Search

Cranial neural crest cells (cNCC) are a multipotent embryonic cell population that give rise to a diverse set of cell types. These cells are particularly vulnerable to external metabolic stressors, as exemplified by the association between maternal hyperglycemia and congenital malformations. We were interested in studying the effect of various concentrations of glucose and pyruvate on cNCC metabolism, migration, and differentiation using an established murine neural crest cell model (O9-1). We unexpectedly observed a pattern of gene expression suggestive of cholesterol biosynthesis induction under glucose depletion conditions in O9-1 cells. We further showed that treatment with two different cholesterol synthesis inhibitors interfered with cell migration and differentiation, inhibiting chondrogenesis while enhancing smooth muscle cell differentiation. As congenital arhinia (absent external nose), a malformation caused by mutations in SMCHD1, appears to represent, in part, a defect in cNCC, we were also interested in investigating the effects of glucose and cholesterol availability on Smchd1 expression in O9-1 cells. Smchd1 expression was induced under high glucose conditions whereas cholesterol synthesis inhibitors decreased Smchd1 expression during chondrogenesis. These data highlight a novel role for cholesterol biosynthesis in cNCC physiology and demonstrate that human phenotypic variability in SMCHD1 mutation carriers may be related, in part, to SMCHD1’s sensitivity to glucose or cholesterol dosage during development.

Background The mother–child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother–child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother–child DNAm associations. Results Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother–newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother–newborn correlations in genome-wide DNAm patterns (Spearman’s rho = 0.91–0.98; p = 4.0 × 10–8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman’s rho = 0.91–0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother–newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother–newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. Conclusion In two independent birth cohorts, we demonstrated strong mother–newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C+, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C+Ly-6A/E+ cDC2 to mature Ly-6C–CD301b+ lung resident cDC2 lacking Ccr7 expression, which then further mature into CD200+ migratory cDC2 expressing Ccr7. Partially mature Ly-6C+Ly-6A/E–CD301b– cDC2, which express Il1b, promote Th17 differentiation. By contrast, CD200+ mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.

Purpose Body mass index (BMI) is associated with asthma but associations of BMI temporal patterns with asthma incidence are unclear. Previous studies suggest that DNA methylation (DNAm) is associated with asthma status and variation in DNAm is a consequence of BMI changes. This study assessed the direct and indirect (via DNAm) effects of BMI trajectories in childhood on asthma incidence at young adulthood. Methods Data from the Isle of Wight (IoW) birth cohort were included in the analyses. Group-based trajectory modelling was applied to infer latent BMI trajectories from ages 1 to 10 years. An R package, ttscreening, was applied to identify differentially methylated CpGs at age 10 years associated with BMI trajectories, stratified for sex. Logistic regressions were used to further exclude CpGs with DNAm at age 10 years not associated with asthma incidence at 18 years. CpGs discovered via path analyses that mediated the association of BMI trajectories with asthma incidence in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Children and Parents (ALSPAC). Results Two BMI trajectories (high vs. normal) were identified. Of the 442,474 CpG sites, DNAm at 159 CpGs in males and 212 in females were potentially associated with BMI trajectories. Assessment of their association with asthma incidence identified 9 CpGs in males and 6 CpGs in females. DNAm at 4 of these 15 CpGs showed statistically significant mediation effects (p-value Conclusion The association of BMI trajectory in childhood with asthma incidence at young adulthood is possibly mediated by DNAm.

Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8α+ dendritic cells present antigens to CD8+ T cells and elicit cytotoxic T cell responses to viruses, bacteria and tumours 1 . Although lineage-specific transcriptional regulators of CD8α+ dendritic cell development have been identified 2 , the molecular pathways that selectively orchestrate CD8α+ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation3,4, but metabolic dependence and regulation of dendritic cell subsets are largely uncharacterized. Here we use a data-driven systems biology algorithm (NetBID) to identify a role of the Hippo pathway kinases Mst1 and Mst2 (Mst1/2) in selectively programming CD8α+ dendritic cell function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ dendritic cells relative to CD8α− dendritic cells. Dendritic cell-specific deletion of Mst1/2—but not Lats1 and Lats2 (Lats1/2) or Yap and Taz (Yap/Taz), which mediate canonical Hippo signalling—disrupts homeostasis and function of CD8+ T cells and anti-tumour immunity. Mst1/2-deficient CD8α+ dendritic cells are impaired in presentation of extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α− dendritic cells that lack Mst1/2 have largely normal function. Mechanistically, compared to CD8α− dendritic cells, CD8α+ dendritic cells exhibit much stronger oxidative metabolism and critically depend on Mst1/2 signalling to maintain bioenergetic activities and mitochondrial dynamics for their functional capacities. Further, selective expression of IL-12 by CD8α+ dendritic cells depends on Mst1/2 and the crosstalk with non-canonical NF-κB signalling. Our findings identify Mst1/2 as selective drivers of CD8α+ dendritic cell function by integrating metabolic activity and cytokine signalling, and highlight that the interplay between immune signalling and metabolic reprogramming underlies the unique functions of dendritic cell subsets. A data-driven analysis helps to identify specific roles of the Hippo signalling kinases Mst1 and Mst2 in integrating metabolic activity and cytokine signalling in dendritic cells, and thereby orchestrating immune cell function.

BackgroundAdolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M.MethodsGenome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n= 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.ResultsIn the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine–phosphate–guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as theAHRRgene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort.ConclusionAdolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.

Background The role of infant feeding for food allergy in children is unclear and studies have not addressed simultaneous exposures to different foods. The goal of this study was to analyze existing data on feeding practices that represent realistic exposure and assess the risk of food allergy symptoms and food allergy in children. Methods The Infant Feeding Practices Study II conducted by the CDC and US-FDA enrolled pregnant women and collected infant feeding information using nine repeated surveys. Participants were re-contacted after 6 years. Food allergy data were collected at 4, 9, 12, and 72 months. In total, 1387 participants had complete infant feeding pattern data for 6 months and information on food allergy symptoms and doctors’ diagnosed food allergy. Feeding patterns constituted six groups: 3-months of feeding at breast followed by mixed feeding, 3-months of breast milk and bottled milk followed by mixed feeding, 1-month of feeding at breast followed by mixed feeding, 6-months of mixed feeding i.e., concurrent feeding of breast milk, bottled milk and formula, 2–3 months of formula followed by formula and solid food, and formula and solid food since the first month. To estimate risks of food allergy, we used linear mixed models, controlling for potential confounders. Results Of the 328 children with food allergy symptoms in infancy and at 6 years, 52 had persistent symptoms from infancy. Children exposed to mixed feeding had a higher risk of food allergy symptoms (Risk Ratio [RR] 1.54; 95% Confidence Interval [CI] 1.04, 2.29) compared to 3-months of feeding at breast adjusted for confounding. No statistically significant risk of infant feeding patterns was found for doctors’ diagnosed food allergy. Paternal allergy posed a higher risk for food allergy symptoms (RR 1.36; 95% CI 1.01, 1.83). Prenatal maternal smoking increased the risk for doctors’ diagnosed food allergy (RR 2.97; 95% CI 1.53, 5.79). Conclusions Analysis of this prospective birth cohort suggest that introduction of multiple feeding source may lead to food allergy symptoms. Future efforts are needed to determine acceptable approaches to improve the ascertainment of food allergy in children and the role of infant feeding.

The median lethal dose for rodent oral acute toxicity (LD50) is a standard piece of information required to categorize chemicals in terms of the potential hazard posed to human health after acute exposure. The exclusive use of in vivo testing is limited by the time and costs required for performing experiments and by the need to sacrifice a number of animals. (Quantitative) structure–activity relationships [(Q)SAR] proved a valid alternative to reduce and assist in vivo assays for assessing acute toxicological hazard. In the framework of a new international collaborative project, the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods and the U.S. Environmental Protection Agency’s National Center for Computational Toxicology compiled a large database of rat acute oral LD50 data, with the aim of supporting the development of new computational models for predicting five regulatory relevant acute toxicity endpoints. In this article, a series of regression and classification computational models were developed by employing different statistical and knowledge-based methodologies. External validation was performed to demonstrate the real-life predictability of models. Integrated modeling was then applied to improve performance of single models. Statistical results confirmed the relevance of developed models in regulatory frameworks, and confirmed the effectiveness of integrated modeling. The best integrated strategies reached RMSEs lower than 0.50 and the best classification models reached balanced accuracies over 0.70 for multi-class and over 0.80 for binary endpoints. Computed predictions will be hosted on the EPA’s Chemistry Dashboard and made freely available to the scientific community.

Polycyclic aromatic hydrocarbons (PAHs) are known for their carcinogenic and teratogenic properties. However, little is known about the effect of PAH on our immune and respiratory systems. Hence, we investigated associations (1) between PAH exposure and IgE levels and asthma in children and (2) between PAH exposure and the oxidative stress marker 8OHdG potentially involved in disease pathogenesis stratifying by (3) sex-based differences. A total of 453 kindergarten children were recruited and provided samples. Urine biomarker of PAH exposure (1-OHP levels) was measured by UPLC-MS/MS and a marker of oxidative stress (8OHdG) was measured by ELISA. Serum IgE were assessed and information on asthma was collected. Associations between 1-OHP levels, 8OHdG, IgE and asthma were analyzed by multivariate linear and logistic regression. A mediation analysis was conducted to evaluate whether the risk of increased IgE and asthma related to PAH exposure is explained by 8OHdG changes. Urine 1-OHP levels were positively related to 8OHdG levels (per ln-unit: β = 0.30kU/l, p = 0.002). Similar results were also found for 1-OHP levels with IgE levels (per ln-unit: β = 0.27 kU/l, p = 0.027). 1-OHP levels (per ln-unit) were significantly associated with asthma, with an OR (95% CI) of 1.42 (1.18–1.70). In addition, 1-OHP levels were associated with asthma. It is estimated that 35% of the effect of PAH exposure on asthma is mediated by 8OHdG levels. Exposure to PAH may enhance oxidative stress and may induce asthma. The effect of PAH exposure on asthma may be mediated by oxidative stress.

The Chernobyl Nuclear Power Plant (CNPP) accident represents one of the most significant civilian releases of 137Cesium (137Cs, radiocesium) in human history. In the Chernobyl-affected region, radiocesium is considered to be the greatest on-going environmental hazard to human health by radiobiologists and public health scientists. The goal of this study was to characterize dosimetric patterns and predictive factors for whole-body count (WBC)-derived radiocesium internal dose estimations in a CNPP-affected children's cohort, and cross-validate these estimations with a soil-based ecological dose estimation model. WBC data were used to estimate the internal effective dose using the International Commission on Radiological Protection (ICRP) 67 dose conversion coefficient for 137Cs and MONDAL Version 3.01 software. Geometric mean dose estimates from each model were compared utilizing paired t-tests and intra-class correlation coefficients. Additionally, we developed predictive models for WBC-derived dose estimation in order to determine the appropriateness of EMARC to estimate dose for this population. The two WBC-derived dose predictive models identified 137Cs soil concentration (P

Background In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life. Methods Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years). Results In total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = −0.063, p-value = 0.0021), cg10473311 (coeff.int = −0.021, p-value = 0.027). Conclusion In utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life. Electronic supplementary material The online version of this article (doi:10.1186/s12940-017-0262-0) contains supplementary material, which is available to authorized users.

Dendritic cells (DCs) are a heterogeneous cell population of great importance in the immune system. The emergence of new genetic technology utilizing the CD11c promoter and Cre recombinase has facilitated the dissection of functional significance and molecular regulation of DCs in immune responses and homeostasis in vivo. For the first time, this strategy allows observation of the effects of DC-specific gene deletion on immune system function in an intact organism. In this review, we present the latest findings from studies using the Cre recombinase system for cell type–specific deletion of key molecules that mediate DC homeostasis and function. Our focus is on the molecular pathways that orchestrate DC life span, migration, antigen presentation, pattern recognition, and cytokine production and signaling.

Maternal allergy and gestational exposures can alter the concentration of type-1/type-2/T-regulatory markers in breast milk. We tested whether maternal risk factors are related to breast milk immune markers. Expecting mothers were enrolled in 2008–2010 in South Carolina in prenatal clinics and classes. Interferon (IFN)-γ–induced protein 10 (CXCL10), CCL11, interleukin (IL)-1β, IL-4, IL-5, IL-6, CXCL8, IL-10, IL-12(p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig)A in 115 whey samples were measured by immunoassays. Maternal asthma, eczema, rhinitis, smoking, urogenital infections during gestation, pet exposure, education, race/ethnicity, age, body mass, and the child’s birth date and sex were ascertained. The effects of these risk factors on immune markers were estimated using general linear models. Maternal asthma was linked to higher levels of IL-5, rhinitis to lower levels of IL-5 and INF-γ, and eczema to lower levels of IL-6. Gestational smoking was related to increased concentrations of CXCL8 and IL-6. African-American mothers had markedly higher levels of IL-6, IFN-γ, and CXCL8. Urogenital infections, maternal age, body mass, child’s sex, and season of birth contributed to the variation. The impact of maternal allergies on immune markers in breast milk was small compared with that of maternal nondisease characteristics.

Changes during puberty may influence final adult height. Height is related to multiple health conditions, including lung function. We investigated the association between the age of onset of five puberty events and height at age 18 years, analyzing boys and girls separately.Of 1456 children recruited into the Isle of Wight birth cohort (1989-1990), 1313 were followed up at age 18 years. Height was measured, and age of pubertal onset was collected at age 18 years. Cluster analysis was performed on the five puberty events in boys and girls and linear regression was applied with the clusters predicting height at age 18 years. Individual linear regression analyses assessed the age of onset of each pubertal event as a potential predictor for height at age 18 years.Of the 1313 children followed up at age 18 years, 653 were males and 660 were females. All puberty variables had high internal consistency. In girls, earlier age of menarche, breast development, and growth spurt were related to shorter height. In boys, earlier age of growth spurt and slower progression through puberty were related to taller height at age 18 years.Given that boys and girls may have opposing associations between pubertal timing and adult height and that height is an important predictor of lung function, the effect of pubertal timing on respiratory health should be explored.

Background Scratching in infants is considered to be related to early development of eczema. Little is known about the effects of maternal immune markers on scratching among infants. The objective is to compare the risks related to maternal serum immune markers (IMs) during pregnancy and IMs in breast milk for the occurrence of scratching in infants at 6 and 12 months of age. Methods Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median 3 weeks prepartum) and breast milk (3 weeks postpartum) samples were collected. The concentrations of interferon (IFN)-γ, IFN gamma-induced protein 10 (IP-10) (or CXCL10), CCL11, interleukin (IL) 1β, IL-4, IL-5, IL-6, IL-8 (CXCL8), IL-10, IL-12 (p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig) A in both maternal serum and whey were assayed using optimized immunoassays. Scratching and skin manifestations were ascertained at 6 and 12 months. Generalized estimating equations were used to estimate relative risks (RRs) of IMs for repeated measurements of scratching, considering intra-individual correlations and adjusting for confounders. Results Of 178 women, 161 provided blood and 115 breast milk samples. IL-1β, IL-4, IL-10, IL-12, and CCL11 in maternal serum and whey were not analyzed due to a large proportion of non-detectable values. Infants in the highest tertile of IL-6 and IL-13 in maternal serum were at higher risk of scratching (RR 1.73 and 1.84, respectively; p ≤ 0.002) compared to infants in the first tertile; similarly, infants born to mothers with high (versus low) levels of serum IL-5 were also at increased risk (RR 1.60, p = 0.002). None of the breast milk IMs studied were associated with scratching. Conclusions Scratching but not doctors diagnosed eczema was associated with higher levels of maternal IL-5, IL-6, and IL-13 during pregnancy. Further investigations are necessary to determine how maternal serum IMs influence infants scratching.

To assess whether breastfeeding protects against acute gastroenteritis (AGE) due to rotavirus (RV) infection compared to RV-negative AGE (RV-) in children age 0-12 months. Data from a community-based study of children with AGE from 30 pediatric practices in Germany, Switzerland, and Austria were evaluated. A case-control design was conducted with RV-positive AGE (RV+) cases and RV- AGE as controls. Odds ratios and 95% confidence intervals were estimated using log-linear regression models adjusting for child's age, family size, number of siblings, child care attendance, and nationality. A total of 1,256 stool samples were collected from infants with AGE; 315 (25%) were RV+ and 941 RV-. Being breastfed in the period of disease inception reduced the risk of AGE due to RV+ (OR, 0.53; 95% CI, 0.37-0.76). In infants 0-6 months of age, the protective effect was stronger (OR, 0.33; 95% CI, 0.19-0.55) than in 7-12-month-old children. Our study adds to the evidence of a protective concurrent effect of breastfeeding against rotavirus infection in infants, particularly in children 6 months and younger. Breastfeeding is important to diminish rotavirus-related gastroenteritis in infants before vaccination can be introduced.

Background The prevalence of eczema is increasing in industrialized nations. Limited evidence has shown the association of DNA methylation (DNA-M) with eczema. We explored this association at the epigenome-scale to better understand the role of DNA-M. Data from the first generation (F1) of the Isle of Wight (IoW) birth cohort participants and the second generation (F2) were examined in our study. Epigenome-scale DNA methylation of F1 at age 18 years and F2 in cord blood was measured using the Illumina Infinium HumanMethylation450 Beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) in the F1 generation were screened via recursive random forest (RF) for their potential association with eczema at age 18. Functional enrichment and pathway analysis of resulting genes were carried out using DAVID gene functional classification tool. Log-linear models were performed in F1 to corroborate the identified CpGs. Findings in F1 were further replicated in F2. Results The recursive RF yielded 140 CpGs, 88 of which showed statistically significant associations with eczema at age 18, corroborated by log-linear models after controlling for false discovery rate (FDR) of 0.05. These CpGs were enriched among many biological pathways, including pathways related to creating transcriptional variety and pathways mechanistically linked to eczema such as cadherins, cell adhesion, gap junctions, tight junctions, melanogenesis, and apoptosis. In the F2 generation, about half of the 83 CpGs identified in F1 showed the same direction of association with eczema risk as in F1, of which two CpGs were significantly associated with eczema risk, cg04850479 of the PROZ gene (risk ratio (RR) = 15.1 in F1, 95 % confidence interval (CI) 1.71, 79.5; RR = 6.82 in F2, 95 % CI 1.52, 30.62) and cg01427769 of the NEU1 gene (RR = 0.13 in F1, 95 % CI 0.03, 0.46; RR = 0.09 in F2, 95 % CI 0.03, 0.36). Conclusions Via epigenome-scaled analyses using recursive RF followed by log-linear models, we identified 88 CpGs associated with eczema in F1, of which 41 were replicated in F2. Several identified CpGs are located within genes in biological pathways relating to skin barrier integrity, which is central to the pathogenesis of eczema. Novel genes associated with eczema risk were identified (e.g., the PROZ and NEU1 genes). Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0108-y) contains supplementary material, which is available to authorized users.