DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study
Tóm tắt
Between 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). We 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 450 K platform. Epigenome-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. We 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.
Tài liệu tham khảo
The National Academy of Sciences, editor. Veterans and Agent Orange: update 11 (2018). Washington, DC: The National Academies Press; 2018.
Mrema EJ, Rubino FM, Brambilla G, Moretto A, Tsatsakis AM, Colosio C. Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology. 2013. https://doi.org/10.1016/j.tox.2012.11.015.
Patrizi B, de Cumis MS. TCDD toxicity mediated by epigenetic mechanisms. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19124101.
Buffler PA, Ginevan ME, Mandel JS, Watkins DK. The Air Force health study: an epidemiologic retrospective. Ann Epidemiol. 2011. https://doi.org/10.1016/j.annepidem.2011.02.001.
Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res. 2007. https://doi.org/10.1194/jlr.R700005-JLR200.
Luo L, Liu M. Adipose tissue in control of metabolism. J Endocrinol. 2016. https://doi.org/10.1530/JOE-16-0211.
Seefeld MD, Corbett SW, Keesey RE, Peterson RE. Characterization of the wasting syndrome in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 1984. https://doi.org/10.1016/0041-008X(84)90337-5.
Magesh SB, Rajappa R, Ramkumar KM, Suryanarayanan S, Madhunapantula SV. Acetyl-L-Carnitine restores abnormal lipid metabolism induced by 2,3,7,8 tetrachlorodibenzo-p-dioxin in mice. Biomed Pharmacol J. 2017;10(2). Available from: http://biomedpharmajournal.org/?p=15336
Brulporta A, Le Correa L, Chagnon M-C. Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet. Toxicology. 2017;390:43–52.
Warner M, et al. In utero dioxin exposure and cardiometabolic risk in the Seveso second generation study. Int J Obes. 2019. https://doi.org/10.1038/s41366-018-0306-8.
van den Dungen MW, Murk AJ, Kok DE, Steegenga WT. Persistent organic pollutants alter DNA methylation during human adipocyte differentiation. Toxicol In Vitro. 2017. https://doi.org/10.1016/j.tiv.2016.12.011.
Bastos Sales L, Kamstra JH, Cenijn PH, van Rijt LS, Hamers T, Legler J. Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation. Toxicol In Vitro. 2013. https://doi.org/10.1016/j.tiv.2013.04.005.
Hsu HF, Tsou TC, Chao HR, Kuo YT, Tsai FY, Yeh SC. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3T3-L1 cells. J Hazard Mater. 2010. https://doi.org/10.1016/j.jhazmat.2010.06.081.
Kim MJ, et al. Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells. Environ Health Perspect. 2012. https://doi.org/10.1289/ehp.1104282.
Houseman EA, Kim S, Kelsey KT, Wiencke JK. DNA methylation in whole blood: uses and challenges. Curr Environ Health Rep. 2015. https://doi.org/10.1007/s40572-015-0050-3.
Pittman GS, et al. Polychlorinated biphenyl exposure and DNA methylation in the Anniston community health survey. Epigenetics. 2019. https://doi.org/10.1080/15592294.2019.1666654.
Pittman GS, et al. Dioxin-like compound exposures and DNA methylation in the Anniston community health survey phase II. Sci Total Environ. 2020;742:140424.
van den Dungen MW, Murk AJ, Kampman E, Steegenga WT, Kok DE. Association between DNA methylation profiles in leukocytes and serum levels of persistent organic pollutants in Dutch men. Environ Epigenet. 2017. https://doi.org/10.1093/eep/dvx001.
Su KY, et al. Perinatal polychlorinated biphenyls and polychlorinated dibenzofurans exposure are associated with DNA methylation changes lasting to early adulthood: findings from Yucheng second generation. Environ Res. 2019. https://doi.org/10.1016/j.envres.2019.01.001.
Lee MH, Cho ER, Lim J, Jee SH. Association between serum persistent organic pollutants and DNA methylation in Korean adults. Environ Res. 2017. https://doi.org/10.1016/j.envres.2017.06.017.
Itoh H, et al. Association between serum organochlorines and global methylation level of leukocyte DNA among Japanese women: a cross-sectional study. Sci Total Environ. 2014. https://doi.org/10.1016/j.scitotenv.2014.05.035.
Lathrop GD, Wolfe WH, Albanese RA, Moynahan PM. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides: study protocol, initial report. Texas: Brooks Air Force Base; 1982.
Lathrop GD, Moynahan PM, Albanese RA, Wolfe WH. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides: baseline morbidity study results. Texas: Brooks Air Force Base; 1984.
Committee on the Management of the Air Force Health Study Data and Specimens. The air force health study assets research program. Washington, DC: National Academies Press; 2015.
C. on the D. of the A. F. H. S. Institute of Medicine, Board on Population Health and Public Health Practice. Disposition of the air force health study. Washington, DC: National Academies Press; 2006.
C. for D. C. U.S Department of Health and Human Services, Public Health Service. Health status of Vietnam veterans: supplement a – laboratory methods and quality control. Atlanta: US Department of Health and Human Services; 1989.
Science Applications International Corporation, “Biomedical test plan. Air Force contract no. F14689-85-D-0010,” 1985.
R Core Team. R: a language and environment for statistical computing. Vienna: R statistical computing software; 2019.
Wilhelm-Benartzi CS, et al. Review of processing and analysis methods for DNA methylation array data. Br J Cancer. 2013. https://doi.org/10.1038/bjc.2013.496.
Chen YA, et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics. 2013. https://doi.org/10.4161/epi.23470.
Triche TJ, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD. Low-level processing of Illumina Infinium DNA methylation BeadArrays. Nucleic Acids Res. 2013. https://doi.org/10.1093/nar/gkt090.
Fortin JP, et al. Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol. 2014. https://doi.org/10.1186/s13059-014-0503-2.
Teschendorff AE, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013. https://doi.org/10.1093/bioinformatics/bts680.
Chen C, et al. Removing batch effects in analysis of expression microarray data: an evaluation of six batch adjustment methods. PLoS One. 2011. https://doi.org/10.1371/journal.pone.0017238.
Leek JT, Storey JD. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 2007. https://doi.org/10.1371/journal.pgen.0030161.
Mallik S, Odom GJ, Gao Z, Gomez L, Chen X, Wang L. An evaluation of supervised methods for identifying differentially methylated regions in Illumina methylation arrays. Brief Bioinform. 2019. https://doi.org/10.1093/bib/bby085.
Wiencke JK, et al. Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival. Clin Epigenetics. 2017. https://doi.org/10.1186/s13148-017-0316-8.
Ambatipudi S, et al. DNA methylation derived systemic inflammation indices are associated with head and neck cancer development and survival. Oral Oncol. 2018. https://doi.org/10.1016/j.oraloncology.2018.08.021.
Giuliani C, et al. First evidence of association between past environmental exposure to dioxin and DNA methylation of CYP1A1 and IGF2 genes in present day Vietnamese population. Environ Pollut. 2018. https://doi.org/10.1016/j.envpol.2018.07.015.
Hannum G, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013. https://doi.org/10.1016/j.molcel.2012.10.016.
Bell CG, et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 2019. https://doi.org/10.1186/s13059-019-1824-y.
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013. https://doi.org/10.1186/gb-2013-14-10-r115.
Levine ME, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany. NY). 2018. https://doi.org/10.18632/aging.101414.
White AJ, et al. Air pollution, particulate matter composition and methylation-based biologic age. Environ Int. 2019. https://doi.org/10.1016/j.envint.2019.105071.
Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol. 2010. https://doi.org/10.1038/nrm2866.
Rouillard AD, et al. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford). 2016. https://doi.org/10.1093/database/baw100.
Yao L, Romero MJ, Toque HA, Yang G, Caldwell RB, Caldwell RW. The role of RhoA/Rho kinase pathway in endothelial dysfunction. J Cardiovasc Dis Res. 2010;1(4):165–70. https://doi.org/10.4103/0975-3583.74258.
Chen W, Mao K, Liu Z, Tuan A, Dinh-Xuan. The role of the RhoA/Rho kinase pathway in anti-angiogenesis and its potential value in prostate cancer (Review). Oncol Lett. 2014;8(5):1907–11.
Carvajal-Gonzalez JM, et al. The dioxin receptor regulates the constitutive expression of the Vav3 proto-oncogene and modulates cell shape and adhesion. Mol Biol Cell. 2009. https://doi.org/10.1091/mbc.E08-05-0451.
Fernandez-Salguero PM. A remarkable new target gene for the dioxin receptor: the Vav3 proto-oncogene links AhR to adhesion and migration. Cell Adh Migr. 2010. https://doi.org/10.4161/cam.4.2.10387.
Houlahan KE, et al. Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin. Toxicology. 2015. https://doi.org/10.1016/j.tox.2014.12.016.
Tuomisto JT, Pohjanvirta R, Unkila M, Tuomisto J. TCDD-induced anorexia and wasting syndrome in rats: effects of diet-induced obesity and nutrition. Pharmacol Biochem Behav. 1999. https://doi.org/10.1016/S0091-3057(98)00224-X.
Danjou AMN, Fervers B, Boutron-Ruault MC, Philip T, Clavel-Chapelon F, Dossus L. Estimated dietary dioxin exposure and breast cancer risk among women from the French E3N prospective cohort. Breast Cancer Res. 2015. https://doi.org/10.1186/s13058-015-0536-9.
Schleinitz D, et al. Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio. Int J Obes. 2014. https://doi.org/10.1038/ijo.2013.56.
Kelsey KT, et al. Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to Agent Orange. Environ Health. 2019. https://doi.org/10.1186/s12940-019-0533-z.
Ruszkowska M, et al. Identification and characterization of long non-coding RNAs in porcine granulosa cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Anim Sci Biotechnol. 2018. https://doi.org/10.1186/s40104-018-0288-3.
Dempsey JL, Cui JY. Long non-coding RNAs: a novel paradigm for toxicology. Toxicol Sci. 2017. https://doi.org/10.1093/toxsci/kfw203.
Dere E, Forgacs AL, Zacharewski TR, Burgoon LD. Genome-wide computational analysis of dioxin response element location and distribution in the human, mouse, and rat genomes. Chem Res Toxicol. 2011. https://doi.org/10.1021/tx100328r.
Hanna A, Shevde LA. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol Cancer. 2016. https://doi.org/10.1186/s12943-016-0509-3.
Cheon HJ, et al. Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages. Exp Mol Med. 2007. https://doi.org/10.1038/emm.2007.58.
Hanlon PR, Ganem LG, Cho YC, Yamamoto M, Jefcoate CR. AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicol Appl Pharmacol. 2003. https://doi.org/10.1016/S0041-008X(03)00083-8.
Davis AP, et al. The comparative toxicogenomics database: update 2019. Nucleic Acids Res. 2019. https://doi.org/10.1093/nar/gky868.
Dhingra R, Nwanaji-Enwerem JC, Samet M, Ward-Caviness CK. DNA methylation age-environmental influences, health impacts, and its role in environmental epidemiology. Curr Environ Health Rep. 2018. https://doi.org/10.1007/s40572-018-0203-2.
Perna L, Zhang Y, Mons U, Holleczek B, Saum KU, Brenner H. Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics. 2016. https://doi.org/10.1186/s13148-016-0228-z.
Roetker NS, Pankow JS, Bressler J, Morrison AC, Boerwinkle E. Prospective study of epigenetic age acceleration and incidence of cardiovascular disease outcomes in the ARIC study (atherosclerosis risk in communities). Circ Genomic Precis Med. 2018. https://doi.org/10.1161/CIRCGEN.117.001937.
Durso DF, et al. Acceleration of leukocytes’ epigenetic age as an early tumorand sex-specific marker of breast and colorectal cancer. Oncotarget. 2017. https://doi.org/10.18632/oncotarget.15573.