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. Author manuscript; available in PMC: 2020 Sep 16.
Published in final edited form as: Discov Med. 2012 Oct;14(77):283–288.

Chemical-induced DNA Damage and Human Cancer Risk

Miriam C Poirier 1
PMCID: PMC7493822  NIHMSID: NIHMS1621939  PMID: 23114584

Abstract

For more than 200 years human cancer induction has been known to be associated with a large variety of chemical exposures. Most exposures to chemical carcinogens occur as a result of occupation, pollution in the ambient environment, lifestyle choices, or pharmaceutical use. Scientific investigations have revealed that the majority of cancer causing chemicals, or chemical carcinogens, act through “genotoxic” or DNA damaging mechanisms, which involve covalent binding of the chemical to DNA (DNA adduct formation). Cancer-inducing exposures are typically frequent and/or chronic over years, and the accumulation of DNA damage or DNA adduct formation is considered to be a necessary requirement for tumor induction. Studies in animal models have indicated that the ability to reduce DNA damage will also result in reduction of tumor risk, leading to the hypothesis that individuals having the highest levels of DNA adducts may have an increased cancer risk, compared to individuals with the lowest levels of DNA adducts. Here we have reviewed twelve investigations showing 2- to 9-fold increased Relative Risks (RR) or Odds Ratios (OR) for cancer in (the 25% of) individuals having the highest DNA adduct levels, compared to (the 25% of) matched individuals with the lowest DNA adducts. These studies also provided preliminary evidence that multiple types of DNA adducts combined, or DNA adducts combined with other risk factors (such as infection or inflammation), may be associated with more than 10-fold higher cancer risks (RR = 34–60), compared to those found with a single carcinogen. Taken together the data suggest that a reduction in human DNA adduct level is likely to produce a reduction in human cancer risk.

Introduction

Chemical exposures known to be associated with induction of human cancers have historically been revealed largely in occupational settings or other instances where exposure to the carcinogenic agent is frequent and long-term. Over 100 years ago the carcinogenic nature of a particular exposure (chimney soot, shale oil, paraffin, aromatic amine and aniline dyes, radium paint, etc.) was often, sadly, revealed by the appearance of cancers in the human population (Poirier, 2004). More recently, though testing for suspected carcinogens is possible in animal models, cancer-causing agents (asbestos, cigarette smoke, chewing tobacco, vinyl chloride, benzene, etc.) continue to be revealed by the appearance of human tumors.

It has been the long-term quest of many investigators to find a biomarker that can be directly associated with cancer risk, and that might possibly be manipulated during the course of human exposure to reduce cancer risk. Many years of cancer studies in animal (largely rodent) models have taught us that accumulation of DNA damage is considered to be necessary but not sufficient for tumor induction, and that reduction in DNA damage level will also result in reduction in tumor incidence. These findings have led to the hypothesis that high levels of DNA adducts in humans may be associated with increased cancer risk, and that effective cancer protection may be achieved through reduction of DNA damage.

Importance of Experimental Models in Understanding Human Cancer Risk

To predict the importance of DNA damage in human cancer risk, it is first necessary to understand the process of tumor induction, much of which we have learned from studies in animal models. Tumors, by definition, are groups of cells that have lost the normal cellular growth control mechanisms. Tumors induced by chemicals are considered to have begun (been “initiated”) at the time of exposure because the chemicals bind to and directly damage the genetic material, DNA. DNA contains the blueprint for all bodily processes, including control of growth. The early events involving chronic exposure include damage to DNA or binding of the chemical to DNA (DNA adduct formation, Figure 1), resulting in permanent DNA mutations. Over time there are altered metabolism, production of abnormal proteins, and chromosomal instability, some of which involve genes that are critical drivers in carcinogenesis, such as oncogenes and tumor suppressor genes. There is typically a long latent period, the better part of a lifetime, between the start of carcinogen exposure and the appearance of a tumor. A familiar example may be smoking and lung cancer, where smoking may begin in the teenage years, but cancers typically appear after age 50. The long latency occurs because cancer induction is a multi-step process where iterative cellular events (some of them mutagenic and some not mutagenic) conspire to produce an expansion of altered clones of cells having hereditary loss of growth control.

Figure 1.

Figure 1.

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Molecular structures of stable carcinogen-DNA adducts formed by covalent binding with deoxyguanosine (shown in boxes) in DNA. (A) N-(deoxyguanosin-8-yl)-2-(amino)fluorene (dG-C8-AF, R=H, or dG-C8-AAF, R=acetyl), formed when N-hydroxyl-aminofluorene reacts with the C8 position of deoxyguanine. (B) (7R)-N2-(10-(7β,8α,9α-trihydroxy-7,8,9,10-tetrahydro-benzo(a)pyrene)-yl)-deoxyguanosine (BPdG) is the major carcinogenic adduct formed between benzo(a)pyrene and the exocyclic amino group of deoxyguanosine; (C) 8,9-dihydro-8-(2,6-diamino-6-formamido-4-oxo-3,4-dihydropyrimid-5-yl-amino) (AFB1-N7-guanine) is the major ring-opened adduct of aflatoxin B1 formed with the C8 position of the deoxyguanine imidazole ring.

In animal models (usually rodents) exposed chronically to genotoxic chemical carcinogens, the tumor incidence typically increases with the concentration of carcinogen given. In the target tissue for tumorigenesis, the dose response curves for chemical exposure also tend to correlate well with DNA damage, and mutation formation (Poirier and Beland, 1992). Furthermore, metabolic modulations that reduce the formation of DNA adducts in the target tissue (Roebuck et al., 1991) have been shown to significantly reduce tumor incidence. In animal models DNA adducts may form in organs that do not develop tumors; however, as tumors do not appear in the absence of DNA damage, DNA damage or DNA adduct formation is generally considered to be “necessary but not sufficient” for tumor induction. There are no direct parallels between cancers in animals occurring as a result of exposure to a single chemical and the human condition where DNA is assaulted by a plethora of carcinogenic chemicals throughout a lifetime. Because DNA adduct formation is essential for tumor induction in animal models, it appears reasonable to assume that DNA adduct formation in humans might connect chemical exposures with cancer risk. Therefore, a long-term goal would be to reduce DNA damage in humans, even though it may not be possible to reduce human carcinogen exposure.

DNA Adduct Formation in Humans

Methodologies able to measure DNA adduct formation in human tissues have become available only in about the last 30 years (Gyorffy et al., 2008; Poirier et al., 2000). The most common include 32P-postlabelling, as well as enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) using antisera elicited against DNA adducts or DNA samples modified with carcinogens. More recently, various mass-spectrometry based methods (Singh and Farmer, 2006) have improved in sensitivity and are able to measure DNA adducts in human tissues using readily-obtainable quantities of DNA. In addition, to measure a chemically-specific DNA adduct in a human sample it is often possible to employ preparative methods for adduct separation before adduct identification. Most DNA adduct methodologies are able to measure as little as 1 DNA adduct/109 nucleotides of DNA using 5–100 μg DNA (Poirier et al., 2000). To date studies have documented the presence of approximately 50 different types of DNA adducts in human tissues (Phillips, 2005). Many of these DNA adducts are formed from chemicals that are known to be carcinogenic in animal models (Gallo et al., 2008; Gyorffy et al., 2008), but are not yet proven to be human carcinogens, and others are clearly associated with a particular human cancer (Jarabek et al., 2009; Phillips, 2005).

DNA Adduct Formation and Human Cancer Risk

The presence of an adduct in human DNA clearly indicates that exposure to the parent compound has occurred; however, in order to evaluate whether or not the adduct alters human cancer risk, in particular whether individuals with the highest DNA adduct levels are at the highest risk, it is necessary to establish associations within epidemiologic study designs. Two of the most common types of epidemiologic study designs used to validate biomarkers are the case-control study and the prospective nested case-control study. In the case-control study, a biological sample is obtained on one occasion from cancer cases, and matched individuals who do not have cancer, and all are assayed for DNA adduct formation. The prospective nested case-control study design is more informative, but also more difficult. The first requirement is collection and storage of samples (blood, urine, or any other human organ) from thousands of individuals who live in an area where a particular type of cancer is endemic. Then, after waiting some years for a sufficient number of cancer cases, matched controls are chosen, and samples from cases and controls are retrieved and assayed for DNA adduct formation. With both study designs the calculations evaluate cancer rates in the individuals positive for the biomarker, compared to cancer rates in individuals negative for the biomarker, and the results are presented as Relative Risk (RR) or Odds Ratio (OR) for cancer in the biomarker positive group. Comparisons are typically made between the 25% (quartile) of individuals with the highest DNA adduct levels and the 25% with the lowest DNA adduct levels.

Table 1 shows case-control studies and prospective nested case-control studies (Agudo et al., 2012; Chen, 2002; Gunter et al., 2007; Peluso et al., 1998; Peluso et al., 2005; Qian et al., 1994; Tang et al., 2001; 1995; Veglia et al., 2008; Wang et al., 1998; Zhu et al., 2003), which have addressed the question: “Are high levels of DNA adduct formation associated with increased cancer risk in the human population?” DNA adducts have been evaluated in peripheral blood mononuclear cells, and in target tissues for the tumor induction. In the three studies where target tissue DNA adducts were evaluated (Chen, 2002; Wang et al., 1998; Zhu et al., 2003), the RR and OR values were similar to those in studies where blood cell DNA was used (Gunter et al., 2007; Tang et al., 1995), suggesting that use of cancer target tissue or peripheral blood, did not make a difference. In Table 1, RRs or ORs were increased 1.6- to 9.1-fold in individuals with the highest DNA adduct levels, compared to those with the lowest DNA adduct levels (RR or OR =1).

Table 1.

Associations (P≤0.05) Between Cancer Risk, and DNA Adduct Value in (the 25% of) Individuals with the Highest Adduct Levels Compared with Those Having the Lowest Adduct Levels.

Carcinogen:
DNA Adduct Source		 Organ:
DNA Adduct Measurement		 Organ:
Cancer Site		 Method of DNA Adduct Measurement RRa or OR for Cancer Risk Reference
4-ABP liver liver IHCb 6.5 Wang et al., 1998
PAHs liver liver IHC 3.9 Chen, 2002
PHIP breast breast IHC 4.0 Zhu et al., 2003
PAHs blood colon ELISAc 2.8 Gunter et al. 2007
PAHs blood lung ELISA 7.7 Tang et al., 1995
AFB1 urine liver HPLCd 9.1 Qian et al., 1994
“Bulky”e blood stomach 32-P-postlabelling 2.2 Agudo et al., 2012
“Bulky” blood colon 32P-postlabelling 2.3 Agudo et al.. 2012
“Bulky” blood bladder 32P-postlabelling 4.1 Peluso et al., 1998
“Bulky” blood
(current smokers)		 lung 32P-postlabclling 3.0 Tang et al., 2001
“Bulky” blood
(current smokers)		 lung 32P-postlabclling 2.0 Peluso et al., 2005
“Bulky” blood
(current smokers)		 lung 32P-postlabelling 1.6 Veglia et al., 2008
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a

RR = Relative Risk or OR = Odds Ratio in the 25% of individuals having the highest DNA adduct levels compared with those having the lowest DNA adduct levels. All values shown arc statistically significant to p≤0.05.

b

IHC = Immunohistochemistry.

c

ELISA = Enzyme linked immunosorbent assay.

d

HPLC = High performance liquid chromatography.

e

“Bulky” DNA adducts isolated by 32P-postlabeling arc typically stable, high-molecular weight DNA adducts that are formed from PAHs, aromatic amines, nitroaromatics, hormones, aflatoxins, and/or other hydrophobic DNA-binding agents (see examples in Figure 1).

In the first six studies shown in Table 1 the DNA adducts measured were formed by a specific carcinogen (aflatoxin B1 [AFB1], 2-amino-1-methyl-6-phenylimidazo[4,5-β]-pyridine [PHIP], 4-aminobiphenyl [4-ABP]), or a class of carcinogenic compounds (polycyclic aromatic hydrocarbons [PAHs]). In the last six studies “bulky” DNA adducts were measured by 32P-postlabelling, a technique which cannot chemically characterize any specific DNA adduct, but is likely to detect DNA adducts of PAHs, aromatic amines, aflatoxins, nitroaromatics, hormones, and other hydrophobic DNA-binding agents. Interestingly, 32P-postlabelling has been criticized for a lack of specificity, but the generalized DNA damage that is detected by this method gives RR and OR values very much in the same range as the methods with higher chemical specificity.

In addition, several studies have reported a negative or equivocal relationship between DNA adducts and cancer risk. For example, increases in breast cancer risk were not clearly associated with high levels of PAH-DNA adducts in breast tissue (Rundle et al., 2000a; 2000b) or in peripheral blood (Sagiv et al., 2009). In addition there was no association between formation of “bulky” DNA adducts, measured by 32P-postlabelling, and breast cancer risk in a large European study (Saieva et al., 2011). Finally, other studies failed to find significant associations between consumption of heavily cooked or grilled meat, known to contain PAHs and heterocyclic amines (such as PHIP), and breast cancer (Steck et al., 2007), prostate cancer (Tang et al., 2007), or colorectal polyps (Shin et al., 2008).

The Impact of Multiple Types of DNA Adducts Combined

Whereas the RR and OR values shown in Table 1 would appear to be low, it is important to consider that there is no current method for evaluating the total DNA damage “burden” carried by an individual. Since we are all exposed to a wide variety of chemicals, each of us likely carries DNA adducts from multiple different DNA damaging agents, and our risk may increase with particular DNA adduct combinations. One study (Chen, 2002) has addressed this question in a population at high risk for liver cancer. There was a 4.4-fold increased OR for liver cancer in individuals with the highest levels of hepatic PAH-DNA adducts. However, in the same study, individuals with the highest combined levels of PAH-DNA adducts, 4-ABP-DNA adducts, and AFB1-DNA adducts, had a 36.7-fold increased OR for liver cancer, indicating that formation of a single type of DNA adduct carried a lower cancer risk, compared to combined adducts from three different types of carcinogens.

Factors Which Act in Combination with DNA Adduct Formation

There is strong evidence that factors other than DNA adduct formation also influence cancer risk. For example, chronic inflammation and rapid cell proliferation are considered to increase cancer risk, while efficient DNA repair (a cellular process that removes DNA damage) and apoptosis may protect. The importance of chronic inflammation, along with DNA adduct formation, in increasing liver cancer risk has been demonstrated in a population in southern China (Qian et al., 1994). In this region, dietary exposure to aflatoxins and carcinogenic mold toxins, and to hepatitis B, which causes chronic liver inflammation, are endemic. In order to understand the influence of each of these two components on liver cancer risk, blood was assayed for hepatitis B serum antibodies and urine was assayed for the AFB1-N7-guanine adduct (Figure 1B), the excised AFB1 adduct. In individuals with measurable urinary AFB1-N7-guanine adduct, and no hepatitis B, the RR for liver cancer was 9.1, compared to individuals with no aflatoxin exposure and no hepatitis B infection (RR = 1). In hepatitis B carriers with no aflatoxin exposure the RR for liver cancer was 7.3, but in individuals with both exposures the RR for liver cancer was 59.4, indicating an essentially multiplicative increase in cancer risk in individuals exposed to the carcinogen who also have chronic hepatitis B, which causes chronic inflammation of the liver. In this situation it has been recognized that both reducing the aflatoxin exposure and reducing the incidence of hepatitis B should result in a lowering of the risk for hepatocellular carcinoma. Whereas attempts to remove the aflatoxin exposures have been challenging, the active program of hepatitis B immunization implemented in this region has been successful in reducing the number of individuals with active hepatitis B infection, and has resulted in a concomitant reduction in hepatocellular carcinoma incidence.

Future Directions and Challenges

Here we have summarized studies showing that DNA adduct formation, whether measured in blood cell or organ DNA, is associated with 1.6- to 9.1-fold increases in risk for various types of cancers. These numbers apply to either a specific DNA adduct, a family of DNA adducts, or DNA adducts formed by a large group of hydrophobic compounds (”bulky” adducts). There is evidence of further enhanced cancer risk when adducts of different chemical classes are evaluated in combination, and when additional factors, such as inflammation, are evaluated in combination with DNA adduct formation. Taken together these studies indicate that increased cancer risk conferred by high levels of DNA adducts of a single chemical class is modest compared with the risk increases generated by combinations of DNA adducts of multiple different types of carcinogens. Continuing research in this area should allow investigators to tease out cancer-associated multifactorial etiologic elements, one or two at a time. Even though such studies are slow and exceedingly laborious, requiring interdisciplinary efforts and considerable resources, a great deal of progress has been achieved.

Conclusion

The current studies indicate that specific types of DNA adducts, measured in human tissues, contribute a relatively modest (1.6- to 9.1-fold) increase in human cancer risk. However, it appears that the total DNA adduct burden results in a higher cancer risk, which is difficult to evaluate. In addition, the combination of chemical exposures with additional factors, such as certain infections or other causes of inflammation, or impairment of DNA repair, is likely to result in much higher human cancer rates. The collaboration of epidemiologic study design with cutting-edge biomarker research will, over time, yield important insights into the types of exposures that confer increased risk of particular types of cancer. This information should lead to strategies to reduce both DNA adduct formation and concomitant events that increase cancer risk.

Footnotes

Disclosure

The author reports no conflicts of interest.

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