed overweight’, and ‘early transient overweight’. Risk factors for being in the early persistent obesity trajectory included maternal smoking during pregnancy (RR 2.16, 95% CI 1.02 to 4.68) and early pregnancy overweight (3.16, 1.52 to 6.58). When comparing the early persistent obesity to the normal trajectory, a 2.15-fold (1.33 to 3.49) increased risk of asthma, 3.2% (0.4% to 6.0%) deficit in FEV₁/FVC ratio, and elevated systolic 11.3 mm Hg (7.1 to 15.4) and diastolic 12.0 mm Hg (8.9 to 15.1) blood pressure were observed at age 18 years. Conclusions: Maternal prenatal exposures show prolonged effects on offspring's propensity towards overweight-obesity. Distinct morbid BMI trajectories are evident during the first 18 years of life that are associated with higher risk of asthma, reduced FEV₁/FVC ratio, and elevated blood pressure.

Background: Prior studies have reported an increased risk of diabetes related to polychlorinated biphenyl (PCB) exposure. No study has yet investigated whether polybrominated biphenyls (PBBs), which are similar in chemical structure, increase the incidence of diabetes. Methods: The Michigan PBB cohort was established in 1976 and surveyed again in 1991–1993 and in 2001. PBB and PCB serum levels were measured from blood collected at enrollment. To determine the incidence of adult-onset diabetes, we analyzed cohort members without diabetes at enrollment, ages 20 years and older, with known PBB and PCB levels, who participated in at least 1 follow-up survey (n = 1384). Using Poisson regression, we determined the incidence density ratio (IDR) of diabetes for different serum levels of PBB and PCB, controlling for age, body mass index, smoking, and alcohol consumption at enrollment. Results: Analyzing 25 years of follow-up data, we did not find that higher PBB serum levels were a risk factor for the incidence of diabetes mellitus. However, in women, but not in men, higher PCB serum levels were associated with increased incidence of diabetes (IDR = 2.33; 95% confidence interval = 1.25–4.34 in the highest PCB group compared with the lowest). In both men and women, overweight and obesity increased the diabetes incidence. Conclusions: We found no association between PBB serum levels and diabetes incidence. In women, there was a positive linear association of diabetes incidence with PCB serum levels at enrollment. This finding is in agreement with 2 prior studies indicating a higher relative risk of diabetes in PCB-exposed women.

Objectives: To investigate the effect of prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyl-dichloroethylene (DDE) on weight, height and body mass index (BMI) in adult female offspring of the Michigan fisheater cohort examined between 1973 and 1991. Methods: 259 mothers from the Michigan fisheater cohort were studied. Prenatal exposure to PCBs and DDE was estimated by extrapolating maternal measurements to the time that the women gave birth. 213 daughters aged 20–50 years in 2000 were identified and 83% of them participated in at least one of two repeated investigations in 2001/02 (n = 151) and 2006/07 (n = 129). To assess the effect of prenatal PCB and DDE exposure on anthropometric measurements, generalised estimating equations nested for repeated measurements (2001/02 and 2006/07) and for sharing the same mother were used. We controlled for maternal height and BMI and for daughters’ age, birth weight, having been breastfed and number of pregnancies. Results: Maternal height and BMI were significant predictors of the daughters’ height, weight and BMI. Low birth weight (<2500 g) was significantly associated with reduced adult offspring weight and BMI. The weight and BMI of adult offspring were statistically significantly associated with the extrapolated prenatal DDE levels of their mothers. Controlling for confounders and compared to maternal DDE levels of 2.9 μg/l. Prenatal PCB levels showed no effect. Conclusion: Prenatal exposure to the oestrogenic endocrine-disrupting chemical DDE may contribute to the obesity epidemic in women.

By the late 1980s, it was clear that allergic diseases, including asthma, eczema, allergic rhinitis and food allergy, had been increasing in recent decades, but the extent of this increase and true prevalence in an unselected population had not been estimated. It was also known that allergic diseases may remit and relapse. So one disease may improve as the child grows, but another may take its place; this pattern was termed ‘atopic or allergic march’. However, the extent and the true nature of this transition were not clear. Additionally, little was known why allergic diseases are increasing, and even less about why allergic disease often remits as the child grows...

Background: The occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M) in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R). We hypothesized that genetic variants ofIL4Rin interaction with DNA-M at cytosine-phosphate-guanine (CpG) sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK). Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.Results: Thirteen single nucleotide polymorphisms (SNPs) and twelve CpG sites ofIL4Rgene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in theIL4Rgene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test:P= 0.01). Log-linear models were used to estimate risk ratios (RRs) for asthma adjusting for uncorrelated SNPs within theIL4Rgene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P= 0.002; after adjusting for false discovery rate). A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’) at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect,P= 0.0003).Conclusions: Adjusting for multiple testing, our results suggest that DNA-M modulates the risk of asthma related to genetic variants in theIL4Rgene. The strong interaction of one SNP and DNA-M is encouraging and provides a novel model of how a joint effect of genetic variants and DNA-M can explain occurrence of asthma.

Phthalates may increase the asthma risk in children. Mechanisms underlying this association remain to be addressed. This study assesses the effect of phthalate exposures on epigenetic changes and the role of epigenetic changes for asthma. In the first step, urine and blood samples from 256 children of the Childhood Environment and Allergic diseases Study (CEAS) were analyzed. Urine 5OH-MEHP levels were quantified as an indicator of exposure, and asthma information was collected. DNA methylation (DNA-M) was measured by quantitative PCR. In the screening part of step 1, DNA-M of 21 potential human candidate genes suggested by a toxicogenomic data were investigated in 22 blood samples. Then, in the testing part of step 1, positively screened genes were tested in a larger sample of 256 children and then validated by protein measurements. In step 2, we replicated the association between phthalate exposure and gene-specific DNA-M in 54 children in the phthalate contaminated food event. In step 3, the risk of DNA-M for asthma was tested in 256 children from CEAS and corroborated in 270 children from the Isle of Wight (IOW) birth cohort. Differential methylation in three genes (AR, TNFα, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNFα gene promoter was lower when children had higher urine 5OH-MEHP values (β = −0.138, P = 0.040). Functional validation revealed that TNFα methylation was inversely correlated with TNFα protein levels (β = −0.18, P = 0.041). In an additional sample of 54 children, we corroborated that methylation of the TNFα gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5′CGI region of TNFα was associated with asthma in 256 CEAS children (OR = 2.15, 95% CI = 1.01 to 4.62). We replicated this in 270 children from the IOW birth cohort study. Methylation of the CpG site cg10717214 was negatively associated with asthma, when children had ‘AA’ or ‘AG’ genotype of the TNFα single nucleotide rs1800610. Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.