P- Reviewer: Morales-Gonzalez J, Ogino S, Palmirotta R, Wang F, Weber V S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ
Published online Apr 15, 2016. doi: 10.4251/wjgo.v8.i4.402
Peer-review started: October 17, 2015
First decision: November 27, 2015
Revised: December 31, 2015
Accepted: January 21, 2016
Article in press: January 22, 2016
Published online: April 15, 2016
Published reports have revealed increased risk of colorectal cancers in people exposed to chlorinated drinking water or chemical derivatives of chlorination. Oestrogen plays a dual positive functions for diminishing the possibilities of such risk by reducing the entrance, and increasing the excretion, of these chemicals. In addition, there are supplementary measures that could be employed in order to reduce this risk further, such as boiling the drinking water, revising the standard concentrations of calcium, magnesium and iron in the public drinking water and prescribing oestrogen in susceptible individuals. Hypo-methylation of genomic DNA could be used as a biological marker for screening for the potential development of colorectal cancers.
Core tip: Oestrogen inhibits the absorption and increases the excretion of xenobiotics and their metabolites via the bile. Oestrogen has anti-hypo methylation activity on the genomic DNA by reducing the plasma levels of homocysteine. Colorectal carcinomas are the third most common tumour in both sexes across the globe. The hazard to develop tumours in different specific sites including colon and rectum in association with the long-term exposure to water disinfectants in drinking water is well established. The risk to develop tumours in the large intestines is dependent on the concentrations and frequency of exposure to the trihalomethanes in the used water for drinking. The risk to develop malignant tumours due to water pollution is higher amongst user of swimming pools and is also dependent on the frequency of showering. Indeed, this risk is much higher in those who are avid consumers of fatty foods and/or their meals lacks vegetables and fruits in this susceptible group amongst those who are users of swimming pools. Yet, this risk could be reduced by adding calcium, magnesium and removing iron from the drinking water. Boiling of drinking water is another effective measure for reducing such risk. Colorectal carcinomas arising from long exposure to trihalomethanes in drinking water are characterised an aggressive courses of development and are rarely diagnosed in early stages. Accordingly, it is quite necessary to screen for their occurrence amongst the susceptible persons. Global DNA hypomethylation is most common amongst all subjects who are susceptible to develop malignant tumours and the levels of hypo methylation increase with the prognosis of the disease. Thus screening for the hypo methylation of the relevant genomic DNA and the plasma concentration of homocysteine would be useful criterion for identifying those at risk.
- Citation: El-Tawil AM. Colorectal cancers and chlorinated water. World J Gastrointest Oncol 2016; 8(4): 402-409
- URL: https://www.wjgnet.com/1948-5204/full/v8/i4/402.htm
- DOI: https://dx.doi.org/10.4251/wjgo.v8.i4.402
Carcinomas of the large intestines are remarkably common across the globe with around 1.4 million new cases diagnosed in 2012. The risk of developing colorectal cancer increases with age and is higher in men than in women.
The different frequencies of cancers in different genders, the recurring diagnosis of malignant tumors of the large intestines in women with breast cancer, the prophylactic effect of gravidity, together with the decreased risk among women on pills after menopause suggest that female hormones may play a role.
In animal models, for example, male rats that were exposed to dimethyl hydrazine (a carcinogenic mediator), had twice the risk of developing colonic tumors and noticeably shorter survival times than their female peers.
Estrogen mainly exerts its actions through its receptors (ERs) that exist on the target cells. ERs have been found in several malignant tumors including those of the alimentary tract.
Yet, whether estrogen contributes in the carcinogenic activity of the trihalomethanes that leads to the development of colorectal carcinoma is still unknown. The objective of this review is to explore the possible mechanism played by oestrogen in the cancer development process.
Poisons, cancer initiators and medicines are examples of xenobiotics. Many metabolizing enzymes are involved in their detoxification. The cluster of cytochrome P450 isoenzymes is one of two known classes that are responsible for the metabolism of these compounds. It consists of many isoforms leading to the oxidation (mainly hydroxylation) of the particles. Isoforms in the clusters 1, 2 and 3 accelerate metabolism of many exogenous compounds. Many poisons and cancer promoters usually necessitate activation by cytochrome P450 isoenzymes in order to be expelled outside the body. In general, the enzymatic activity of cytochrome P450 isoenzymes has three specific and consecutive phases: Phase I metabolism, is largely for catalysing the first step of biotransformation. However, if this catalysing activity follows a variety of conjugation steps it is entitled phase II metabolism. This stage is usually accelerated by a variety of enzymatic systems, of which UDP Glucuronosyltransferases is the most important. The purpose for conjugating the xenobiotics to the glucuronic acid is to make them soluble in water and consequently fit for excretion in bile[19,20]. Other models of phase II systems include sulfotransferases, acetyltransferases and glutathione-s-transferase.
Later reports have added the transport steps and considered them as part of the detoxification process. The role of the export pumps is to reduce the cellular concentrations of these poisons and thereby decreasing the associated harm.
These transport proteins mainly exist in the apical membrane of epithelial cells, such as enterocytes, which lie directly opposite to these exogenous toxins. The protein transporters can limit the entrance of the harmful compounds and facilitate the excretion of their metabolites as well. The last step is entitled “phase III metabolism” in order to link it to the oxidation and conjugation steps. Yet, directing the poisons to enter into the enterocytes has been considered as first line of defence and accordingly has been entitled “phase 0 metabolism”.
These protein transporters exert their activities in an active ATP dependent manner against the concentration gradients. The two most common models of these transporters are the multidrug resistance transporter 1 (MDR1) and multidrug resistance associated protein 2 (MRP2). These transporters play a remarkable role in phase 0 and phase III defence against xenobiotics. They are present in both the intestine and liver and thence can reduce the oral bioavailability by direct inhibition of gut absorption and speedy excretion of xenobiotics and their metabolites via bile[19,20].
MDR1 is active against xenobiotics in both the blood-brain barrier and in the gut. MDR1 are expressed in the small and large intestines but they are mostly manifested in the large intestine[23,24].
MRP2 was first identified in the apical membrane domain of hepatocytes. The main function of MRP2 is to facilitate the transport of a variety of organic anions, especially the conjugated formulas, into bile and thence out of the body. This means that MRP2 are capable of restricting whole body load of endogenous and exogenous toxins. MRP2 are also expressed in the kidney, in the epithelial cells of the intestine, in the placenta, and in the blood-brain barrier. In the rat intestine, MRP2 expression is highest in the duodenum but few are found in the colon MRP2 actively ejects the xenobiotics after hydroxylating them in the form of glucuronide, sulfate or glutathione conjugates.
The influence of pharmacological levels of ethynylestradiol (EE) on the expression and activity of MRP2, MDR1 and breast cancer resistance proteins (BCRP) in in vitro models of drug transport, such as CaCo2 cells has been examined.
Cells treated with either 0.5 or 5 pmol/L EE for 48 h showed an increase in MRP2 (+75% and +88%) and MDR1 (+158% and +162%) protein expression, with respect to control cells. Yet, no effects were observed when cells were treated with all other concentrations tested. In additional experiments performed to determine protein expression of MRP2 and MDR1in total cellular membranes as well as their mRNA levels in cells treated with 5 pmol/L EE, an increase in MRP2 (+56%) and MDR1 (+128%) protein expression, with respect to control cells was noted.
When MRP2 activity was evaluated using DNP-SG as a model substrate treatment with 5 pmol/L EE increased the ratio of protein expression by 39% when compared to control cells. To the contrary, when MDR1 activity was evaluated using Rh123 as a model substrate the intracellular accumulation of Rh123 correlated inversely with MDR1 extrusion activity. Treatment with 5 pmol/L EE decreased substrate accumulation by 19% when compared to control cells. Such decreased accumulation will lead to reduction in the length and concentrations of exposure and accordingly a reduction in the risk of the associated hypomethylation of repetitive DNA elements.
Further, when the protective effect of EE against CDNB and PQ cytotoxicity was evaluated through determination of the cell survival IC50 value related to CDNB, IC50 values were higher in cells treated with 5 pmol/L EE (33.3 ± 0.5) than in control cells (25.5 ± 0.5). Likewise, the IC50 value related to PQ cytotoxicity was higher in cells treated with 5 pmol/L EE (8.8 ± 0.8) vs control cells (6.8 ± 0.5 mmol/L).
The same researchers also tried to evaluate whether ER mediates transporter modulation by EE. For achieving that goal, they measured MRP2 and MDR1 protein expression after treatment with 5 pmol/L EE for 48 h, in the presence or absence of ICI 182/780. The findings were that MRP2and MDR1 protein up-regulation was abolished by the ER antagonist (EE vs EE + ICI).
The first reported epigenetic changes in human cancer of losses of DNA methylation (methylated 5C component was replaced by non-methylated C component) was published in 1983. In their study, Gama-Sosa et al noticed this change in DNA methylation thru the genome in a variety of carcinomas against a broad diversity of ordinary tissues. Then in further published work, Feinberg et al[34,35] reported hypomethylation of unrelated gene areas to cancer in colon adenocarcinomas compared with normal controls.
DNA hypo-methylation appears much more extensive in metastases. Many subsequent reports have confirmed the recurring global genomic hypo-methylation in cancers when compared with normal tissues[36-42]. This conclusion has been recently bolstered. In a 2014 report by Kaz et al genetic alterations in the methylation of genes known for their participation in the colonic carcinogenic process of the normal colon, where no colonic tumour existed suggest that these genetic alterations precede any changes in the colonic tissues and could be potentially used as predictors for the development of colorectal cancers.
Phases of DNA Hypo-methylation status is a significant feature during the early stages of the development of tumours or in other abnormal growths, such as hyperplasia[42,44-46]. This conclusion was confirmed further by the findings of DNA hypo-methylation prior to the identification of aneuploidy in gastrointestinal cancers. Hypo-methylation of DNA, in general, increases with the tumour progression or grade of malignancy[48-51]. Yet, cancers arising from long exposure to chlorinated water are not exceptional. In a study on an animal model, Coffin et al examined the influence of the exposure to trihalomethanes in the used water for drinking on the tumour progression and DNA methylation of female B6 C3 F1 mouse liver cell line. The main finding of this study was that the trihalomethanes administered by gavage enhanced the multiplicity of the hepatocytes and decreased the methylation of the c-myc gene.
Oestrogen has anti-cancer activity and plays a significant role in suppressing the development of colorectal cancer. This clearly appears from the frequently reported hypermethylation of the ER-α gene in malignant tumours of the large intestines[54,55], suggesting that ER-α gene hypermethylation could be used as a predictor for the development of large bowel cancers. ER-α is a transcription factor that, upon binding to oestrogen transfers to the nucleus to activate various genes including those involved in the inhibition of cell multiplicity. The insertion of ER-α gene into ER-negative colon cancer cells suppressed cell proliferation. Retrieval of an epigenetically inactivated ER gene resulted in suppression of large bowel cancer cells development in vitro and in vivo. Experimental work have shown that ER-α gene is also hypermethylated in azoxymethane (AOM)-induced carcinoma of the large intestines in rats, lending support to a pragmatic approach to cancer suppression.
Chloroform, Bromodichloromethane, Chlorodibromomethane, and Bromoform are common contaminants in chlorinated water.
Chloroform is considered a facilitator for the development of cancers in humans based on data from animal studies.
Oral contact to chloroform initiated tumours in two kinds of rats and at two different places. Direct gastric administration of chloroform by stomach tube caused hepatocellular carcinoma in mice of both sexes and renal epithelial tumours in male mice and rats[61,62].
Benign hepatic adenomas were observed in female rats drank contaminated water with chloroform[63,64] and in female mice breathed contaminated air with Chloroform. Renal tubular-cell adenomas, carcinomas, or adenocarcinoma were observed in male rats drank contaminated water with chloroform[62,63], in male mice breathed contaminated air with chloroform, and in male rats following combined exposure to chloroform via breathing and drinking contaminated suppliers.
No cause-effect relationship has been established between human cancer and exposure specifically to chloroform. However, an association between exposure to contaminated water and development of specific kinds of cancers has been established by community-based, cohort and case control studies[67,68], but a causal relationship could not be inferred[69-77].
Similarly, bromodichloromethane is also considered a facilitator for the development of cancers in humans based on data from animal studies. Drinking contaminated water with bromodichloromethane caused tumours at several different places in mice and rats. Direct gut administration of bromodichloromethane by a stomach tube caused renal tubular-cell adenomas and adenocarcinomas in male mice and in rats of both sexes, hepatocellular adenomas and carcinomas in female mice, and colonic adenomatous polyps and adenocarcinomas in rats of both sexes[71,77-79].
The data available from epidemiological studies are not conclusive to confirm on a possible relationship between the development of cancers in humans and the exposure specifically to bromodichloromethane. Several epidemiological studies indicated a possible association between drinking chlorinated water and increased risk of cancer, but these studies could not provide information on whether any observed effects were specifically related to bromodichloromethane.
When the risk to develop cancers due to long-term exposure to trihalomethanes via drinking, breathing and dermal contact from supply water of five water suppliers were analysed chloroform was the major component that caused cancer risk through both oral and dermal routes whereas bromodichloromethane was the major component through inhalation. The main risk factors that enhance the development of cancers are the existence of Chloroform in the contaminated water, body weight and then the long-term exposure to chlorinated water[82,83].
Evidence exists to prove that low concentrations of calcium (Ca) and/or magnesium (Mg) in the used water for drinking increase the carcinogenic effect of TTHM and thence the development of cancers of oesophagus, kidney, rectum and pancreas.
On the other hand, it was found that the presence of Fe3+ increases the carcinogenic activity of THMs in humans. It was estimated that the risk to develop cancer from long-term skin exposure to trihalomethanes while swimming is as high as 94%.
In a randomized double-blind, placebo-controlled, cross-over study consisting of two different stages, placebo and conjugated horsey oestrogen, Friso et al investigated the effect of administration of oestrogen in thirteen volunteer postmenopausal women on the genomic and promoter DNA methylation in peripheral mononuclear cells and on the plasma concentrations of homocysteine, folate, vitamins B6 and B12. In this study, oestrogen was prescribed as oral pills containing 0.625 mg CEE while placebo consisted of twin pills but lacking the active constituent. Each course lasted 8 wk and these two courses were separated by a 4-wk period. At week 8 of each stage, blood samples were taken for measuring plasma homocysteine, plasma pyridoxal-50-phosphate, serum folate and vitamin B12 levels. DNA was extracted from peripheral blood mononuclear cells in order to estimate genomic and promoter DNA methylation status.
The findings of this study were that: (1) plasma homocysteine levels were markedly decreased during the CEE phase compared with the placebo; (2) mean homocysteine levels during the placebo phase were 9.29 mmol/L (it was within the normal reported range by Stabler et al in 2004; (3) the oestrogen treatment reduced the mean concentration of homocysteine to 8.08 mmol/L; (4) the extent of genomic DNA methylation in peripheral mononuclear cells was noticeably increased after the oestrogen treatment as opposed to the placebo; (5) there was no significant difference in the promoter DNA methylation of the ERa, ERb and p16 genes between the oestrogen and placebo; and (6) there were no significant differences in serum folic acid, vitamin B12 and plasma vitamin B6 levels between the two treatment arms. These findings indicate that oestrogen administration could increase the methylation of the genomic DNA. Together with the well-documented data proving that a decreased level of genomic DNA methylation is a common feature of tumorigenesis, that it appears early prior to the DNA mutation that takes place later in the evolution of neoplasm this means that oestrogen administration has a prophylactic function against the development of cancers by enhancing genomic DNA methylation.
Chlorine is commonly used as a chemical disinfectant in water supplies, in the prevention of algal, bacterial and general slime growths in treatment plants and pipe works, in the control of tastes and odours, and in the removal of iron, manganese and colouring additives.
Trihalomethanes are derivatives of the outcome of the reaction between chlorine/chloride, with contaminants in water supplies, such as organic compounds, bromide and iron.
The associated health threats including colorectal cancers are dependent on the frequency of exposure to and the levels of trihalomethanes in the used water for drinking. These threats could be reduced by restricting the use and contamination by trihalomethanes of public drinking water[83,93], or by boiling the water (Table 1), or by adjusting the concentrations of calcium, magnesium and iron[83-87].
|Original tap water||80 °C 1 min||100 °C 0 min||Boiling 1 min||Boiling 5 min|
Genomic DNA hypo-methylation could be used as a reliable biomarker for identifying susceptible cases and oestrogen replacement therapy could be used for reversing detected hypo-methylation and consequently reducing the risk of the carciogenesis[86,89,90].
However, in cancers of the colon and rectum, like other ER-linked cancers, the ablation of the sex hormones would be necessary, once the disease occurs, for delaying the progress of the disease. It is well-documented that once the disease manifests the role of oestrogen would be altered in that it will enhance global DNA hypo-methylation and thereby restricting of its availability would be beneficial.
|1.||Available from: http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/colorectal-cancer-statistics.|
|2.||Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z. SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD. Based on November. 2013;SEER data submission, posted to the SEER Web site Available from: http://seer.cancer.gov/csr/1975_2011/browse_csr.php?sectionSEL=6&pageSEL=sect_06_table.19.html.|
|3.||El-Tawil AM. Colorectal cancer and pollution. World J Gastroenterol. 2010;16:3475-3477. [PubMed]|
|4.||Rahman MB, Cowie C, Driscoll T, Summerhayes RJ, Armstrong BK, Clements MS. Colon and rectal cancer incidence and water trihalomethane concentrations in New South Wales, Australia. BMC Cancer. 2014;14:445. [PubMed] [DOI]|
|5.||Kuo HW, Peng CY, Feng A, Wu TN, Yang CY. Magnesium in drinking water modifies the association between trihalomethanes and the risk of death from colon cancer. J Toxicol Environ Health A. 2011;74:392-403. [PubMed] [DOI]|
|6.||Kuo HW, Tiao MM, Tsai SS, Wu TN, Yang CY. Does calcium in drinking water modify the association between trihalomethanes and the risk of death from colon cancer? J Toxicol Environ Health A. 2010;73:657-668. [PubMed] [DOI]|
|7.||Geter DR, Moore TM, George MH, Kilburn SR, Allen JW, Nelson GM, Winkfield E, DeAngelo AB. Tribromomethane exposure and dietary folate deficiency in the formation of aberrant crypt foci in the colons of F344/N rats. Food Chem Toxicol. 2005;43:1405-1412. [PubMed]|
|8.||Geter DR, George MH, Moore TM, Kilburn SR, Huggins-Clark G, DeAngelo AB. The effects of a high animal fat diet on the induction of aberrant crypt foci in the colons of male F344/N rats exposed to trihalomethanes in the drinking water. Toxicol Lett. 2004;147:245-252. [PubMed]|
|9.||DeAngelo AB, Geter DR, Rosenberg DW, Crary CK, George MH. The induction of aberrant crypt foci (ACF) in the colons of rats by trihalomethanes administered in the drinking water. Cancer Lett. 2002;187:25-31. [PubMed]|
|10.||Landi S, Hanley NM, Warren SH, Pegram RA, DeMarini DM. Induction of genetic damage in human lymphocytes and mutations in Salmonella by trihalomethanes: role of red blood cells and GSTT1-1 polymorphism. Mutagenesis. 1999;14:479-482. [PubMed]|
|11.||Daniel FB, Reddy TV, Stober JA, Olson GR. Site-specific modulation of carcinogen-induced gastrointestinal tract nuclear anomalies in B6C3F1 mice by chloroform. Anticancer Res. 1991;11:665-670. [PubMed]|
|12.||Isacson P, Bean JA, Splinter R, Olson DB, Kohler J. Drinking water and cancer incidence in Iowa. III. Association of cancer with indices of contamination. Am J Epidemiol. 1985;121:856-869. [PubMed]|
|13.||Williamson SJ. Epidemiological studies on cancer and organic compounds in U.S. drinking waters. Sci Total Environ. 1981;18:187-203. [PubMed]|
|14.||Di Leo A, Messa C, Cavallini A, Linsalata M. Estrogens and colorectal cancer. Curr Drug Targets Immune Endocr Metabol Disord. 2001;1:1-12. [PubMed]|
|15.||Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol. 2015;5:19. [PubMed] [DOI]|
|16.||Anzenbacher P, Anzenbacherová E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci. 2001;58:737-747. [PubMed]|
|17.||Werck-Reichhart D, Feyereisen R. Cytochromes P450: a success story. Genome Biol. 2000;1:REVIEWS3003. [PubMed]|
|18.||Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581-616. [PubMed]|
|19.||Pfeifer ND, Hardwick RN, Brouwer KL. Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. Annu Rev Pharmacol Toxicol. 2014;54:509-535. [PubMed] [DOI]|
|20.||Hardwick RN, Cherrington NJ. Measuring altered disposition of xenobiotics in experimental models of liver disease. Curr Protoc Toxicol. 2012;Chapter 23:Unit 23.1. [PubMed] [DOI]|
|21.||Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 1992;17:463-468. [PubMed]|
|22.||Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit. 2000;22:137-140. [PubMed]|
|23.||Suzuki H, Sugiyama Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur J Pharm Sci. 2000;12:3-12. [PubMed]|
|24.||Fricker G, Drewe J, Huwyler J, Gutmann H, Beglinger C. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation. Br J Pharmacol. 1996;118:1841-1847. [PubMed]|
|25.||Jansen PL, van Klinken JW, van Gelder M, Ottenhoff R, Elferink RP. Preserved organic anion transport in mutant TR- rats with a hepatobiliary secretion defect. Am J Physiol. 1993;265:G445-G452. [PubMed]|
|26.||Oude Elferink RP, Meijer DK, Kuipers F, Jansen PL, Groen AK, Groothuis GM. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim Biophys Acta. 1995;1241:215-268. [PubMed]|
|27.||Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W, Schrenk D. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol. 2000;157:1575-1580. [PubMed]|
|28.||St-Pierre MV, Serrano MA, Macias RI, Dubs U, Hoechli M, Lauper U, Meier PJ, Marin JJ. Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1495-R1503. [PubMed]|
|29.||Miller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Fricker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol. 2000;58:1357-1367. [PubMed]|
|30.||Rost D, Mahner S, Sugiyama Y, Stremmel W. Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. Am J Physiol Gastrointest Liver Physiol. 2002;282:G720-G726. [PubMed]|
|31.||Arias A, Rigalli JP, Villanueva SS, Ruiz ML, Luquita MG, Perdomo VG, Vore M, Catania VA, Mottino AD. Regulation of expression and activity of multidrug resistance proteins MRP2 and MDR1 by estrogenic compounds in Caco-2 cells. Role in prevention of xenobiotic-induced cytotoxicity. Toxicology. 2014;320:46-55. [PubMed]|
|32.||Madrigano J, Baccarelli A, Mittleman MA, Wright RO, Sparrow D, Vokonas PS, Tarantini L, Schwartz J. Prolonged exposure to particulate pollution, genes associated with glutathione pathways, and DNA methylation in a cohort of older men. Environ Health Perspect. 2011;119:977-982. [PubMed] [DOI]|
|33.||Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983;11:6883-6894. [PubMed]|
|34.||Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301:89-92. [PubMed]|
|35.||Feinberg AP, Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983;111:47-54. [PubMed]|
|36.||Bedford MT, van Helden PD. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res. 1987;47:5274-5276. [PubMed]|
|37.||Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21:5400-5413. [PubMed]|
|38.||de Capoa A, Musolino A, Della Rosa S, Caiafa P, Mariani L, Del Nonno F, Vocaturo A, Donnorso RP, Niveleau A, Grappelli C. DNA demethylation is directly related to tumour progression: evidence in normal, pre-malignant and malignant cells from uterine cervix samples. Oncol Rep. 2003;10:545-549. [PubMed]|
|39.||Brothman AR, Swanson G, Maxwell TM, Cui J, Murphy KJ, Herrick J, Speights VO, Isaac J, Rohr LR. Global hypomethylation is common in prostate cancer cells: a quantitative predictor for clinical outcome? Cancer Genet Cytogenet. 2005;156:31-36. [PubMed]|
|40.||Seifert HH, Schmiemann V, Mueller M, Kazimirek M, Onofre F, Neuhausen A, Florl AR, Ackermann R, Boecking A, Schulz WA. In situ detection of global DNA hypomethylation in exfoliative urine cytology of patients with suspected bladder cancer. Exp Mol Pathol. 2007;82:292-297. [PubMed]|
|41.||Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res. 2006;66:8469-8476. [PubMed]|
|42.||Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988;48:1159-1161. [PubMed]|
|43.||Kaz AM, Wong CJ, Dzieciatkowski S, Luo Y, Schoen RE, Grady WM. Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age. Epigenetics. 2014;9:492-502. [PubMed] [DOI]|
|44.||Narayan A, Ji W, Zhang XY, Marrogi A, Graff JR, Baylin SB, Ehrlich M. Hypomethylation of pericentromeric DNA in breast adenocarcinomas. Int J Cancer. 1998;77:833-838. [PubMed]|
|45.||Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228:187-190. [PubMed]|
|46.||Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, Fiegl H, Müller-Holzner E, Widschwendter M, Ehrlich M. DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol Ther. 2004;3:1225-1231. [PubMed]|
|47.||Suzuki K, Suzuki I, Leodolter A, Alonso S, Horiuchi S, Yamashita K, Perucho M. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell. 2006;9:199-207. [PubMed]|
|48.||Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, San Jose-Eneriz E, Garate L, Cordeu L, Cervantes F, Prosper F. Repetitive DNA hypomethylation in the advanced phase of chronic myeloid leukemia. Leuk Res. 2008;32:487-490. [PubMed]|
|49.||Park SY, Yoo EJ, Cho NY, Kim N, Kang GH. Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection. J Pathol. 2009;219:410-416. [PubMed]|
|50.||Qu G, Dubeau L, Narayan A, Yu MC, Ehrlich M. Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential. Mutat Res. 1999;423:91-101. [PubMed]|
|51.||Ehrlich M, Woods CB, Yu MC, Dubeau L, Yang F, Campan M, Weisenberger DJ, Long T, Youn B, Fiala ES. Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors. Oncogene. 2006;25:2636-2645. [PubMed]|
|52.||Coffin JC, Ge R, Yang S, Kramer PM, Tao L, Pereira MA. Effect of trihalomethanes on cell proliferation and DNA methylation in female B6C3F1 mouse liver. Toxicol Sci. 2000;58:243-252. [PubMed]|
|53.||Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23:29-39. [PubMed]|
|54.||Jubb AM, Bell SM, Quirke P. Methylation and colorectal cancer. J Pathol. 2001;195:111-134. [PubMed]|
|55.||Reid G, Denger S, Kos M, Gannon F. Human estrogen receptor-alpha: regulation by synthesis, modification and degradation. Cell Mol Life Sci. 2002;59:821-831. [PubMed]|
|56.||Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994;7:536-540. [PubMed]|
|57.||al-Azzawi F, Wahab M. Estrogen and colon cancer: current issues. Climacteric. 2002;5:3-14. [PubMed]|
|58.||Pereira MA, Tao L, Wang W, Li Y, Umar A, Steele VE, Lubet RA. Modulation by celecoxib and difluoromethylornithine of the methylation of DNA and the estrogen receptor-alpha gene in rat colon tumors. Carcinogenesis. 2004;25:1917-1923. [PubMed]|
|59.||National Toxicology Program. Carcinogenesis bioassay of trichloroethylene. Natl Cancer Inst Carcinog Tech Rep Ser. 1976;2:1-215. [PubMed]|
|60.||International Agency for Research on Cancer (IARC). Chapter 1 Tumours of the Kidney. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Available from: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb7/bb7-chap1.pdf.|
|61.||Moore DH, Chasseaud LF, Majeed SK, Prentice DE, Roe FJ, Van Abbé NJ. The effect of dose and vehicle on early tissue damage and regenerative activity after chloroform administration to mice. Food Chem Toxicol. 1982;20:951-954. [PubMed]|
|62.||International Agency for Research on Cancer (IARC). Tumours of the Liver and Intrahepatic Bile Ducts. Pathology and Genetics of Tumours of the Digestive System. Available from: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb2/bb2-chap8.pdf.|
|63.||World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Available from: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71.pdf.|
|64.||Yamamoto S, Nishizawa T, Nagano K, Aiso S, Kasai T, Takeuchi T, Matsushima T. Development of resistance to chloroform toxicity in male BDF1 mice exposed to a stepwise increase in chloroform concentration. J Toxicol Sci. 1999;24:421-424. [PubMed]|
|65.||Nagano K, Kano H, Arito H, Yamamoto S, Matsushima T. Enhancement of renal carcinogenicity by combined inhalation and oral exposures to chloroform in male rats. J Toxicol Environ Health A. 2006;69:1827-1842. [PubMed]|
|66.||Cantor KP, Hoover R, Mason TJ, McCabe LJ. Associations of cancer mortality with halomethanes in drinking water. J Natl Cancer Inst. 1978;61:979-985. [PubMed]|
|67.||Hogan MD, Chi PY, Hoel DG, Mitchell TJ. Association between chloroform levels in finished drinking water supplies and various site-specific cancer mortality rates. J Environ Pathol Toxicol. 1979;2:873-887. [PubMed]|
|68.||World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Available from: http://monographs.iarc.fr/ENG/Monographs/vol1-42/mono27.pdf.|
|69.||World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Available from: http://monographs.iarc.fr/ENG/Monographs/vol1-42/mono42.pdf.|
|70.||World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Available from: http://monographs.iarc.fr/ENG/Monographs/vol73/mono73.pdf.|
|71.||Villanueva CM, Cantor KP, Cordier S, Jaakkola JJ, King WD, Lynch CF, Porru S, Kogevinas M. Disinfection byproducts and bladder cancer: a pooled analysis. Epidemiology. 2004;15:357-367. [PubMed]|
|72.||Geter DR, Chang LW, Hanley NM, Ross MK, Pegram RA, DeAngelo AB. Analysis of in vivo and in vitro DNA strand breaks from trihalomethane exposure. J Carcinog. 2004;3:2. [PubMed]|
|73.||Michaud DS, Kogevinas M, Cantor KP, Villanueva CM, Garcia-Closas M, Rothman N, Malats N, Real FX, Serra C, Garcia-Closas R. Total fluid and water consumption and the joint effect of exposure to disinfection by-products on risk of bladder cancer. Environ Health Perspect. 2007;115:1569-1572. [PubMed]|
|74.||King WD, Marrett LD, Woolcott CG. Case-control study of colon and rectal cancers and chlorination by-products in treated water. Cancer Epidemiol Biomarkers Prev. 2000;9:813-818. [PubMed]|
|75.||Wang FI, Kuo ML, Shun CT, Ma YC, Wang JD, Ueng TH. Chronic toxicity of a mixture of chlorinated alkanes and alkenes in ICR mice. J Toxicol Environ Health A. 2002;65:279-291. [PubMed]|
|76.||National Toxicology Program. Toxicology and carcinogenesis studies of bromodichloromethane. Available from: http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr321.pdf.|
|77.||Agency for Toxic Substances and Disease Registry U. S. Public Health Service. In collaboration with: U.S. Environmental Protection Agency (EPA). Toxicological profile for bromodichloromethane. Available from: http://www.atsdr.cdc.gov/toxprofiles/tp129.pdf.|
|78.||World Health Organization International Agency for Research on Cancer. IARC monograhs on the evaluation of carcinogenic risks to humas. Available from: http://monographs.iarc.fr/ENG/Monographs/vol52/mono52.pdf.|
|79.||George MH, Olson GR, Doerfler D, Moore T, Kilburn S, DeAngelo AB. Carcinogenicity of bromodichloromethane administered in drinking water to Male F344/N Rats and B6C3F1 mice. Int J Toxicol. 2002;21:219-230. [PubMed]|
|80.||Tumasonis CF, McMartin DN, Bush B. Toxicity of chloroform and bromodichloromethane when administered over a lifetime in rats. J Environ Pathol Toxicol Oncol. 1987;7:55-63. [PubMed]|
|81.||Kumari M, Gupta SK, Mishra BK. Multi-exposure cancer and non-cancer risk assessment of trihalomethanes in drinking water supplies - A case study of Eastern region of India. Ecotoxicol Environ Saf. 2015;113:433-438. [PubMed] [DOI]|
|82.||Lee J, Kim ES, Roh BS, Eom SW, Zoh KD. Occurrence of disinfection by-products in tap water distribution systems and their associated health risk. Environ Monit Assess. 2013;185:7675-7691. [PubMed] [DOI]|
|83.||Tsai SS, Chiu HF, Yang CY. Trihalomethanes in drinking water and the risk of death from esophageal cancer: does hardness in drinking water matter? J Toxicol Environ Health A. 2013;76:120-130. [PubMed] [DOI]|
|84.||Liao YH, Chen CC, Chang CC, Peng CY, Chiu HF, Wu TN, Yang CY. Trihalomethanes in drinking water and the risk of death from kidney cancer: does hardness in drinking water matter? J Toxicol Environ Health A. 2012;75:340-350. [PubMed] [DOI]|
|85.||Kuo HW, Chen PS, Ho SC, Wang LY, Yang CY. Trihalomethanes in drinking water and the risk of death from rectal cancer: does hardness in drinking water matter? J Toxicol Environ Health A. 2010;73:807-818. [PubMed] [DOI]|
|86.||Chiu HF, Tsai SS, Wu TN, Yang CY. Effect modification of the association between trihalomethanes and pancreatic cancer by drinking water hardness: evidence from an ecological study. Environ Res. 2010;110:513-518. [PubMed] [DOI]|
|87.||Liu S, Zhu Z, Fan C, Qiu Y, Zhao J. Seasonal variation effects on the formation of trihalomethane during chlorination of water from Yangtze River and associated cancer risk assessment. J Environ Sci (China). 2011;23:1503-1511. [PubMed]|
|88.||Panyakapo M, Soontornchai S, Paopuree P. Cancer risk assessment from exposure to trihalomethanes in tap water and swimming pool water. J Environ Sci (China). 2008;20:372-378. [PubMed]|
|89.||Friso S, Lamon-Fava S, Jang H, Schaefer EJ, Corrocher R, Choi SW. Oestrogen replacement therapy reduces total plasma homocysteine and enhances genomic DNA methylation in postmenopausal women. Br J Nutr. 2007;97:617-621. [PubMed] [DOI]|
|90.||Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon RO. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med. 1997;336:683-690. [PubMed]|
|91.||Stabler SP, Allen RH. Megaloblastic anemias. Textbook of Medicine. 22nd ed. Philadelphia: Saunders 2004; 1050-1057.|
|92.||White GC. The Handbook of Chlorination. 2nd ed. New York: Van Nostrand Reinhold 1986; .|
|93.||Chlorlnated drinking-water. IARC Monographs. Available from: http://monographs.iarc.fr/ENG/Monographs/vol52/mono52-6.pdf.|
|94.||Lahl U, Cetinkaya M, Duszeln JV, Gabel B, Stachel B, Thiemann W. Health risks for infants caused by trihalomethane generation during chemical disinfection of feeding utensils. Ecol Food Nutr. 1982;12:7-17. [DOI]|