Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene

Tetyana V. Bagnyukova, Volodymyr P. Tryndyak, Beverly Montgomery, Mona I. Churchwell, Adam R. Karpf, Smitha R. James, Levan Muskhelishvili, Frederick A. Beland, Igor P. Pogribny

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Genotoxic carcinogens, including 2-acetylaminofluorene (2-AAF), in addition to exerting their genotoxic effects, often cause a variety of non-genotoxic alterations in cells. It is believed that these non-genotoxic effects may be indispensable events in tumorigenesis; however, there is insufficient knowledge to clarify the role of carcinogens in both the genetic and epigenetic changes in premalignant tissues and a lack of conclusive information on the link between epigenetic alterations and carcinogenic exposure. In the current study, we investigated whether or not the mechanism of 2-AAF-induced hepatocarcinogenesis consists of both genotoxic (genetic) and non-genotoxic (epigenetic) alterations. Male and female Sprague-Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 6, 12, 18 or 24 weeks. The levels of DNA adducts obtained from 2-AAF in liver and kidney tissues were assessed by high-performance liquid chromatography combined with electrospray tandem mass spectrometry (HPLC-ES-MS/MS). N-(Deoxyguanosine-8-yl)-2-aminofluorene was the major adduct detected at all time points in both tissues. Global DNA methylation in the livers and kidneys, as determined by an HpaII-based cytosine extension assay and by HPLC-ES-MS/MS, did not change over the 24-week period. In the livers of male rats, there was a progressive decrease of global and long interspersed nucleotide element-1-associated histone H4 lysine 20 trimethylation, as well as hypermethylation of the p16INK4A gene. These epigenetic changes were not observed in the livers of female rats or the kidneys of both sexes. Importantly, morphological evidence of formation and progression of neoplastic process was observed in the liver of male rats only. In conclusion, we have demonstrated that exposure of rats to genotoxic hepatocarcinogen 2-AAF, in addition to formation of 2-AAF-specific DNA lesions, resulted in substantial alterations in cellular epigenetic status.

Original languageEnglish (US)
Pages (from-to)638-646
Number of pages9
JournalCarcinogenesis
Volume29
Issue number3
DOIs
StatePublished - Mar 1 2008

Fingerprint

2-Acetylaminofluorene
Epigenomics
Liver
High Pressure Liquid Chromatography
Kidney
Carcinogens
Long Interspersed Nucleotide Elements
p16 Genes
Neoplastic Processes
DNA Adducts
Cytosine
DNA Methylation
Tandem Mass Spectrometry
Histones
Lysine
Sprague Dawley Rats
Carcinogenesis
Diet
DNA

ASJC Scopus subject areas

  • Cancer Research

Cite this

Bagnyukova, T. V., Tryndyak, V. P., Montgomery, B., Churchwell, M. I., Karpf, A. R., James, S. R., ... Pogribny, I. P. (2008). Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene. Carcinogenesis, 29(3), 638-646. https://doi.org/10.1093/carcin/bgm303

Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene. / Bagnyukova, Tetyana V.; Tryndyak, Volodymyr P.; Montgomery, Beverly; Churchwell, Mona I.; Karpf, Adam R.; James, Smitha R.; Muskhelishvili, Levan; Beland, Frederick A.; Pogribny, Igor P.

In: Carcinogenesis, Vol. 29, No. 3, 01.03.2008, p. 638-646.

Research output: Contribution to journalArticle

Bagnyukova, TV, Tryndyak, VP, Montgomery, B, Churchwell, MI, Karpf, AR, James, SR, Muskhelishvili, L, Beland, FA & Pogribny, IP 2008, 'Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene', Carcinogenesis, vol. 29, no. 3, pp. 638-646. https://doi.org/10.1093/carcin/bgm303
Bagnyukova, Tetyana V. ; Tryndyak, Volodymyr P. ; Montgomery, Beverly ; Churchwell, Mona I. ; Karpf, Adam R. ; James, Smitha R. ; Muskhelishvili, Levan ; Beland, Frederick A. ; Pogribny, Igor P. / Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene. In: Carcinogenesis. 2008 ; Vol. 29, No. 3. pp. 638-646.
@article{6e8be332813046439b5b9ea6f422a2b5,
title = "Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene",
abstract = "Genotoxic carcinogens, including 2-acetylaminofluorene (2-AAF), in addition to exerting their genotoxic effects, often cause a variety of non-genotoxic alterations in cells. It is believed that these non-genotoxic effects may be indispensable events in tumorigenesis; however, there is insufficient knowledge to clarify the role of carcinogens in both the genetic and epigenetic changes in premalignant tissues and a lack of conclusive information on the link between epigenetic alterations and carcinogenic exposure. In the current study, we investigated whether or not the mechanism of 2-AAF-induced hepatocarcinogenesis consists of both genotoxic (genetic) and non-genotoxic (epigenetic) alterations. Male and female Sprague-Dawley rats were fed NIH-31 diet containing 0.02{\%} of 2-AAF for 6, 12, 18 or 24 weeks. The levels of DNA adducts obtained from 2-AAF in liver and kidney tissues were assessed by high-performance liquid chromatography combined with electrospray tandem mass spectrometry (HPLC-ES-MS/MS). N-(Deoxyguanosine-8-yl)-2-aminofluorene was the major adduct detected at all time points in both tissues. Global DNA methylation in the livers and kidneys, as determined by an HpaII-based cytosine extension assay and by HPLC-ES-MS/MS, did not change over the 24-week period. In the livers of male rats, there was a progressive decrease of global and long interspersed nucleotide element-1-associated histone H4 lysine 20 trimethylation, as well as hypermethylation of the p16INK4A gene. These epigenetic changes were not observed in the livers of female rats or the kidneys of both sexes. Importantly, morphological evidence of formation and progression of neoplastic process was observed in the liver of male rats only. In conclusion, we have demonstrated that exposure of rats to genotoxic hepatocarcinogen 2-AAF, in addition to formation of 2-AAF-specific DNA lesions, resulted in substantial alterations in cellular epigenetic status.",
author = "Bagnyukova, {Tetyana V.} and Tryndyak, {Volodymyr P.} and Beverly Montgomery and Churchwell, {Mona I.} and Karpf, {Adam R.} and James, {Smitha R.} and Levan Muskhelishvili and Beland, {Frederick A.} and Pogribny, {Igor P.}",
year = "2008",
month = "3",
day = "1",
doi = "10.1093/carcin/bgm303",
language = "English (US)",
volume = "29",
pages = "638--646",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Genetic and epigenetic changes in rat preneoplastic liver tissue induced by 2-acetylaminofluorene

AU - Bagnyukova, Tetyana V.

AU - Tryndyak, Volodymyr P.

AU - Montgomery, Beverly

AU - Churchwell, Mona I.

AU - Karpf, Adam R.

AU - James, Smitha R.

AU - Muskhelishvili, Levan

AU - Beland, Frederick A.

AU - Pogribny, Igor P.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - Genotoxic carcinogens, including 2-acetylaminofluorene (2-AAF), in addition to exerting their genotoxic effects, often cause a variety of non-genotoxic alterations in cells. It is believed that these non-genotoxic effects may be indispensable events in tumorigenesis; however, there is insufficient knowledge to clarify the role of carcinogens in both the genetic and epigenetic changes in premalignant tissues and a lack of conclusive information on the link between epigenetic alterations and carcinogenic exposure. In the current study, we investigated whether or not the mechanism of 2-AAF-induced hepatocarcinogenesis consists of both genotoxic (genetic) and non-genotoxic (epigenetic) alterations. Male and female Sprague-Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 6, 12, 18 or 24 weeks. The levels of DNA adducts obtained from 2-AAF in liver and kidney tissues were assessed by high-performance liquid chromatography combined with electrospray tandem mass spectrometry (HPLC-ES-MS/MS). N-(Deoxyguanosine-8-yl)-2-aminofluorene was the major adduct detected at all time points in both tissues. Global DNA methylation in the livers and kidneys, as determined by an HpaII-based cytosine extension assay and by HPLC-ES-MS/MS, did not change over the 24-week period. In the livers of male rats, there was a progressive decrease of global and long interspersed nucleotide element-1-associated histone H4 lysine 20 trimethylation, as well as hypermethylation of the p16INK4A gene. These epigenetic changes were not observed in the livers of female rats or the kidneys of both sexes. Importantly, morphological evidence of formation and progression of neoplastic process was observed in the liver of male rats only. In conclusion, we have demonstrated that exposure of rats to genotoxic hepatocarcinogen 2-AAF, in addition to formation of 2-AAF-specific DNA lesions, resulted in substantial alterations in cellular epigenetic status.

AB - Genotoxic carcinogens, including 2-acetylaminofluorene (2-AAF), in addition to exerting their genotoxic effects, often cause a variety of non-genotoxic alterations in cells. It is believed that these non-genotoxic effects may be indispensable events in tumorigenesis; however, there is insufficient knowledge to clarify the role of carcinogens in both the genetic and epigenetic changes in premalignant tissues and a lack of conclusive information on the link between epigenetic alterations and carcinogenic exposure. In the current study, we investigated whether or not the mechanism of 2-AAF-induced hepatocarcinogenesis consists of both genotoxic (genetic) and non-genotoxic (epigenetic) alterations. Male and female Sprague-Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 6, 12, 18 or 24 weeks. The levels of DNA adducts obtained from 2-AAF in liver and kidney tissues were assessed by high-performance liquid chromatography combined with electrospray tandem mass spectrometry (HPLC-ES-MS/MS). N-(Deoxyguanosine-8-yl)-2-aminofluorene was the major adduct detected at all time points in both tissues. Global DNA methylation in the livers and kidneys, as determined by an HpaII-based cytosine extension assay and by HPLC-ES-MS/MS, did not change over the 24-week period. In the livers of male rats, there was a progressive decrease of global and long interspersed nucleotide element-1-associated histone H4 lysine 20 trimethylation, as well as hypermethylation of the p16INK4A gene. These epigenetic changes were not observed in the livers of female rats or the kidneys of both sexes. Importantly, morphological evidence of formation and progression of neoplastic process was observed in the liver of male rats only. In conclusion, we have demonstrated that exposure of rats to genotoxic hepatocarcinogen 2-AAF, in addition to formation of 2-AAF-specific DNA lesions, resulted in substantial alterations in cellular epigenetic status.

UR - http://www.scopus.com/inward/record.url?scp=40949106395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40949106395&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgm303

DO - 10.1093/carcin/bgm303

M3 - Article

C2 - 18204080

AN - SCOPUS:40949106395

VL - 29

SP - 638

EP - 646

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 3

ER -