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Book: Carcinogenesis

Waalkes, Michael Phillip

(Target organ toxicology series)

1994

Author's details	ed. Michael P. Waalkes
Series title	Target organ toxicology series
Keywords	Neoplasms / chemically induced ; Neoplasms / physiopathology ; Carcinogenese
Subject	Krebs ; Krebsentstehung ; Karzinogenese ; Kanzerogenese ; Onkogenese
Language	English
Size	XI, 478 S. : Ill., graph. Darst.
Publisher	Raven Press
Publishing place	New York
Publishing country	United States
Document type	Book
HBZ-ID	HT006285182
ISBN	0-7817-0124-4 ; 978-0-7817-0124-2
Database	Catalogue ZB MED Medicine, Health

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Article: Cadmium-stimulated invasion of rat liver cells during malignant transformation: Evidence of the involvement of oxidative stress/TET1-sensitive machinery

Hirao-Suzuki, Masayo / Takeda, Shuso / Sakai, Genki / Waalkes, Michael P / Sugihara, Narumi / Takiguchi, Masufumi

Toxicology. 2021 Jan. 15, v. 447

2021

Abstract: Cadmium (Cd) is recognized as a highly toxic heavy metal for humans in part because it is a multi-organ carcinogen. To clarify the mechanism of Cd carcinogenicity, we have established an experimental system using rat liver TRL1215 cells exposed to 2.5 μM ...

Abstract	Cadmium (Cd) is recognized as a highly toxic heavy metal for humans in part because it is a multi-organ carcinogen. To clarify the mechanism of Cd carcinogenicity, we have established an experimental system using rat liver TRL1215 cells exposed to 2.5 μM Cd for 10 weeks and then cultured in Cd-free medium for an additional 4 weeks (total 14 weeks). Recently, we demonstrated, by using this experimental system, that 1) Cd stimulates cell invasion by suppression of apolipoprotein E (ApoE) expression, and 2) Cd induces DNA hypermethylation of the regulatory region of the ApoE gene. However, the underlying mechanism(s) as well as other potential genetic participants in the Cd-stimulated invasion are undefined. In the present work, we found that concurrent with enhanced invasion, Cd induced oxidative stress, coupled with the production of oxidative stress-sensitive metallothionein 2A (MT2A), which lead to down-modulation of ten-eleven translocation methylcytosine dioxygenase 1 (TET1: DNA demethylation) in addition to ApoE, without impacting DNA methyltransferases (DNMTs: DNA methylation) levels. Furthermore, the expression of tissue inhibitor of metalloproteinase 2 and 3 (TIMP2 and TIMP3) that are positively regulated by TET1, were decreased by Cd. The genes (ApoE/TET1/TIMP2/TIMP3) suppressed by Cd were further suppressed by hydroquinone (HQ; a reactive oxygen species [ROS] producer), whereas N-acetyl-l-cysteine (NAC; a ROS scavenger) prevented the suppression of their expression by HQ. In addition, NAC reversed their expression suppressed by Cd. Cd-stimulated cell invasion was clearly dampened by NAC in a concentration-dependent manner. Overall these findings suggest that 1) altered TET1 expression and activity together with ApoE are likely involved in the enhanced invasiveness due to Cd exposure, and 2) Cd down-regulation of TET1 likely evokes a reduction in ApoE expression (possible by DNA hypermethylation), and 3) anti-oxidants are effective in abrogation of the enhanced invasiveness that occurs concurrently with Cd-induced malignant transformation.
Keywords	DNA ; DNA demethylation ; DNA hypermethylation ; acetylcysteine ; apolipoprotein E ; cadmium ; carcinogenicity ; carcinogens ; enzyme inhibitors ; gene expression regulation ; genes ; heavy metals ; hepatocytes ; hydroquinone ; liver ; metalloproteinases ; metallothionein ; methyltransferases ; oxidative stress ; quinones ; rats ; reactive oxygen species
Language	English
Dates of publication	2021-0115
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2020.152631
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cadmium-stimulated invasion of rat liver cells during malignant transformation: Evidence of the involvement of oxidative stress/TET1-sensitive machinery.

Hirao-Suzuki, Masayo / Takeda, Shuso / Sakai, Genki / Waalkes, Michael P / Sugihara, Narumi / Takiguchi, Masufumi

Toxicology

2020 Volume 447, Page(s) 152631

Abstract	Cadmium (Cd) is recognized as a highly toxic heavy metal for humans in part because it is a multi-organ carcinogen. To clarify the mechanism of Cd carcinogenicity, we have established an experimental system using rat liver TRL1215 cells exposed to 2.5 μM Cd for 10 weeks and then cultured in Cd-free medium for an additional 4 weeks (total 14 weeks). Recently, we demonstrated, by using this experimental system, that 1) Cd stimulates cell invasion by suppression of apolipoprotein E (ApoE) expression, and 2) Cd induces DNA hypermethylation of the regulatory region of the ApoE gene. However, the underlying mechanism(s) as well as other potential genetic participants in the Cd-stimulated invasion are undefined. In the present work, we found that concurrent with enhanced invasion, Cd induced oxidative stress, coupled with the production of oxidative stress-sensitive metallothionein 2A (MT2A), which lead to down-modulation of ten-eleven translocation methylcytosine dioxygenase 1 (TET1: DNA demethylation) in addition to ApoE, without impacting DNA methyltransferases (DNMTs: DNA methylation) levels. Furthermore, the expression of tissue inhibitor of metalloproteinase 2 and 3 (TIMP2 and TIMP3) that are positively regulated by TET1, were decreased by Cd. The genes (ApoE/TET1/TIMP2/TIMP3) suppressed by Cd were further suppressed by hydroquinone (HQ; a reactive oxygen species [ROS] producer), whereas N-acetyl-l-cysteine (NAC; a ROS scavenger) prevented the suppression of their expression by HQ. In addition, NAC reversed their expression suppressed by Cd. Cd-stimulated cell invasion was clearly dampened by NAC in a concentration-dependent manner. Overall these findings suggest that 1) altered TET1 expression and activity together with ApoE are likely involved in the enhanced invasiveness due to Cd exposure, and 2) Cd down-regulation of TET1 likely evokes a reduction in ApoE expression (possible by DNA hypermethylation), and 3) anti-oxidants are effective in abrogation of the enhanced invasiveness that occurs concurrently with Cd-induced malignant transformation.
MeSH term(s)	Animals ; Cadmium/toxicity ; Cell Proliferation/drug effects ; Cell Proliferation/physiology ; Cells, Cultured ; DNA Methylation/drug effects ; DNA Methylation/physiology ; Dioxygenases/antagonists & inhibitors ; Dioxygenases/biosynthesis ; Dose-Response Relationship, Drug ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Neoplasm Invasiveness/pathology ; Oxidative Stress/drug effects ; Oxidative Stress/physiology ; Rats ; Rats, Inbred F344
Chemical Substances	Cadmium (00BH33GNGH) ; TET1 protein, rat (EC 1.-) ; Dioxygenases (EC 1.13.11.-)
Language	English
Publishing date	2020-11-11
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2020.152631
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Article ; Online: Metallothionein blocks oxidative DNA damage induced by acute inorganic arsenic exposure.

Qu, Wei / Waalkes, Michael P

Toxicology and applied pharmacology

2014 Volume 282, Issue 3, Page(s) 267–274

Abstract: We studied how protein metallothionein (MT) impacts arsenic-induced oxidative DNA damage (ODD) using cells that poorly express MT (MT-I/II double knockout embryonic cells; called MT-null cells) and wild-type (WT) MT competent cells. Arsenic (as NaAsO2) ... ...

Abstract	We studied how protein metallothionein (MT) impacts arsenic-induced oxidative DNA damage (ODD) using cells that poorly express MT (MT-I/II double knockout embryonic cells; called MT-null cells) and wild-type (WT) MT competent cells. Arsenic (as NaAsO2) was less cytolethal over 24h in WT cells (LC50=11.0±1.3μM; mean±SEM) than in MT-null cells (LC50=5.6±1.2μM). ODD was measured by the immuno-spin trapping method. Arsenic (1 or 5μM; 24h) induced much less ODD in WT cells (121% and 141% of control, respectively) than in MT-null cells (202% and 260%). In WT cells arsenic caused concentration-dependent increases in MT expression (transcript and protein), and in the metal-responsive transcription factor-1 (MTF-1), which is required to induce the MT gene. In contrast, basal MT levels were not detectable in MT-null cells and unaltered by arsenic exposure. Transfection of MT-I gene into the MT-null cells markedly reduced arsenic-induced ODD levels. The transport genes, Abcc1 and Abcc2 were increased by arsenic in WT cells but either showed no or very limited increases in MT-null cells. Arsenic caused increases in oxidant stress defense genes HO-1 and GSTα2 in both WT and MT-null cells, but to much higher levels in WT cells. WT cells appear more adept at activating metal transport systems and oxidant response genes, although the role of MT in these responses is unclear. Overall, MT protects against arsenic-induced ODD in MT competent cells by potential sequestration of scavenging oxidant radicals and/or arsenic.
MeSH term(s)	Animals ; Arsenic/toxicity ; Carcinogens/toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage/genetics ; DNA-Binding Proteins/genetics ; Environmental Pollutants/toxicity ; Gene Expression Regulation/drug effects ; Glutathione Transferase/genetics ; Heme Oxygenase-1/genetics ; Isoenzymes/genetics ; Membrane Proteins/genetics ; Metallothionein/genetics ; Metallothionein/metabolism ; Mice ; Multidrug Resistance-Associated Protein 2 ; Multidrug Resistance-Associated Proteins/genetics ; Oxidative Stress ; Transcription Factors/genetics ; Transcription Factor MTF-1
Chemical Substances	Carcinogens ; DNA-Binding Proteins ; Environmental Pollutants ; Isoenzymes ; Membrane Proteins ; Multidrug Resistance-Associated Protein 2 ; Multidrug Resistance-Associated Proteins ; Transcription Factors ; Metallothionein (9038-94-2) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Hmox1 protein, mouse (EC 1.14.14.18) ; Glutathione Transferase (EC 2.5.1.18) ; glutathione S-transferase alpha (EC 2.5.1.18) ; Arsenic (N712M78A8G) ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2014-12-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2014.11.014
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Article ; Online: Silencing KRAS Overexpression in Cadmium-Transformed Prostate Epithelial Cells Mitigates Malignant Phenotype.

Ngalame, Ntube N O / Waalkes, Michael P / Tokar, Erik J

Chemical research in toxicology

2016 Volume 29, Issue 9, Page(s) 1458–1467

Abstract: Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by ... ...

Abstract	Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by arsenic, and KRAS activation is key to causation and maintenance of this phenotype. Although Cd and arsenic can both transform prostate epithelial cells, it is uncertain whether their mechanisms are similar. Thus, here we determined whether KRAS activation is critical in causing and maintaining Cd-induced malignant transformation in CTPE cells. Expression of KRAS, miRNAs, and other genes of interest was analyzed by Western blot and RT-PCR. Following stable KRAS knockdown (KD) by RNA interference using shRNAmir, the malignant phenotype was assessed by various physical and genetic parameters. CTPE cells greatly overexpressed KRAS by 20-fold, indicating a likely role in Cd transformation. Thus, we attempted to reverse the malignant phenotype via KRAS KD. Two weeks after shRNAmir transduction, KRAS protein was undetectable in CTPE KD cells, confirming stable KD. KRAS KD reduced stimulated RAS/ERK and PI3K/AKT signaling pathways and markedly mitigated multiple physical and molecular malignant cell characteristics including: hypersecretion of MMP-2, colony formation, cell survival, and expression of cancer-relevant genes (reduced proliferation and cell cycle-related genes; activated tumor suppressor PTEN). However, KRAS KD did not reverse miRNA expression originally down-regulated by Cd transformation. These data strongly suggest KRAS is a key gene in development and maintenance of the Cd-induced malignant phenotype, at least in the prostate. It is not, however, the only genetic factor sustaining this phenotype.
MeSH term(s)	Cadmium/chemistry ; Cadmium/toxicity ; Cell Line ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Epithelial Cells/pathology ; Epithelial Cells/physiology ; Gene Expression/genetics ; Gene Knockdown Techniques ; Gene Silencing ; Humans ; Male ; Prostate/physiopathology ; Prostatic Neoplasms/physiopathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction/genetics
Chemical Substances	KRAS protein, human ; Cadmium (00BH33GNGH) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2016-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.6b00137
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Article: Cadmium carcinogenesis.

Waalkes, Michael P

Mutation research

2003 Volume 533, Issue 1-2, Page(s) 107–120

Abstract: Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies ... ...

Abstract	Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.
MeSH term(s)	Animals ; Cadmium/metabolism ; Cadmium/pharmacology ; Cadmium/toxicity ; Carcinogens/toxicity ; Environmental Pollutants/toxicity ; Humans ; Models, Biological ; Neoplasms/chemically induced ; Occupational Exposure ; Rats
Chemical Substances	Carcinogens ; Environmental Pollutants ; Cadmium (00BH33GNGH)
Language	English
Publishing date	2003-10-17
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	206607-5
ISSN	1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
ISSN (online)	1873-135X
ISSN	0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
DOI	10.1016/j.mrfmmm.2003.07.011
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Article ; Online: Arsenic-induced cancer cell phenotype in human breast epithelia is estrogen receptor-independent but involves aromatase activation.

Xu, Yuanyuan / Tokar, Erik J / Waalkes, Michael P

Archives of toxicology

2013 Volume 88, Issue 2, Page(s) 263–274

Abstract: Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast ... ...

Abstract	Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast epithelial cell line, MCF-10A. Cells were chronically exposed to a low-level arsenite (500 nM) for up to 24 weeks. Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells (SCs) were examined. After 24 weeks, chronic arsenic-exposed breast epithelial (CABE) cells showed increases in secreted MMP activity, colony formation, invasion, and proliferation rate, indicating an acquired cancer cell phenotype. These CABE cells presented with basal-like breast cancer characteristics, including ER-α, HER-2, and progesterone receptor negativity, and overexpression of K5 and p63. Putative CD44(+)/CD24(-/low) breast SCs were increased to 80 % over control in CABE cells. CABE cells also formed multilayer cell mounds, indicative of loss of contact inhibition. These mounds showed high levels of K5 and p63, indicating the potential presence of cancer stem cells (CSCs). Epithelial-to-mesenchymal transition occurred during arsenic exposure. Overexpression of aromatase, a key rate-limiting enzyme in estrogen synthesis, occurred with arsenic starting early on in exposure. Levels of 17β-estradiol increased in CABE cells and their conditioned medium. The aromatase inhibitor letrozole abolished arsenic-induced increases in 17β-estradiol production and reversed cancer cell phenotype. Thus, chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs. Arsenic appears to transform breast epithelia through overexpression of aromatase, thereby activating oncogenic processes independent of ER.
MeSH term(s)	Aromatase/metabolism ; Arsenic/toxicity ; Breast Neoplasms/chemically induced ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line/drug effects ; Cell Transformation, Neoplastic/chemically induced ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Epithelial-Mesenchymal Transition/drug effects ; Estradiol/metabolism ; Estrogen Receptor alpha/metabolism ; Female ; Humans ; Mammary Glands, Human/cytology ; Mammary Glands, Human/drug effects ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Neoplastic Stem Cells/drug effects ; Receptors, Estrogen/metabolism ; Toxicity Tests, Chronic
Chemical Substances	ESR1 protein, human ; Estrogen Receptor alpha ; Receptors, Estrogen ; Estradiol (4TI98Z838E) ; Aromatase (EC 1.14.14.1) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2013-09-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-013-1131-4
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Article ; Online: Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium.

Pelch, Katherine E / Tokar, Erik J / Merrick, B Alex / Waalkes, Michael P

Toxicology and applied pharmacology

2015 Volume 286, Issue 3, Page(s) 159–167

Abstract: Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line ( ... ...

Abstract	Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10μM Cd for 11weeks (CTPE) or 5μM iAs for 29weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>25-fold) and S100P (>40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>15-fold) and NTM (>1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status.
MeSH term(s)	Arsenic/toxicity ; Cadmium/toxicity ; Cell Line ; Cell Line, Transformed ; DNA Methylation/drug effects ; DNA Methylation/physiology ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Epithelial Cells/physiology ; Humans ; Male ; Prostate/drug effects ; Prostate/pathology ; Prostate/physiology ; Transcription, Genetic/drug effects ; Transcription, Genetic/physiology
Chemical Substances	Cadmium (00BH33GNGH) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2015-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2015.04.011
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Article ; Online: Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic.

Tokar, Erik J / Kojima, Chikara / Waalkes, Michael P

Archives of toxicology

2013 Volume 88, Issue 2, Page(s) 249–261

Abstract: Inorganic arsenic (iAs) and its toxic methylated metabolite, methylarsonous acid (MMA(III)), both have carcinogenic potential. Prior study shows iAs-induced malignant transformation in both arsenic methylation-proficient (liver) and methylation-deficient ...

Abstract	Inorganic arsenic (iAs) and its toxic methylated metabolite, methylarsonous acid (MMA(III)), both have carcinogenic potential. Prior study shows iAs-induced malignant transformation in both arsenic methylation-proficient (liver) and methylation-deficient (prostate) cells, but only methylation-proficient cells show oxidative DNA damage (ODD) during this transformation. To further define whether arsenic methylation is necessary for transformation or ODD induction, here we chronically exposed these same liver or prostate cell lines to MMA(III) (0.25-1.0 μM) and tested for acquired malignant phenotype. Various metrics of oncogenic transformation were periodically assessed along with ODD during chronic MMA(III) exposure. Methylation-deficient and methylation-proficient cells both acquired a cancer phenotype with MMA(III) exposure at about 20 weeks, based on increased matrix metalloproteinase secretion, colony formation, and invasion. In contrast, prior work showed iAs-induced transformation took longer in biomethylation-deficient cells (~30 weeks) than in biomethylation-proficient cells (~18 weeks). In the present study, MMA(III) caused similar peak ODD levels at similar concentrations and at similar exposure times (18-22 weeks) in both cell types. At the approximate peak of ODD production, both cell types showed similar alterations in arsenic and oxidative stress adaptation factors (i.e., ABCC1, ABCC2, GST-π, SOD-1). Thus, MMA(III) causes oncogenic transformation associated with ODD in methylation-deficient cells, indicating that further methylation is not required to induce ODD. Together, these results show that MMA(III) and iAs cause an acquired malignant phenotype in methylation-deficient cells, yet iAs does not induce ODD. This indicates iAs likely has both genotoxic and non-genotoxic mechanisms dictated by the target cell's ability to methylate arsenic.
MeSH term(s)	Adaptation, Physiological/drug effects ; Adaptation, Physiological/physiology ; Animals ; Arsenic Poisoning/pathology ; Arsenicals/pharmacology ; Cell Line/drug effects ; Cell Transformation, Neoplastic/chemically induced ; DNA Damage/drug effects ; Humans ; Liver/cytology ; Liver/drug effects ; Male ; Methylation ; Multidrug Resistance-Associated Protein 2 ; Oxidation-Reduction ; PTEN Phosphohydrolase/genetics ; Prostate/cytology ; Prostate/metabolism ; Rats ; Toxicity Tests, Chronic
Chemical Substances	ABCC2 protein, human ; Arsenicals ; Multidrug Resistance-Associated Protein 2 ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; Pten protein, rat (EC 3.1.3.67) ; monomethylarsonic acid (J37VJ5709S)
Language	English
Publishing date	2013-10-05
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-013-1141-2
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Article: Early-life arsenic exposure: methylation capacity and beyond.

Waalkes, Michael P / Liu, Jie

Environmental health perspectives

2008 Volume 116, Issue 3, Page(s) A104

MeSH term(s)	Arsenic Poisoning/complications ; Arsenic Poisoning/metabolism ; Environmental Exposure/adverse effects ; Female ; Humans ; Malnutrition/complications ; Maternal Exposure/adverse effects ; Methylation ; Pregnancy ; Water Pollutants, Chemical/toxicity
Chemical Substances	Water Pollutants, Chemical
Language	English
Publishing date	2008-03-12
Publishing country	United States
Document type	Comment ; Editorial
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/ehp.11276
Database	MEDical Literature Analysis and Retrieval System OnLINE

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