Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to Agent Orange

Kelsey, Karl T.; Rytel, Matthew; Dere, Edward; Butler, Rondi A.; Eliot, Melissa; Huse, Susan M.; Houseman, E. Andrés; Koestler, Devin C.; Boekelheide, Kim

doi:10.1186/s12940-019-0533-z

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…Most of the other genes associated with the signi cantly methylated regions encoded non-coding RNAs. This is similar to our prior analysis of methylation in the sperm genome of these Ranch Hand veterans, where the gene H19, which encodes a long non-coding RNA (lncRNA), was altered [55]. Recent studies measuring the expression pro le of lncRNAs suggest that these molecules could regulate gene expression related to the cellular responses to TCDD [56], [57].…”

Section: Discussionsupporting

confidence: 82%

“…One CpG, contained within PTPRN2, was marginally signi cantly differentially methylated in the highly burdened group compared to the control. In the sperm data from our previous analysis, PTPRN2 also contained a CpG that was one of the top 50 altered loci by change in beta value [55], suggesting that this gene could be aberrantly methylated with dioxin exposure in multiple tissues. Intriguingly, a study that searched the human genome for dioxin response elements -locations in the DNA where AHR binds to induce transcription -found PTPRN2 to contain more of these loci than any other gene [58].…”

Section: Discussionmentioning

confidence: 95%

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DNA Methylation in the Adipose Tissue and Whole Blood of Agent Orange-exposed Operation Ranch Hand Veterans

Rytel

Butler

Eliot

et al. 2020

Preprint

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BackgroundBetween 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). MethodsWe received adipose tissue (n=37) and whole blood (n=42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450K platform.ResultsEpigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q<0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q<0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. ConclusionWe found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 95%

DNA Methylation in the Adipose Tissue and Whole Blood of Agent Orange-exposed Operation Ranch Hand Veterans

Rytel

Butler

Eliot

et al. 2020

Preprint

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“…Unfortunately, while there is a high number of datasets in whole blood, suitable data for non-blood tissues, such as sperm that could be relevant in sexual assault cases, are not of sufficient quantity or quality to conduct analysis of high power. For example, existing data in small numbers use a different type of platform used [ 43 ], do not include age information or include only elderly males (>70 years old, [ 44 ]). Nevertheless, we expect that the collection of large genome-wide DNA methylation data in sperm (such as by Jenkins et al, [ 6 , 45 ]) will raise soon in the coming, ‘open-access’ era.…”

Section: Discussionmentioning

confidence: 99%

Male-specific age estimation based on Y-chromosomal DNA methylation

Vidaki

González

Jiménez

et al. 2021

Aging

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Although DNA methylation variation of autosomal CpGs provides robust age predictive biomarkers, no male-specific age predictor exists based on Y-CpGs yet. Since sex chromosomes play an important role in aging, a Y-chromosome-based age predictor would allow studying male-specific aging effects and would also be useful in forensics. Here, we used blood-based DNA methylation microarray data of 1,057 males from six cohorts aged 15-87 and identified 75 Y-CpGs with an interquartile range of ≥0.1. Of these, 22 and six were significantly hyper- and hypomethylated with age (p(cor)<0.05, Bonferroni), respectively. Amongst several machine learning algorithms, a model based on support vector machines with radial kernel performed best in male-specific age prediction. We achieved a mean absolute deviation (MAD) between true and predicted age of 7.54 years (cor=0.81, validation) when using all 75 Y-CpGs, and a MAD of 8.46 years (cor=0.73, validation) based on the most predictive 19 Y-CpGs. The accuracies of both age predictors did not worsen with increased age, in contrast to autosomal CpG-based age predictors that are known to predict age with reduced accuracy in the elderly. Overall, we introduce the first-of-its-kind male-specific epigenetic age predictor for future applications in aging research and forensics.

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“…Standard protocols were followed for the normalization and quality control of raw DNA methylation data (Kelsey et al 2019;Wilhelm-Benartzi et al 2013). Briefly, we removed samples with >5% high detection p-values (p > 1 × 10 −7 ; n = 4) and probes with at least one high-detection p-value using the same cutoff.…”

Section: Dna Methylation Analysismentioning

confidence: 99%

Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study

Liu

Eliot

Papandonatos

et al. 2022

Environ Health Perspect

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BACKGROUND: DNA methylation alterations may underlie associations between gestational perfluoroalkyl substances (PFAS) exposure and later-life health outcomes. To the best of our knowledge, no longitudinal studies have examined the associations between gestational PFAS and DNA methylation. OBJECTIVES: We examined associations of gestational PFAS exposure with longitudinal DNA methylation measures at birth and in adolescence using the Health Outcomes and Measures of the Environment (HOME) Study (2003Study ( -2006 Cincinnati, Ohio). METHODS: We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in mothers during pregnancy. We measured DNA methylation in cord blood (n = 266) and peripheral leukocytes at 12 years of age (n = 160) using the Illumina HumanMethylation EPIC BeadChip. We analyzed associations between log 2 -transformed PFAS concentrations and repeated DNA methylation measures using linear regression with generalized estimating equations. We included interaction terms between children's age and gestational PFAS. We performed Gene Ontology enrichment analysis to identify molecular pathways. We used Project Viva (1999-2002 Boston, Massachusetts) to replicate significant associations. RESULTS: After adjusting for covariates, 435 cytosine-guanine dinucleotide (CpG) sites were associated with PFAS (false discovery rate, q < 0:05). Specifically, we identified 2 CpGs for PFOS, 12 for PFOA, 8 for PFHxS, and 413 for PFNA; none overlapped. Among these, 2 CpGs for PFOA and 4 for PFNA were replicated in Project Viva. Some of the PFAS-associated CpG sites annotated to gene regions related to cancers, cognitive health, cardiovascular disease, and kidney function. We found little evidence that the associations between PFAS and DNA methylation differed by children's age. DISCUSSION: In these longitudinal data, PFAS biomarkers were associated with differences in several CpGs at birth and at 12 years of age in or near genes linked to some PFAS-associated health outcomes. Future studies should examine whether DNA methylation mediates associations between gestational PFAS exposure and health.

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Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to Agent Orange

Cited by 15 publications

References 47 publications

DNA Methylation in the Adipose Tissue and Whole Blood of Agent Orange-exposed Operation Ranch Hand Veterans

DNA Methylation in the Adipose Tissue and Whole Blood of Agent Orange-exposed Operation Ranch Hand Veterans

Male-specific age estimation based on Y-chromosomal DNA methylation

Gestational Perfluoroalkyl Substance Exposure and DNA Methylation at Birth and 12 Years of Age: A Longitudinal Epigenome-Wide Association Study

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