title: The NRF2-KEAP1 pathway is an early responsive gene network in arsenic exposed lymphoblastoid cells.
abstract: Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs.
authors: Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México.
authors: Emilio J
authors: EJ
authors: Córdova
authors: Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México.
authors: Angélica
authors: A
authors: Martínez-Hernández
authors: Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México.
authors: Laura
authors: L
authors: Uribe-Figueroa
authors: Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México.
authors: Federico
authors: F
authors: Centeno
authors: Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad México, México City, México.
authors: Mirna
authors: M
authors: Morales-Marín
authors: Lawrence Livermore National Laboratory, Livermore, California, United States of America.
authors: Harsha
authors: H
authors: Koneru
authors: Lawrence Livermore National Laboratory, Livermore, California, United States of America ; Department of Radiation Oncology, Davis Medical Center, University of California Davis, Sacramento, California, United States of America.
authors: Matthew A
authors: MA
authors: Coleman
authors: Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México ; Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad México, México City, México.
authors: Lorena
authors: L
authors: Orozco
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000494:pharmacology*
chemical_list: D018053:Arsenites; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017670:Sodium Compounds; C017947:sodium arsenite