Environmental Toxicants and Perturbation of miRNA Signaling

Bailey, Kathryn A.; Fry, Rebecca C.

doi:10.1002/9781118695999.ch2

Cited by 5 publications

(5 citation statements)

References 209 publications

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“…It was predicted that between 7% and 35% of the formaldehyde-associated transcripts were regulated by formaldehyde-responsive miRNAs. These data suggest that the miRNAs may be operating through mechanisms other than mRNA degradation (Bailey and Fry, 2013;Filipowicz et al, 2008) and that other transcriptional regulators, such as DNA methylation and histone modifications (Cedar and Bergman, 2009), may play a role in formaldehyde-induced genomic responses. Our group has shown in vitro that formaldehyde binds to lysine molecules in histone 4 (Lu et al, 2008).…”

Section: Discussionmentioning

confidence: 91%

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Formaldehyde-Associated Changes in microRNAs: Tissue and Temporal Specificity in the Rat Nose, White Blood Cells, and Bone Marrow

Rager

Moeller

et al. 2013

Toxicological Sciences

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MicroRNAs (miRNAs) are critical regulators of gene expression, yet much remains unknown regarding their changes resulting from environmental exposures as they influence cellular signaling across various tissues. We set out to investigate miRNA responses to formaldehyde, a critical air pollutant and known carcinogen that disrupts miRNA expression profiles. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde for 7, 28, or 28 days followed by a 7-day recovery. Genome-wide miRNA expression profiles were assessed within the nasal respiratory epithelium, circulating white blood cells (WBC), and bone marrow (BM). miRNAs showed altered expression in the nose and WBC but not in the BM. Notably in the nose, miR-10b and members of the let-7 family, known nasopharyngeal carcinoma players, showed decreased expression. To integrate miRNA responses with transcriptional changes, genome-wide messenger RNA profiles were assessed in the nose and WBC. Although formaldehyde-induced changes in miRNA and transcript expression were largely tissue specific, pathway analyses revealed an enrichment of immune system/inflammation signaling in the nose and WBC. Specific to the nose was enrichment for apoptosis/proliferation signaling, involving let-7a, let-7c, and let-7f. Across all tissues and time points assessed, miRNAs were predicted to regulate between 7% and 35% of the transcriptional responses and were suggested to play a role in signaling processes including immune/inflammation-related pathways. These data inform our current hypothesis that formaldehyde-induced inflammatory signals originating in the nose may drive WBC effects.

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Section: Discussionmentioning

confidence: 91%

“…MicroRNAs (miRNAs) are key players in cellular responses to toxic agents in the environment, including carcinogens (Bailey and Fry, 2013). miRNAs are short (~21 nucleotides in length), noncoding RNAs that regulate gene expression by base pairing to target transcripts and causing transcript degradation and/or translational repression (Filipowicz et al, 2008).…”

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confidence: 99%

Formaldehyde-Associated Changes in microRNAs: Tissue and Temporal Specificity in the Rat Nose, White Blood Cells, and Bone Marrow

Rager

Moeller

et al. 2013

Toxicological Sciences

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“…The role of microRNAs (miRNAs) in these cellular processes is still unclear. These molecules are members of the RNA interference system, and have attracted great interest in toxicology because of their role in cellular responses to xenobiotic exposure [ 19 , 20 ]. miRNAs are ubiquitously expressed short RNAs approximately 22 nucleotides (nt) in length and are particularly suitable for studying grids of molecular processes underlying pathological alterations of cells and tissues at the gene and protein levels [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Illumina Sequencing Reveals Aberrant Expression of MicroRNAs and Their Variants in Whitefish (Coregonus lavaretus) Liver after Exposure to Microcystin-LR

et al. 2016

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Molecular analyses show that challenging fish with microcystin-LR (MC-LR) causes perturbations of microRNA (miRNA) signaling. However, the significance and scope of these alterations is currently unknown. To address this issue, we studied miRNA gene expression in the liver of juvenile whitefish, C. lavaretus, during 28 days of exposure to a subacute dose of MC-LR (100 μg·kg-1 body mass). Using genomic resources of Atlantic salmon (AGKD03), the mature miRNA library of Atlantic salmon (miRBase-21) and bioinformatics tools (sRNAbench), we discovered and annotated a total of 377 distinct mature miRNAs belonging to 93 families of evolutionary conserved miRNAs, as well as 24 novel mature miRNA candidates that were mapped to 14 distinct S. salar miRNA precursors. miRNA-Seq transcriptome profiling of liver tissues revealed differential miRNA expression in control and treated fish at 14 days (73 miRNAs were modulated) and at 28 days (83 miRNAs) of the treatment, subsequently validated by qPCR for nine selected differentially expressed miRNAs. Additional qPCR study confirmed the miRNA-Seq data and revealed consistent, aberrant miRNAs expression profile in the later phase of MC-LR hepatotoxicity (7–28 d). Functional annotation analysis revealed that the aberrantly expressed miRNAs have target genes involved in cytoskeletal remodeling, cell metabolism, cell cycle regulation and apoptosis; dysregulation of these processes in liver cells leads to cirrhosis and hepatocellular carcinoma in humans. To enable deeper insight into the molecular responses of liver cells in fish exposed to MC-LR, we expanded the miRNAome analysis by inclusion of miRNA variants (isomiRs) profiles, and we showed that the isomiR profiles of liver specific MiR122, and a few other miRNAs, correlated with MC-LR treatment. Given the importance of isomiRs for disease biology in mammals, we believe that further research focused on the miRNA isoforms will bring us closer to better understanding the molecular mechanisms of MC-LR hepatotoxicity.

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“…Interestingly, it was estimated that between 7% and 35% of the FA-responsive transcripts were regulated by FA-associated miRNAs. These data, on the one side, suggest that the miRNAs may be operating through mechanisms other than mRNA degradation [46,60], but also that, on the other side, other transcriptional regulators, such as DNA methylation and histone modifications [61], may play a role in FA-induced genomic responses. It may be argued that, DNMTs may cooperate with histone modifying enzymes to repress specific gene region expression, conversely, histone modifications may impact DNA methylation patterns, and also a bidirectional influence between miRNA and DNA methylation can exist [42].…”

Section: Discussionmentioning

confidence: 94%

Formaldehyde Exposure and Epigenetic Effects: A Systematic Review

et al. 2020

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Formaldehyde (FA) is a general living and occupational pollutant, classified as carcinogenic for humans. Although genotoxicity is recognized as a FA mechanism of action, a potential contribution of epigenetic effects cannot be excluded. Therefore, aim of this review is to comprehensively assess possible epigenetic alterations induced by FA exposure in humans, animals, and cellular models. A systematic review of Pubmed, Scopus, and Isi Web of Science databases was performed. DNA global methylation changes were demonstrated in workers exposed to FA, and also in human bronchial cells. Histone alterations, i.e., the reduction in acetylation of histone lysine residues, in human lung cells were induced by FA. Moreover, a dysregulation of microRNA expression in human lung adenocarcinoma cells as well as in the nose, olfactory bulb and white blood cells of rodents and nonhuman primates was reported. Although preliminary, these findings suggest the role of epigenetic modifications as possible FA mechanisms of action that need deeper qualitative and quantitative investigation. This may allow to define the role of such alterations as indicators of early biological effect and the opportunity to include such information in future risk assessment and management strategies for public and occupationally FA-exposed populations.

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Environmental Toxicants and Perturbation of miRNA Signaling

Cited by 5 publications

References 209 publications

Formaldehyde-Associated Changes in microRNAs: Tissue and Temporal Specificity in the Rat Nose, White Blood Cells, and Bone Marrow

Formaldehyde-Associated Changes in microRNAs: Tissue and Temporal Specificity in the Rat Nose, White Blood Cells, and Bone Marrow

Illumina Sequencing Reveals Aberrant Expression of MicroRNAs and Their Variants in Whitefish (Coregonus lavaretus) Liver after Exposure to Microcystin-LR

Formaldehyde Exposure and Epigenetic Effects: A Systematic Review

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