Epigenetic reprogramming of liver cells in tamoxifen‐induced rat hepatocarcinogenesis

Tryndyak, Volodymyr; Kovalchuk, Olga; Muskhelishvili, Levan; Montgomery, Beverly; Rodriguez-Juarez, Rocio; Melnyk, Stepan; Ross, Sharon A.; Beland, Frederick A.; Pogribny, Igor P.

doi:10.1002/mc.20263

Cited by 46 publications

(18 citation statements)

References 54 publications

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“…It has been shown that genome-wide DNA hypomethylation in cancer, including liver cancer, largely affects repetitive DNA elements [28,40,41]. Additionally, recent evidence indicates that hypomethylation of retroelements occurs even in precancerous stages of development of human hepatocellular carcinoma [41,42], as well as at early stages of non-genotoxic and genotoxic rodent hepatocarcinogenesis [43,44]. Loss of cytosine methylation at repetitive DNA sequences is associated with increased transcription of these elements.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor α

Pogribny

Tryndyak

Woods

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Peroxisome proliferators are potent rodent liver carcinogens that act via a non-genotoxic mechanism. The mode of action of these agents in rodent liver includes increased cell proliferation, decreased apoptosis, secondary oxidative stress and other events; however, it is not well understood how peroxisome proliferators are triggering the plethora of the molecular signals leading to cancer. Epigenetic changes have been implicated in the mechanism of liver carcinogenesis by a number of environmental agents. Short-term treatment with peroxisome proliferators and other non-genotoxic carcinogens leads to global and locus-specific DNA hypomethylation in mouse liver, events that were suggested to correlate with a burst of cell proliferation. In the current study, we investigated the effects of long-term exposure to a model peroxisome proliferator WY-14,643 on DNA and histone methylation. Male SV129 mice were fed a control or WY-14,643-containing (1000 ppm) diet for 1 wk, 5 wks or 5 months. Treatment with WY-14,643 led to progressive global hypomethylation of liver DNA as determined by an HpaII-based cytosine extension assay with the maximum effect reaching over 200% at 5 months. Likewise, trimethylation of histone H4 lysine 20 and H3 lysine 9 was significantly decreased at all time points. The majority of cytosine methylation in mammals resides in repetitive DNA sequences. In view of this, we measured the effect of WY-14,643 on the methylation status of major and minor satellites, as well as in IAP, LINE1 and LINE2 elements in liver DNA. Exposure to WY-14,643 resulted in a gradual loss of cytosine methylation in major and minor satellites, IAP, LINE1 and LINE2 elements. The epigenetic changes correlated with the temporal effects of WY-14,643 on cell proliferation rates in liver, but no sustained effect on c-Myc promoter methylation was observed. Finally, WY-14,643 had no effect on DNA and histone methylation status in Pparα-null mice at any of the time points considered in this study. These data indicate the importance of epigenetic alterations in the mechanism of action of peroxisome proliferators and the key role of PPARα.

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Section: Discussionmentioning

confidence: 99%

Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor α

Pogribny

Tryndyak

Woods

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…DNA methylation is the most stable epigenetic modification of mammalian genomes and is crucial for normal development, proliferation, and maintenance of genome stability [Jones and Gonzalgo, 1997;Rizwana and Hahn, 1999;Swales and Spears, 2005;Doerfler, 2006;Jones and Baylin, 2007]. DNA methylation patterns are disrupted in cancers [Jones and Gonzalgo, 1997;Feinberg and Tycko, 2004;Ehrlich, 2006;Jones and Baylin, 2007] and following exposure to genotoxic agents [Minamoto et al, 1999;Raiche et al, 2004;Tryndyak et al, 2007]. Differential methylation can arise in the germline; methylation changes at CpG sites in specific loci have been observed in the descendents of animals exposed to endocrine disrupting chemicals Skinner and Anway, 2005;Koturbash et al, 2006a] or ionizing radiation [Koturbash et al, 2006b].…”

Section: Introductionmentioning

confidence: 99%

Tandem repeat mutation, global DNA methylation, and regulation of DNA methyltransferases in cultured mouse embryonic fibroblast cells chronically exposed to chemicals with different modes of action

Yauk

Polyzos

Rowan-Carroll

et al. 2008

Environ and Mol Mutagen

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Mutations at expanded simple tandem repeat (ESTR) DNA sequences provide a useful tool for screening germline mutation. However, the mechanisms resulting in induced mutations are unknown and provide an impediment to the utility of the method. Induced ESTR mutations arise through a nontargeted mechanism resulting in destabilization of the repeat locus. We hypothesized that alterations in DNA methylation, or in DNA methyltransferase expression, may be associated with this indirect mechanism of mutation. DNA mutation frequency was measured in C3H/10T1/2 mouse embryonic fibroblast cells following chronic exposure to six chemicals exhibiting different modes of genotoxic action: N‐nitroso‐N‐ethylurea (ENU); benzo(a)pyrene (BaP); etoposide (ETOP); okadaic acid (OA); cisplatin (CisPt); and 5‐azacytidine (5azadC). Induced mutation ranged from 2‐fold (ENU, BaP, ETOP), to 1.3–1.4 fold (OA, 5azadC), to nonresponsive (CisPt). Global DNA methylation, measured using the cytosine extension assay, revealed hypomethylation following exposure to ENU and 5azadC, hypermethylation following BaP and OA exposure, and no change following treatment with ETOP or CisPt. DNA methyltransferase transcription (Dnmt1, Dnmt3a, Dnmt3b) was significantly affected by all treatments except ETOP, with the vast majority of changes being downregulation. There was no direct correlation between ESTR mutation, global methylation, or DNA methyltransferase transcription. However, 4/5 ESTR mutagens caused changes in global methylation, while the noninducer (CisPt) did not cause changes in methylation. We hypothesize that chemicals that modify chromatin conformation through changes in methylation may compromise the ability of mismatch repair enzymes (or other enzymes) to access and repair secondary structures that may form across ESTR loci resulting in mutation. Environ. Mol. Mutagen., 2008. Published 2008 Wiley‐Liss, Inc.

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“…DNA methylation is the most stable epigenetic modification of mammalian genomes and is crucial for normal development, proliferation and maintenance of genome stability (29)(30)(31)(32)(33). DNA methylation patterns are disrupted in cancers (29,(33)(34)(35) and following exposure to genotoxic agents (36)(37)(38). Differential methylation has been observed in the descendents of animals exposed to various agents (39)(40)(41), suggesting a potential link to nontargeted DNA mutations and transgenerational effects.…”

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confidence: 99%

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Yauk¹,

Polyzos²,

Rowan-Carroll³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/ urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPAfiltered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.DNA adducts ͉ DNA strand breaks ͉ tandem repeat mutation C ombustion of fossil fuels results in the production of complex mixtures of chemicals that are released into the environment and potentially affect millions of people globally. Previous work demonstrated that the offspring of wild birds breeding near integrated steel mills on the North American Great Lakes inherited increased numbers of tandem repeat DNA sequence mutations compared with those from areas without steel mills (1, 2). Subsequent studies investigated expanded simple tandem repeat (ESTR) mutation in outbred laboratory mice caged near two integrated steel mills and a major highway in Hamilton, Ontario, Canada, and at a rural reference site (3, 4). Using a pedigree approach (5), a significant increase in germ-line mutation rate was found in mice housed in the industrial environment compared with the reference site. The majority of mutations were transmitted through the paternal germ line. High-efficiency particulate-air (HEPA) filtration of the ambient air resulted in a significant reduction in mutation frequency, down to levels measured at the reference location (4). Therefore, the particulate fraction of air in this industrial location was largely responsible for the mutagenic hazard.These findings show that chemical pollutants may cause heritable mutation. Further research is required to confirm these results...

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Epigenetic reprogramming of liver cells in tamoxifen‐induced rat hepatocarcinogenesis

Cited by 46 publications

References 54 publications

Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor α

Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor α

Tandem repeat mutation, global DNA methylation, and regulation of DNA methyltransferases in cultured mouse embryonic fibroblast cells chronically exposed to chemicals with different modes of action

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

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