Abstract
BackgroundNickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers. Our earlier studies showed that the nickel-exposure-induced genome-wide transcriptional changes, which persist even after the termination of exposure may underlie nickel pathogenesis. However, the mechanisms that drive nickel-induced persistent changes to the transcriptome remain elusive.ResultsTo elucidate the mechanisms that underlie nickel-induced long-term transcriptional changes, in this study, we examined the transcriptome and the epigenome of human lung epithelial cells during nickel exposure and after the termination of exposure. We identified two categories of persistently differentially expressed genes: (i) the genes that were differentially expressed during nickel exposure; and (ii) the genes that were differentially expressed only after the termination of exposure. Interestingly, > 85% of the nickel-induced gene expression changes occurred only after the termination of exposure. We also found extensive genome-wide alterations to the activating histone modification, H3K4me3, after the termination of nickel exposure, which coincided with the post-exposure gene expression changes. In addition, we found significant post-exposure alterations to the repressive histone modification, H3K27me3.ConclusionOur results suggest that while modest first wave of transcriptional changes occurred during nickel exposure, extensive transcriptional changes occurred during a second wave of transcription for which removal of nickel ions was essential. By uncovering a new category of transcriptional and epigenetic changes, which occur only after the termination of exposure, this study provides a novel understanding of the long-term deleterious consequences of nickel exposure on human health.
Highlights
Nickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers
Nickel exposure induces persistent gene expression changes BEAS-2B cells were exposed to non-cytotoxic and physiologically relevant concentration of 100 μM NiCl2 for 6 weeks [4, 19]
We identified two categories of PU genes: (iii) persistently upregulatedA (PU-A) genes—a subset of the PU genes (115 genes), which were upregulated during nickel exposure and the increased expression continued after the termination of exposure. (iv) persistently upregulated-B (PU-B) genes—a subset of PU genes (963 genes), whose expression remained unaltered during nickel exposure
Summary
Nickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers. EMT, the process during which the epithelial cells lose their polarity and cell–cell adhesion and acquire migratory and invasive phenotype, is associated with asthma, bronchitis, fibrosis, cancer and metastasis, diseases commonly associated with nickel exposure [1, 2, 5,6,7]. This suggests that the persistent transcriptional changes caused by nickel exposure could be a predisposing factor in the development of nickelexposure-associated diseases. Unravelling the mechanisms that underlie the global gene expression changes that persist post nickel-exposure is critical for a comprehensive understanding of the long-term impact of nickel exposure on human health
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
