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PLoS One. 2014 Feb 7;9(2):e88069. doi: 10.1371/journal.pone.0088069. eCollection 2014.

The NRF2-KEAP1 pathway is an early responsive gene network in arsenic exposed lymphoblastoid cells.

Author information

1
Immunogenomics and Metabolics Disease Laboratory, Instituto Nacional de Medicina Genómica, SS, México City, México.
2
Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad México, México City, México.
3
Lawrence Livermore National Laboratory, Livermore, California, United States of America.
4
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.
5
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.

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.

PMID:
24516582
PMCID:
PMC3917856
DOI:
10.1371/journal.pone.0088069
[Indexed for MEDLINE]
Free PMC Article

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