Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: A global assessment.

The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

Role of oxygen radicals in DNA damage and cancer incidence

Mendelian randomization is the term applied to the random assortment of alleles at the time of gamete formation. This results in population distributions of genetic variants that are generally independent of behavioural and environmental factors that typically confound epidemiological associations between putative risk factors and disease. In some circumstances this can provide a study design akin to randomized comparisons. The principles of Mendelian randomization can serve to limit several potential problems in observational epidemiology (Table 1). The avoidance of confounding is clearly a key advantage, and in view of this, Martin Tobin and colleagues6 have suggested that the approach should be termed ‘Mendelian deconfounding’. However, there are several additional and perhaps equally important ways in which Mendelian randomization can strengthen inferences drawn from observational studies. In the example Katan originally presented—that of the association between low serum cholesterol levels and cancer—the most plausible bias would be introduced by reverse causation. The early stages of cancer could lead to a decrease in circulating cholesterol levels, generating an inverse association between cholesterol levels and cancer morbidity or mortality.1 Early stages of cancer will not, however, change inherited genetic variants that are associated with cholesterol levels. Thus if low cholesterol level were a cause of increased cancer risk then individuals with genetic variants associated with lower cholesterol levels should have a higher cancer risk. If, on the other hand, reverse causation is responsible for the association between cholesterol level and cancer, there should be no association between genetic variants related to cholesterol level and cancer risk. Biological forms of reverse causation may influence many epidemiological associations—for example, those between markers of inflammation and coronary heart disease, where existing atherosclerosis may influence the level of factors such as fibrinogen and C-reactive protein.13 Reverse causation can also occur through exposure assignment—for example, people with early stages of coronary heart disease may take vitamin supplements because they believe these will reduce their risk of cardiovascular events. This will tend to generate a positive association between vitamin intake and disease. A form of reverse causation can also occur through reporting bias, with the presence of disease influencing reporting disposition. In casecontrol studies people with the disease under investigation may report on their prior exposure history in a different way than do controls—perhaps because the former will think harder about potential reasons that account for why they have developed the disease. In this situation the association between genetic variants related to the exposure and disease outcome will not usually be biased. In observational studies associations between an exposure and disease will generally be biased if there is selection according to an exposure–disease combination in case-control studies, or according to an exposure–disease risk combination in prospective studies. If, for example, people with an exposure and at low risk of disease for other reasons were differentially excluded from a study the exposure would appear to be positively related to disease outcome, even if there were no such association in the underlying population. This is a form of ‘Berkson’s bias’, well known to epidemiologists.14 A possible example of such associative selection bias relates to the finding in the large American Cancer Society volunteer cohort that high alcohol consumption was associated with a reduced risk of stroke.15 This is somewhat counter-intuitive as the outcome category included haemorrhagic stroke (for which there is no obvious mechanism through which alcohol would reduce risk) and because alcohol is known to increase blood pressure16,17— a major causal factor for stroke.18 Population-based studies have found that alcohol tends to increase stroke risk.19–21 Heavy drinkers who volunteer for a study known to be about the health effects of their lifestyle are likely to be very unrepresentative of all heavy drinkers in the population, in ways that render them to be at low risk of stroke. Moderate and non-drinkers

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Mendelian randomization: prospects, potentials, and limitations

https://www.meatinstitute.org/index.php?ht=a/GetDocumentAction/i/50895

Food sources of nitrates and nitrites: the physiologic context for potential health benefits

Human alteration of the nitrogen cycle has resulted in steadily accumulating nitrate in our water resources. The U.S. maximum contaminant level and World Health Organization guidelines for nitrate in drinking water were promulgated to protect infants from developing methemoglobinemia, an acute condition. Some scientists have recently suggested that the regulatory limit for nitrate is overly conservative; however, they have not thoroughly considered chronic health outcomes. In August 2004, a symposium on drinking-water nitrate and health was held at the International Society for Environmental Epidemiology meeting to evaluate nitrate exposures and associated health effects in relation to the current regulatory limit. The contribution of drinking-water nitrate toward endogenous formation of N-nitroso compounds was evaluated with a focus toward identifying subpopulations with increased rates of nitrosation. Adverse health effects may be the result of a complex interaction of the amount of nitrate ingested, the concomitant ingestion of nitrosation cofactors and precursors, and specific medical conditions that increase nitrosation. Workshop participants concluded that more experimental studies are needed and that a particularly fruitful approach may be to conduct epidemiologic studies among susceptible subgroups with increased endogenous nitrosation. The few epidemiologic studies that have evaluated intake of nitrosation precursors and/or nitrosation inhibitors have observed elevated risks for colon cancer and neural tube defects associated with drinking-water nitrate concentrations below the regulatory limit. The role of drinking-water nitrate exposure as a risk factor for specific cancers, reproductive outcomes, and other chronic health effects must be studied more thoroughly before changes to the regulatory level for nitrate in drinking water can be considered.

Workgroup report: Drinking-water nitrate and health--recent findings and research needs.

Colorectal cancer is one of the most common internal malignancies in Western society. The cause of this disease appears to be multifactorial and involves genetic as well as environmental aspects. The human colon is continuously exposed to a complex mixture of compounds, which is either of direct dietary origin or the result of digestive, microbial and excretory processes. In order to establish the mutagenic burden of the colorectal mucosa, analysis of specific compounds in feces is usually preferred. Alternatively, the mutagenic potency of fecal extracts has been determined, but the interpretation of these more integrative measurements is hampered by methodological shortcomings. In this review, we focus on exposure of the large bowel to five different classes of fecal mutagens that have previously been related to colorectal cancer risk. These include heterocyclic aromatic amines (HCA) and polycyclic aromatic hydrocarbons (PAH), two exogenous factors that are predominantly ingested as pyrolysis products present in food and (partially) excreted in the feces. Additionally, we discuss N-nitroso-compounds, fecapentaenes and bile acids, all fecal constituents (mainly) of endogenous origin. The mutagenic and carcinogenic potency of the above mentioned compounds as well as their presence in feces, proposed mode of action and potential role in the initiation and promotion of human colorectal cancer are discussed. The combined results from in vitro and in vivo research unequivocally demonstrate that these classes of compounds comprise potent mutagens that induce many different forms of genetic damage and that particularly bile acids and fecapentaenes may also affect the carcinogenic process by epigenetic mechanisms. Large inter-individual differences in levels of exposures have been reported, including those in a range where considerable genetic damage can be expected based on evidence from animal studies. Particularly, however, exposure profiles of PAH and N-nitroso compounds (NOC) have to be more accurately established to come to a risk evaluation. Moreover, lack of human studies and inconsistency between epidemiological data make it impossible to describe colorectal cancer risk as a result of specific exposures in quantitative terms, or even to indicate the relative importance of the mutagens discussed. Particularly, the polymorphisms of genes involved in the metabolism of heterocyclic amines are important determinants of carcinogenic risk. However, the present knowledge of gene-environment interactions with regard to colorectal cancer risk is rather limited. We expect that the introduction of DNA chip technology in colorectal cancer epidemiology will offer new opportunities to identify combinations of exposures and genetic polymorphisms that relate to increased cancer risk. This knowledge will enable us to improve epidemiological study design and statistical power in future research.

Evaluation of fecal mutagenicity and colorectal cancer risk

Carcinogenesis 2001 Mar;22(3):395-401 Related Articles, Books, LinkOut A multi-biomarker approach to study the effects of smoking on oxidative DNA damage and repair and antioxidative defense mechanisms. Nia AB, Van Schooten FJ, Schilderman PA, De Kok TM, Haenen GR, Van Herwijnen MH, Van Agen E, Pachen D, Kleinjans JC. Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. We investigated the effects of smoking-induced oxidative stress in healthy volunteers (21 smokers versus 24 non-smokers) by quantifying various markers of oxidative DNA damage and repair, and antioxidative defense mechanisms. Lymphocytic 7-hydroxy-8-oxo-2'-deoxyguanosine (8-oxo-dG) levels measured by high performance liquid chromatography with electrochemical detection, were significantly lower in smokers as compared with non-smokers (38.6 +/- 5.2 versus 50.9 +/- 4.6/10(6) dG, P = 0.05). The levels of oxidized pyrimidine bases in lymphocytes of smokers quantified by the endonuclease III-modified comet assay were non-significantly lower than those of non-smokers (% DNA in tail: 13 +/- 3 versus 14 +/- 2; tail length: 69 +/- 13 versus 96 +/- 10; tail moment: 6416 +/- 1220 versus 7545 +/- 1234). Urinary excretion levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) assessed by enzyme-linked immunosorbent assay did not differ significantly between smokers and non-smokers (197 +/- 31 versus 240 +/- 33 ng/body mass index, P = 0.3). Overall DNA repair activity expressed as unscheduled DNA synthesis in blood leukocytes, was not significantly different between smokers and non-smokers (2.9 +/- 0.3 versus 3.3 +/- 0.3, P = 0.4). Plasma antioxidative capacity measured by the Trolox equivalent antioxidant capacity assay was slightly higher in smokers as compared with non-smokers (440 +/- 16 versus 400 +/- 15 microM Trolox equivalent, P = 0.09), and it was significantly related to lymphocytic 8-oxo-dG levels (r = 0.4, P = 0.001). Genotyping of human 8-OH-dG glycosylase/apurinic lyase and glutathione S-transferase M1 showed that a polymorphism in either or both of the two genes does not affect any of the quantified biomarkers. We conclude that oxidative stress imposed by cigarette smoking has a low impact upon certain pathways involved in DNA damage and the antioxidative defense system.

A multi-biomarker approach to study the effects of smoking on oxidative DNA damage and repair and antioxidative defense mechanisms.

In the multistage model of human colorectal tumorigenesis, both genetic and environmental factors play an important role. The identity of the environmental factors involved, however, still remains to be elucidated. As fecal bile acids are proposed as candidates, we compared the concentration of bile acids in fecal water from patients at different risk of developing colorectal cancer. In addition, pH of fecal water as well as its cytotoxicity to HT-29 colonic cells was determined. The high-risk group consisted of individuals diagnosed with one or more (tubulo)villous colorectal adenomas larger than 1 cm in diameter and containing moderate or severe dysplasia (N = 20). Subjects with colorectal adenomas smaller than 1 cm and showing only minor dysplasia were assigned to the medium risk group (N = 19). The control group consisted of persons with normal findings by colonoscopy (N = 25). The results show no significant differences in fecal water bile acid concentrations between the three groups. However, 46% of the observed cytotoxicity is explained in a regression model that includes pH and the concentrations of deoxycholic acid, cholic acid, and ursodeoxycholic acid. The pH of fecal water is found to be significantly lower in the high risk group as compared to the controls, suggesting that a relatively high fecal pH has a protective effect on the development of colorectal adenomas. Although hyperproliferation as a result of cytotoxicity has been suggested to contribute to tumor formation in the colon, the pH-dependent cytotoxicity of bile acids in fecal water was not found to be associated with adenoma formation in the present study.

Bile acid concentrations, cytotoxicity, and pH of fecal water from patients with colorectal adenomas.

In recent years, several studies have addressed a possible relationship between nitrate exposure and childhood type 1 insulin-dependent diabetes mellitus. The present ecologic study describes a possible relation between the incidence of type 1 diabetes and nitrate levels in drinking water in The Netherlands, and evaluates whether the World Health Organization and the European Commission standard for nitrate in drinking water (50 mg/L) is adequate to prevent risk of this disease. During 1993-1995 in The Netherlands, 1,104 cases of type 1 diabetes were diagnosed in children 0-14 years of age. We were able to use 1,064 of these cases in a total of 2,829,020 children in this analysis. We classified mean nitrate levels in drinking water in 3,932 postal code areas in The Netherlands in 1991-1995 into two exposure categories. One category was based on equal numbers of children exposed to different nitrate levels (0.25-2.08, 2.10-6.42, and 6.44-41.19 mg/L nitrate); the other was based on cut-off values of 10 and 25 mg/L nitrate. We determined standardized incidence ratios (SIRs) for type 1 diabetes in subgroups of the 2,829,020 children with respect to both nitrate exposure categories, sex, and age and as compared in univariate analysis using the chi-square test for trend. We compared the incidence rate ratios (IRRs) by multivariate analysis in a Poisson regression model. We found an effect of increasing age of the children on incidence of type 1 diabetes, but we did not find an effect of sex or of nitrate concentration in drinking water using the two exposure categories. For nitrate levels > 25 mg/L, an increased SIR and an increased IRR of 1.46 were observed; however, this increase was not statistically significant, probably because of the small number of cases (15 of 1,064). We concluded that there is no convincing evidence that nitrate in drinking water at current exposure levels is a risk factor for childhood type 1 diabetes mellitus in The Netherlands, although a threshold value > 25 mg/L for the occurrence of this disease can not be excluded. Chemicals/CAS: Nitrates; Water Pollutants, Chemical

Does the risk of childhood diabetes mellitus require revision of the guideline values for nitrate in drinking water

In patients with inflammatory bowel disease (IBD), an increased incidence of colorectal cancer is observed.1 Although severe inflammatory conditions per se represent a risk factor for neoplasia, we would like to draw attention to the possible role of increased activity of inducible nitric oxide synthase (iNOS), as found in IBD patients,2 in the endogenous formation of carcinogenic N -nitroso compounds (NOC). In healthy individuals, relatively small amounts of NOC are formed by the interaction between NOC precursors (NOCP), present in dietary items such as meat and fish, and nitrosating agents derived from dietary nitrate. It has been proposed that endogenous formation of NOC may explain the link between meat consumption and colon cancer risk found in epidemiological studies.3 We hypothesised that as a result …

https://gut.bmj.com/content/gutjnl/54/5/731.2.full.pdf

T.M.C.M. de Kok

Papers

Evaluation of fecal mutagenicity and colorectal cancer risk

A multi-biomarker approach to study the effects of smoking on oxidative DNA damage and repair and antioxidative defense mechanisms.

Bile acid concentrations, cytotoxicity, and pH of fecal water from patients with colorectal adenomas.

Does the risk of childhood diabetes mellitus require revision of the guideline values for nitrate in drinking water

Inflammatory bowel disease stimulates formation of carcinogenic N-nitroso compounds