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. 2019 Oct 29;18(1):91.
doi: 10.1186/s12940-019-0533-z.

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

Karl T Kelsey  1   2 , Matthew Rytel  3 , Edward Dere  4 , Rondi Butler  3   4 , Melissa Eliot  3 , Susan M Huse  5 , E Andres Houseman  6 , Devin C Koestler  7 , Kim Boekelheide  4
Affiliations

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

Karl T Kelsey et al. Environ Health. .

Abstract

Background: Exposure to the herbicide Agent Orange during the Vietnam War was widespread and is associated with numerous adverse health outcomes. A continuing concern of veterans is the possibility that exposure to the dioxin-containing herbicide might induce adverse reproductive outcomes. We sought to assess whether exposure to Agent Orange in Vietnam was associated with changes in DNA methylation in sperm in a subset of Vietnam veterans who participated in the Air Force Health Study (AFHS).

Methods: We studied 37 members of the AFHS chosen to have no, low, medium or high exposure to Agent Orange, based upon serum dioxin levels obtained during a series of examinations. DNA from stored semen was extracted and DNA methylation assessed on the Illumina 450 K platform.

Results: Initial epigenome-wide analysis returned no loci that survived control for false discovery. However, the TEAD3 gene had four different CpG sites that showed loss of DNA methylation associated with dioxin exposure. Analysis assessing regional DNA methylation changes revealed 36 gene regions, including the region of the imprinted gene H19 to have altered DNA methylation associated with high exposure compared to the low exposure group. Additional comparison of our data with sperm DNA methylation data from Russian boys exposed to dioxin found an additional 5 loci that were altered in both studies and exhibited a consistent direction of association.

Conclusions: Studying a small number of sperm samples from veterans enrolled in the AFHS, we did not find evidence of significant epigenome-wide alterations associated with exposure to Agent Orange. However, additional analysis showed that the H19 gene region is altered in the sperm of Agent Orange-exposed Ranch Hand veterans. Our study also replicated several findings of a prior study of dioxin-exposed Russian boys. These results provide additional candidate loci for further investigation and may have implications for the reproductive health of dioxin-exposed individuals.

Keywords: Agent Orange; DNA methylation; Dioxin; Epigenetics; Sperm.

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Conflict of interest statement

Dr. Karl Kelsey is a founder and advisor for Cellintec. The other authors declare they have no actual or potential competing financial interests.

Figures

Fig. 1
Fig. 1
Heatmap of the unstructured cluster analysis of DNA methylation in sperm of high dioxin serum level Ranch Hand veterans compared with controls
Fig. 2
Fig. 2
Manhatten plot of the regions where alterations in DNA methylation were significantly associated with dioxin serum level
See this image and copyright information in PMC

References

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