Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (rS-values>−0.62), but in girls only 207 (41%) showed inverse correlation (rS-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

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A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00233 ◽

2020 ◽

Vol 14 ◽

Cited By ~ 1

Author(s):

Mette Soerensen ◽

Dominika Marzena Hozakowska-Roszkowska ◽

Marianne Nygaard ◽

Martin J. Larsen ◽

Veit Schwämmle ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Cognitive Functioning ◽

Association Study ◽

Gene Expression Data ◽

Monozygotic Twins ◽

Later Life ◽

Expression Data ◽

Genome Wide ◽

A Genome

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Effects on DNA methylation of arsenic exposure in utero

Arsenic in the Environment - Proceedings - Arsenic Research and Global Sustainability ◽

10.1201/b20466-207 ◽

2016 ◽

pp. 446-447

Author(s):

K Engström ◽

M Kippler ◽

R Raqib ◽

S Ahmed ◽

M Vahter ◽

...

Keyword(s):

Dna Methylation ◽

Arsenic Exposure ◽

In Utero

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Exposure to Gestational Diabetes Enriches Immune-Related Pathways in the Transcriptome and Methylome of Human Amniocytes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa466 ◽

2020 ◽

Vol 105 (10) ◽

pp. 3250-3264 ◽

Cited By ~ 1

Author(s):

Sara E Pinney ◽

Apoorva Joshi ◽

Victoria Yin ◽

So Won Min ◽

Cetewayo Rashid ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Gestational Diabetes ◽

Gestational Age ◽

In Utero ◽

Interferon Response ◽

Metabolic Dysfunction ◽

Chromosome Conformation ◽

Obesity And Diabetes ◽

Genome Wide

Abstract Context Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu and is linked to obesity and diabetes in offspring, but the mechanisms driving these effects remain largely unknown. Alterations in DNA methylation and gene expression in amniocytes exposed to GDM in utero represent a potential mechanism leading to metabolic dysfunction later in life. Objective To profile changes in genome-wide DNA methylation and expression in human amniocytes exposed to GDM. Design A nested case-control study (n = 14 pairs) was performed in amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis, and gestational age at birth. Sex-specific genome-wide DNA methylation analysis and RNA-sequencing were completed and differentially methylated regions (DMRs) and gene expression changes were identified. Ingenuity pathway analysis identified biologically relevant pathways enriched after GDM exposure. In silico high-throughput chromosome conformation capture (Hi-C) analysis identified potential chromatin interactions with DMRs. Results Expression of interferon-stimulated genes was increased in GDM amniocytes, accounting for 6 of the top 10 altered genes (q < 0.05). Enriched biological pathways in GDM amniocytes included pathways involving inflammation, the interferon response, fatty liver disease, monogenic diabetes, and atherosclerosis. Forty-two DMRs were identified in male GDM-exposed amniocytes and 20 in female amniocyte analysis (q < 0.05). Hi-C analysis identified interactions between DMRs and 11 genes with significant expression changes in male amniocytes and 9 in female amniocytes (P < .05). Conclusion In a unique repository of human amniocytes exposed to GDM in utero, transcriptome analysis identified enrichment of inflammation and interferon-related pathways and novel DMRs with potential distal regulatory functions.

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What is the evidence in humans that DNA methylation changes link events in utero and later life disease?

Clinical Endocrinology ◽

10.1111/cen.12164 ◽

2013 ◽

Vol 78 (6) ◽

pp. 814-822 ◽

Cited By ~ 48

Author(s):

Rebecca M. Reynolds ◽

Greta H. Jacobsen ◽

Amanda J. Drake

Keyword(s):

Dna Methylation ◽

Later Life ◽

In Utero

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The Epigenetic Impact Of In Utero Smoke Exposure In Later Life: A Genome-Wide Survey Of Site-Specific CPG Methylation In Asthmatics

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a1005 ◽

2011 ◽

Author(s):

Carrie Breton ◽

Kimberly D. Siegmund ◽

Haiying Kong ◽

Weiliang Qiu ◽

K.Talat S. Islam ◽

...

Keyword(s):

Later Life ◽

In Utero ◽

Smoke Exposure ◽

Cpg Methylation ◽

Site Specific ◽

Genome Wide ◽

A Genome ◽

Genome Wide Survey

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Multi-generational impacts of arsenic exposure on genome-wide DNA methylation and the implications for arsenic-induced skin lesions

Environment International ◽

10.1016/j.envint.2018.06.024 ◽

2018 ◽

Vol 119 ◽

pp. 250-263 ◽

Cited By ~ 8

Author(s):

Xiaojuan Guo ◽

Xushen Chen ◽

Jie Wang ◽

Zhiyue Liu ◽

Daniel Gaile ◽

...

Keyword(s):

Dna Methylation ◽

Arsenic Exposure ◽

Skin Lesions ◽

Genome Wide

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In utero Bisphenol A Exposure Is Linked with Sex Specific Changes in the Transcriptome and Methylome of Human Amniocytes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz037 ◽

2019 ◽

Vol 105 (2) ◽

pp. 453-467

Author(s):

Amita Bansal ◽

Nicole Robles-Matos ◽

Paul Zhiping Wang ◽

David E Condon ◽

Apoorva Joshi ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Bisphenol A ◽

Gestational Age ◽

Molecular Mechanisms ◽

In Utero ◽

Metabolic Dysfunction ◽

Altered Expression ◽

Obesity And Diabetes ◽

Genome Wide

Abstract Context Prenatal exposure to bisphenol A (BPA) is linked to obesity and diabetes but the molecular mechanisms driving these phenomena are not known. Alterations in deoxyribonucleic acid (DNA) methylation in amniocytes exposed to BPA in utero represent a potential mechanism leading to metabolic dysfunction later in life. Objective To profile changes in genome-wide DNA methylation and expression in second trimester human amniocytes exposed to BPA in utero. Design A nested case-control study was performed in amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis, and gestational age at birth. Cases had amniotic fluid BPA measuring 0.251 to 23.74 ng/mL. Sex-specific genome-wide DNA methylation analysis and RNA-sequencing (RNA-seq) were performed to determine differentially methylated regions (DMRs) and gene expression changes associated with BPA exposure. Ingenuity pathway analysis was performed to identify biologically relevant pathways enriched after BPA exposure. In silico Hi-C analysis identified potential chromatin interactions with DMRs. Results There were 101 genes with altered expression in male amniocytes exposed to BPA (q < 0.05) in utero, with enrichment of pathways critical to hepatic dysfunction, collagen signaling and adipogenesis. Thirty-six DMRs were identified in male BPA-exposed amniocytes and 14 in female amniocyte analysis (q < 0.05). Hi-C analysis identified interactions between DMRs and 24 genes with expression changes in male amniocytes and 12 in female amniocytes (P < 0.05). Conclusion In a unique repository of human amniocytes exposed to BPA in utero, sex-specific analyses identified gene expression changes in pathways associated with metabolic disease and novel DMRs with potential distal regulatory functions.

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