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In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue—Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (β = −0.62, 95% CI: −1.17, −0.06; β = −0.32, 95% CI: −0.63, −0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.

Additional file 1. Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta. This supplementary material contains 7 supplementary figures and 8 supplementary table. An additional 10 large supplementary tables are provided as comma separated value tables.

Additional file 3. This file contains Figures S1-S44.

Additional file 32. Review history.

Supplemental Tables and Figures for the Endocrinology Submission "Developmental Programming: Impact of Prenatal Testosterone Excess on Liver and Muscle Transcriptome and the Relationship Between Non-Coding and Coding RNA Networks in Female Sheep"

Supplemental Tables and Figures for the Endocrinology Submission "Developmental Programming: Impact of Prenatal Testosterone Excess on Liver and Muscle Transcriptome and the Relationship Between Non-Coding and Coding RNA Networks in Female Sheep"

PurposePrior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.MethodsData from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.ResultsUse of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

Additional file 1: Figure S1. Global CpG methylation is associated with diagnosis and behavioral outcome scores only in males. Figure S2. The proportion of nRBCs is associated with behavioral outcome and global CpG methylation in males. Figure S3. Methylation at ASD DMRs in the discovery set is specifically associated with behavioral outcome. Figure S4. DMRs identified in all discovery subjects distinguish ASD from TD subjects. Figure S5. Sequencing platform has a larger effect on 10 kb window methylation than ASD diagnosis, sex, or study. Figure S6. DMRs identified in males and females distinguish ASD from TD subjects in the replication set. Figure S7. Methylation at ASD DMRs in the replication set is specifically associated with behavioral outcome. Figure S8. DMRs identified in all replication subjects distinguish ASD from TD subjects. Figure S9. The majority of ASD DMRs do not overlap probes on the 450 K and EPIC arrays. Figure S10. DMR methylation assayed by WGBS correlates with DMR methylation assayed by bisulfite pyrosequencing. Figure S11. A subset of ASD diagnosis DMRs are associated with ASD severity in independent sample sets. Figure S12. Machine learning methods workflow. Figure S13. Summary of machine learning datasets and results for males. Figure S14. Summary of machine learning datasets and results for females. Figure S15. ASD DMRs identified with adjustment for sex miss many genes found when stratifying for sex. Figure S16. Replicated ASD DMB genes overlap with replicated ASD DMR genes. Figure S17. ASD DMB genes are enriched for membrane, cell adhesion, and embryo-expressed genes. Figure S18. Neurodevelopmental genes are overrepresented on the X chromosome. Figure S19. Replicated DMR genes on the X chromosome are expressed in fetal brain. Figure S20. Female-specific replicated DMR genes on the X chromosome are expressed in fetal brain. Figure S21. Cord blood ASD DMR genes are significantly enriched for epigenetically dysregulated genes in ASD brain. Figure S22. Selected regions with replicated sex-independent DMR genes on the X chromosome. Figure S23. Selected regions with replicated male-specific DMR genes on the X chromosome. Figure S24. Selected regions with replicated female-specific DMR genes on the X chromosome. Figure S25. ASD DMRs in replication subjects are differentially enriched for chromatin states on the X chromosome. Figure S26. ASD DMRs in discovery subjects are differentially enriched for histone PTMs on the X chromosome. Figure S27. ASD DMRs in replication subjects are differentially enriched for histone PTMs on the X chromosome. Figure S28. ASD DMRs on the X chromosome are enriched near CpG islands only in females.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2× 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.