title: Arsenic alters global histone modifications in lymphocytes in vitro and in vivo.
abstract: Arsenic, an established carcinogen and toxicant, occurs in drinking water and food and affects millions of people worldwide. Arsenic appears to interfere with gene expression through epigenetic processes, such as DNA methylation and post-translational histone modifications. We investigated the effects of arsenic on histone residues in vivo as well as in vitro. Analysis of H3K9Ac and H3K9me3 in CD4+ and CD8+ sorted blood cells from individuals exposed to arsenic through drinking water in the Argentinean Andes showed a significant decrease in global H3K9me3 in CD4+ cells, but not CD8+ cells, with increasing arsenic exposure. In vitro studies of inorganic arsenic-treated T lymphocytes (Jurkat and CCRF-CEM, 0.1, 1, and 100 μg/L) showed arsenic-related modifications of H3K9Ac and changes in the levels of the histone deacetylating enzyme HDAC2 at very low arsenic concentrations. Further, in vitro exposure of kidney HEK293 cells to arsenic (1 and 5 μM) altered the protein levels of PCNA and DNMT1, parts of a gene expression repressor complex, as well as MAML1. MAML1 co-localized and interacted with components of this complex in HEK293 cells, and in silico studies indicated that MAML1 expression correlate with HDAC2 and DNMT1 expression in kidney cells. In conclusion, our data suggest that arsenic exposure may lead to changes in the global levels of H3K9me3 and H3K9Ac in lymphocytes. Also, we show that arsenic exposure affects the expression of PCNA and DNMT1-proteins that are part of a gene expression silencing complex.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Pournara
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Kippler
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Holmlund
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ceder
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Roland
authors.initials: R
authors.lastname: Grafström
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, S-171 77, Stockholm, Sweden. annika.wallberg@ki.se.
authors.forename: Annika E
authors.initials: AE
authors.lastname: Wallberg
mesh_terms: D000328:Adult; D001151:Arsenic / Q000009:adverse effects* / Q000097:blood; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D060766:Drinking Water; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D057809:HEK293 Cells; D042421:Histone Code / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D060766:Drinking Water; D006657:Histones; C430872:MAML1 protein, human; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D001151:Arsenic
keywords: Arsenic; Histone modifications; Lymphocytes; MAML1