Influence of Arsenic on Global Levels of Histone Posttranslational Modifications: a Review of the Literature and Challenges in the Field
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Arsenic is a human carcinogen and also increases the risk for non-cancer outcomes. Arsenic-induced epigenetic dysregulation may contribute to arsenic toxicity. Although there are several reviews on arsenic and epigenetics, these have largely focused on DNA methylation. Here, we review investigations of the effects of arsenic on global levels of histone posttranslational modifications (PTMs). Multiple studies have observed that arsenic induces higher levels of H3 lysine 9 dimethylation (H3K9me2) and also higher levels of H3 serine 10 phosphorylation (H3S10ph), which regulate chromosome segregation. In contrast, arsenic causes a global loss of H4K16ac, a histone PTM that is a hallmark of human cancers. Although the findings for other histone PTMs have not been entirely consistent across studies, we discuss biological factors which may contribute to these inconsistencies, including differences in the dose, duration, and type of arsenic species examined; the tissue or cell line evaluated; differences by sex; and exposure timing. We also discuss two important considerations for the measurement of histone PTMs: proteolytic cleavage of histones and arsenic-induced alterations in histone expression.
KeywordsArsenic Histone posttranslational modifications
This work was supported by NIH grants P42 ES010349, RO1 CA133595, RO1 ES017875, T32 ES007322, P30 ES009089, and F31ES025100.
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Conflict of Interest
Caitlin G. Howe and Mary V. Gamble declare they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain primary data from any studies with animal or human subjects performed by the authors.
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- 1.World Health Organization. Arsenic and arsenic compounds. IARC Monographs. 2012;100C.Google Scholar
- 2.National Research Council. Critical aspects of EPA's IRIS assessment of inorganic arsenic. National Research Council Interim Report. 2013.Google Scholar
- 3.World Health Organization. Arsenic Fact Sheet No 372. 2012.Google Scholar
- 7.Hall MN, Gamble MV. Nutritional manipulation of one-carbon metabolism: effects on arsenic methylation and toxicity. J Toxicol. 2012;2012.Google Scholar
- 9••.Steinmaus CM, Ferreccio C, Romo JA, et al. Drinking water arsenic in northern Chile: high cancer risks 40 years after exposure cessation. Cancer Epidemiol Biomark Prev. 2013;22(4):623–30. This study demonstrated that cancer risks persist decades after arsenic exposure has been reduced, indicating the need for public health interventions which complement arsenic remediation efforts.CrossRefGoogle Scholar
- 13.Falchi L, Verstovsek S, Ravandi-Kashani F, et al. The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. Cancer. 2015.Google Scholar
- 37.Rahman S, Housein Z, Dabrowska A, Mayan MD, Boobis AR, Hajji N. E2F1-mediated FOS induction in arsenic trioxide-induced cellular transformation: effects of global H3K9 hypoacetylation and promoter-specific hyperacetylation in vitro. Environ Health Perspect. 2015;123(5):484–92.PubMedPubMedCentralGoogle Scholar
- 39.Ray PD, Huang BW, Tsuji Y. Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene. Biochim Biophys Acta. 2015;10(88):18.Google Scholar
- 50••.Tyler CR, Hafez AK, Solomon ER, Allan AM. Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region-and sex-specific manner in the adult mouse brain. Toxicol Appl Pharmacol. 2015;288(1):40–51. This is the first animal study to examine the effects of arsenic on PTMs separately by sex and in different tissue types.PubMedCrossRefGoogle Scholar
- 53•.Howe, CG, Liu, X, Hall, MN, et al. Associations between blood and urine arsenic concentrations and post-translational histone modifications in Bangladeshi men and women. Environ Health Perspect. 2016. This is the first large human study to evaluate the effects of arsenic exposure, due to arsenic-contaminated drinking water, on PTMs separately by sex . Google Scholar
- 54•.Ma, L, Li, J, Zhan, Z, et al. Specific histone modification responds to arsenic-induced oxidative stress. Toxicol Appl Pharmacol. 2016. This is the first large human study to evaluate the effects of arsenic exposure, due to use of arsenic-contaminated coal, on histone PTMs. This study also evaluated the effect of short versus long duration arsenic exposures on the same PTMs in vitro . Google Scholar
- 55•.Pournara, A, Kippler, M, Holmlund, T, et al. Arsenic alters global histone modifications in lymphocytes in vitro and in vivo. Cell Biol Toxicol. 2016. This is the first human study to evaluate the effects of arsenic exposure on histone PTMs in sorted lymphocytes.Google Scholar
- 59.Rivera, C, Saavedra, F, Alvarez, F, et al. Methylation of histone H3 lysine 9 occurs during translation. Nucleic Acids Res. 2015;gkv929.Google Scholar
- 81•.Broberg K, Ahmed S, Engstrom K, et al. Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys. J Dev Orig Health Dis. 2014;5(04):288–98. This study examined the effects of arsenic on genome-wide DNA methylation in cord blood separately by sex and observed that the effects were more pronounced among boys.PubMedPubMedCentralCrossRefGoogle Scholar
- 82•.Pilsner JR, Hall MN, Liu X, et al. Influence of prenatal arsenic exposure and newborn sex on global methylation of cord blood DNA. PLoS One. 2012;7(5):e37147. This study examined the effects of arsenic on global DNA methylation levelsof DNA methylation in cord blood separately by sex and observed that the effects were in opposite directions for boys and girls.PubMedPubMedCentralCrossRefGoogle Scholar
- 83•.Niedzwiecki MM , Liu X, Hall MN. Sex-specific associations of arsenic exposure with global DNA methylation and hydroxymethylation in leukocytes: results from two studies in Bangladesh. Cancer Epidemiol Biomark Prev. 2015; 24(11):1748-1757. This was the first human study to examine the effects of arsenic on both 5-methylcytosine and 5-hydroxymethylcytosine. Differences by sex were evaluated and the associations between arsenic and these marks differed between men and women. CrossRefGoogle Scholar
- 89••.Dhaenens M, Glibert P, Meert P, Vossaert L, Deforce D. Histone proteolysis: a proposal for categorization into ‘clipping’and ‘degradation’. Bioessays. 2015;37(1):70–9. This is a very comphrensive review of all of studies which have identified histone proteolysis and it provides important discussion about the difficulties in distinguishing between biological histone clipping versus histone degradation.PubMedCrossRefGoogle Scholar
- 92•.Howe CG, Gamble MV. Enzymatic cleavage of histone H3: a new consideration when measuring histone modifications in human samples. Clin Epigenetics. 2015;7(1):1. This letter presents evidence that histone H3 is cleaved in human peripheral blood mononuclear cells and demonstrates that this influences the measurement of certain PTMs.CrossRefGoogle Scholar
- 93••.Brocato J, Fang L, Chervona Y, et al. Arsenic induces polyadenylation of canonical histone mRNA by down-regulating stem-loop-binding protein gene expression. J Biol Chem. 2014;289(46):31751–64. This study demonstrated that arsenic increases the expression of the canonical histone proteins.PubMedPubMedCentralCrossRefGoogle Scholar
- 100•.Rea, M, Jiang, T, Eleazer, R, et al. Quantitative mass spectrometry reveals changes in histone H2B variants as cells undergo inorganic arsenic-mediated cellular transformation. Mol Cell Proteomics. 2016. This is the first study to demonstrate that arsenic differentially alters H2B variants.Google Scholar
- 105.Davison JM, Mellott TJ, Kovacheva VP, Blusztajn JK. Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem. 2009;284(4):1982–9.PubMedPubMedCentralCrossRefGoogle Scholar