What causes human cancer? Approaches from the chemistry of DNA damage
© The Author(s) 2016
Received: 8 April 2016
Accepted: 11 May 2016
Published: 1 July 2016
To prevent human cancers, environmental mutagens must be identified. A common mechanism of carcinogenesis is DNA damage, and thus it is quite possible that environmental mutagens can be trapped as adducts by DNA components. It is also important to identify new types of DNA damaging reactions and clarify their mechanisms. In this paper, I will provide typical examples of our efforts to identify DNA damage by environmental agents, from chemistry-based studies. 1) Oxidative DNA damage: 8-Hydroxydeoxyguanosine (8-OHdG, 8-oxodG) was discovered during a structural study of DNA modifications caused in vitro by heating glucose, which was used as a model of cooked foods. We found that various oxygen radical-forming agents induced the formation of 8-OHdG in DNA, in vitro and in vivo. Analyses of the urinary 8-OHdG levels are useful to assess the extent of oxidative DNA damage in a human population. 2) Lipid peroxide-derived DNA adducts: We searched for mutagens that react with deoxynucleosides, in model systems of lipid peroxidation. The reaction mixtures were analyzed by high performance liquid chromatography (HPLC), and we discovered various lipid peroxide-derived mutagens, including new mutagens. Some of these adducts were detected in human DNA. These mutagens may be involved in lipid peroxide-related cancers. 3) Methylation of cytosine by free radicals: Methylation of the cytosine C-5 position is an important mechanism of carcinogenesis, in addition to gene mutations. However, the actual mechanisms of de novo methylation in relation to environmental agents are not clear. We found that cytosine C-5 methylation occurred by a free radical mechanism. The possible role of this radical-induced DNA methylation in carcinogenesis will be discussed, in relation to the presently accepted concept of cancer epigenetics. In these studies, chemical analyses of the adducts formed in model reactions led to the discoveries of new mutagens and important types of DNA modifications, which seem to be involved in human carcinogenesis.
As a postdoctoral fellow, I was involved in studies on modifications of nucleic acids by carcinogens, such as benzo[a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA), mostly in collaboration with a group at the Institute of Cancer Research, Columbia University [7–12]. These studies involved the isolation of modified nucleosides (BP-Guo, DMBA-Guo) on a microgram scale and their structure determination by mass-, UV-, CD-, and NMR-spectra. These micro-techniques in organic chemistry actually formed the basis for my subsequent chemical studies on DNA adducts. These experiences also gave me hints toward the idea that environmental mutagens can be trapped as nucleoside-mutagen-adducts.
On the occasion of the 10th anniversary of the foundation of the Journal, Genes and Environment, I am summarizing my 35 years of work on chemistry-based studies of DNA damage. This is also a review of my plenary lecture at ICEM Brazil in 2012, and my presentation at the Kitashi Mochizuki Memorial Symposium, Molecular Mechanisms of Mutagenesis, during the 2015 JEMS Meeting at Fukuoka, Japan.
In this paper, I discuss typical examples of our studies to identify DNA (nucleosides) damage induced by model systems, such as heated glucose, ω-3-fat-hemin-, and ω-6-fat hemin-peroxidation systems, especially in relation to diet. It is also important to identify new types of DNA damaging reactions and clarify their mechanisms. Accordingly, we examined the methylation of cytosine C-5 by methyl radicals, generated from environmental and endogenous compounds. This may be related to epigenetic changes during carcinogenesis, in relation to inflammation.
Sensitive detection of mutagens as adducts with a fluorescent guanosine derivative
Oxidative DNA damage: 8-Hydroxydeoxyguanosine
The number of published reports with 8-OHdG in the title is presently 1,420, and most have focused on human urine. The reports include the effects of chemicals (animal, 70; human, 120), radiation (84), diseases (494), lifestyles (694) and antioxidants (229). For example, in relation to dietary habits, when a vitamin-deficient diet (for two months) and a commercially available sweet beverage (for two weeks) were administered to mice, the urinary 8-OHdG levels clearly increased . These results indicated that oxidative stress could be elevated by the prolonged intake of an unbalanced diet. Regarding the risk of ionizing radiation, the relationship between low dose (<100 mSv) radiation and cancer risk is still unclear. We studied the effects of low dose radiation on 8-OHdG formation in mouse DNA and urine . After whole body irradiation by X-rays, the 8-OHdG levels in liver DNA and urine increased from the 500 and 200 mGy doses, respectively. These results indicated that living organisms have a defense system against ionizing radiation, and a threshold seems to exist for oxidative DNA damage. Regarding human occupational and environmental exposure to chemicals, increases of 8-OHdG were detected in relation to exposure to benzene, ethylbenzene, styrene, trichloroethylene, polycyclic aromatic hydrocarbons, di-(2-ethylhexyl)phthalate (plastic recycling), PCBs, dioxin, As, Cr, Cd, Ni, Se, nanoparticles (copier), PM2.5 in diesel exhaust particles, and environmental tobacco smoke. In addition, elevated 8-OHdG levels were detected in workers in the asbestos-, azo-dye-, and rubber-industries, coke oven workers, foundry workers, bus drivers, traffic policemen, hair salon employees (volatile organic compounds), people exposed to cooking oil fumes, ash treatment, and an antineoplastic drug (5-FU), and agricultural workers (organophosphate). For more information, please see the review papers [21, 41, 42].
Lipid peroxide-derived DNA adducts
The mutagen involved in the formation of adducts 8 and 11 seemed to be 2,3-epoxyoctanal. In fact, synthetic 2,3-epoxyoctanal showed potent mutagenicity in the TA 100 and TA104 strains without S-9 mix. As many epoxy compounds are carcinogenic, it is quite possible that this compound may be involved in human carcinogenesis. It can be formed by various pathways; for example, from 9-hydroperoxy-octadecadienoic acid via 2,4-decadienal and 2-octenal, or from 13-hydroperoxy-octadecadienoic acid via an epoxy derivative. We found that 2,3-epoxyoctanal readily formed under acidic conditions. These results suggested that this mutagen could be efficiently formed during storage and cooking, or during digestion in the stomach, under acidic conditions.
A known mutagen, 4-oxo-2-nonenal (4-ONE), was presumed to be involved in the formation of adducts 7 and 9. In addition, 4-oxo-2-octenal (4-OOE) was proposed as the possible mutagen involved in the formation of the dCyd adduct 10.
Methylation of cytosine by free radicals
In addition to genetic changes, epigenetic changes are an important mechanism of aberrant gene expression and carcinogenesis. Environmental factors and dietary and lifestyle factors are closely related to the induction of both genetic and epigenetic changes. A key molecule involved in epigenetic change is 5-methyl-2’-deoxycytidine (m5dCyd). Methylation of CpG islands is associated with gene silencing, while DNA hypermethylation of tumor suppressor genes plays a critical role in carcinogenesis . It is widely accepted that the methyl group is enzymatically introduced at the dCyd C-5 position. DNA methyltransferases are involved in both de novo methylation and maintenance methylation . After DNA methylation, methylated DNA binding domain protein (MBD) binds to the methylated site, a histone deacetylase is recruited, and finally gene inactivation occurs . However, the exact mechanisms of hypermethylation, particularly in relation to environmental factors, are not clear.
As another example, I will summarize our results about dCyd methylation by methionine sulfoxide (MetO) plus • OH . Methionine sulfoxide is an oxidized product of methionine, and a biomarker of oxidative stress. It is generated in proteins by smoking , inflammation  and aging . We confirmed that MetO generated methyl radicals with an oxygen radical forming system, and modified dCyd to m5dCyd, in vitro (Fig. 14). To confirm whether this reaction is biologically relevant, MetO was administered to non-alcoholic steatohepatitis (NASH) mice . It is well known that NASH mice have high oxidative stress in the liver. The incidences of hepatocellular carcinoma were higher in the MetO-administered groups. The multiplicity (number of tumors per mouse) was also increased in the MetO-administered groups. We also analyzed DNA methylation, by methylation-specific PCR. The DNA methylation status of the p16 gene promoter region was higher in the livers of the MetO-treated mice. These results suggested that MetO plus ROS actually triggers DNA methylation via methyl radicals in vivo.
About 90–95 % of cancers are induced by environmental factors, including diet (30–35 %) and smoking (25–30 %) . Although the detailed mechanisms of carcinogenesis, such as gene mutations and epigenetic changes, are being clarified by recent progress in the molecular biology of cancer, the global identification of mutagens, especially in food, is necessary for cancer prevention. Only a limited number of food mutagens, such as aflatoxin B1, N-nitrosamines, polycyclic aromatic hydrocarbons, heterocyclic amines, have been identified in foods . I think they are only the tip of the iceberg, if we consider the thousands of unknown food mutagens. Methods such as 32P-postlabeling and LC/MS/MS can be used to detect many DNA adducts in human DNA with high sensitivity; however, the detected adducts are mostly unknown and none of the above known mutagens are the major sources of the adducts [71, 72]. We are currently only able to assess human cancer risk by using information such as the potency of genotoxicity, the amounts in foods, and the DNA adduct levels of these known mutagens. Without exhaustive research on food mutagens including unknown mutagens, risk assessments of food-derived cancer are either unreliable or impossible. To my great regret, fundamental studies to search for new environmental mutagens (not analyses of known mutagens), in food, air, and water, have seemed to decline recently. Young researchers are not interested in these projects, and have shifted their focus to molecular biology, because the former are high-risk; i.e., these projects require extensive efforts with the potential for meager outcomes. Looking back on my 35 years of research, fewer than 10 new discoveries of mutagens or DNA modifications were reported. They are the oxidative DNA damage 8-OHdG; the new mutagens MRA, HMRA, ethyl glyoxal, 4-oxo-2-hexenal, and 2,3-epoxyoctanal; and the methylation of cytosine C-5 by a free radical mechanism, etc. These studies were neither efficient nor elegant, because the daily experiments were mostly fruitless and interesting results were only obtained on very rare occasions. Fortunately, most of the adducts detected by HPLC (7 out of 11) were new types of modifications, except for the adducts with ONE, glyoxal, and glyoxylic acid. Furthermore, many of the adducts were detected in human DNA by LC/MS/MS. Especially, 8-OHdG was the seed for many important research developments in various fields, as shown in Fig. 9. In a sense, these unique chemistry-based approaches are more efficient for new discoveries, as compared to molecular biology-based approaches. In the latter approaches, many researchers must compete to obtain new findings with similar projects in the modern trend.
Further chemistry-based studies to search for new environmental mutagens and DNA modifications should be encouraged, especially for young researchers.
To prevent human cancers, environmental mutagens must be identified. Chemical analyses of the adducts formed in model reactions led to the discoveries of new mutagens and important types of DNA modifications, which seem to be involved in human carcinogenesis.
I thank Dr. S. Nishimura, the previous head of the Biology Division, National Cancer Center Research Institute, Tokyo, Japan, for encouragement and support of my studies in the former period (1982-1993). I also thank all of my collaborators, especially Drs. T. Hirano, H. Kamiya, K. Kawai, Y.S. Li, and all of the graduated students, of the Department of Environmental Oncology, University of Environmental Health, Kitakyushu, Japan, for their support in the latter period (1994-present).
The author declares that he has no competing interests.
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