Intake Of Heterocyclic Aromatic Amines Research Articles

Zachowania żywieniowe chorych na nowotwory hematologiczne — prospektywne badanie jednoośrodkowe

Introduction. Oncohaematological diseases are a special group of cancer diseases. An important role in their pathogenesis may play exposure to carcinogenic compounds, including substances present in food, such as polycyclic aromatic hydrocarbons (PAH), heterocyclic aromatic amines (HCA), acrylamide, nitrosamines or ethanol. Aims and assumptions were analysis of eating behaviours leading to the consumption of carcinogenic compounds and assessment of frequency of carcinogenic compounds intake. Material and methods. 201 patients with haematological cancers participated in the study. The survey used authorial questionnaire. Selected eating habits and frequency of carcinogenic compounds intake were examined in the study. The results were developed in the Statistica 12 program. Results. Patients presented different eating habits. 28.3% (N = 34) of the respondents did not read the compositions of the products they buy, regardless of their place of residence. 46.0% (N = 92) of respondents most often consumed fried products. Only 30% of men and women (N = 27) negated frying on the same fat. Most women — 44.3% (N = 39) declared consumption of pork, most men 44.2% (N = 50) of poultry. 58.2% of respondents (N = 117) were characterized by low frequency of PAH, HCA and nitrosamine intake. Only 0.5% (N = 1) of the patients had very low acrylamide intake; 56.2% (N = 113) average. 66.2% (N = 133) of the respondents had low frequency of alcohol consumption. Conclusions. Eating habits leading to the consumption of carcinogens are: not reading labels, frying and pork consumption. Patients with hematological cancers had average frequency of carcinogen intake and low frequency of alcohol consumption.

Dietary Carcinogens and Cancer Risk: Findings From Japanese Studies

Background: Red meat and processed meat consumption are established risk factors for colorectal cancer. One hypothesized mechanism for this association is through exposure to heterocyclic aromatic amines (HAAs), which are formed when meat is cooked at high temperature for a long duration. Although they are mutagenic and carcinogenic in nonhuman primates, the findings of epidemiologic studies that have specifically examined the association between HAA intake and colorectal cancer risk have been inconsistent. Moreover, since N-acetyltransferase 2 (NAT2) has been shown to play a critical role in the bioactivation of HAAs, an interaction between HAA intake and NAT2 on colorectal cancer has been hypothesized and the findings in the previous studies have been inconsistent. Aim: To investigate the association of meat- and fish-derived HAA intake, which were estimated by our validated food frequency questionnaire and population-specific data on HAA contents in meat and fish items with the risk of colorectal adenoma, precursor of colorectal cancer, among middle-aged and elderly Japanese in Japan and Japanese Brazilians in Sao Paulo. In addition, to test the modifying effect of NAT2 on the association of HAA intake on colorectal adenoma risk. Methods: Tokyo adenoma study includes 738 patients with adenoma and 697 controls who underwent total colonoscopy in National Cancer Center, Japan. Brazil adenoma study includes 316 patients with adenoma and 403 controls who underwent total colonoscopy in 2 hospitals in Sao Paulo. HAA intake was estimated from meat and fish intake based on an HAA database that was validated against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) values measured in human hair. NAT2 acetylation genotype was inferred using 2 SNPs in the NAT2 gene. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence interval (CI) for the association between HAA intake and colorectal adenoma risk after adjusting for potential confounders. Results: Tokyo adenoma study showed that high intake of 2-amino-3,4-dimethylimidazo[4, 5-f]quinoline (MeIQ) and total HAA was significantly associated with an increased risk of colorectal adenoma in women but not in men. No clear association with PhIP or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intakes and no effect modification by NAT2 genotype was observed. Brazil adenoma study found no association for HAAs and no effect modification by NAT2 genotype. Conclusion: Tokyo Adenoma Study suggests that high MeIQ and total HAA intakes are positively associated with colorectal adenoma risk among Japanese women in Japan. However, Brazil adenoma study failed to observe positive associations. The possible explanations of inconsistent findings and the difficulty of the studies will be discussed.

Abstract P184: Meat Cooking Methods and Risk of Hypertension: Results From Three Prospective Cohort Studies

Background: The role of open-flame and/or high-temperature cooking (grilling/barbequing, broiling, or roasting) and doneness preferences (rare, medium, or well-done) in the association between meat consumption and risk of hypertension remains unknown. This study aimed to examine cooking methods for meats (red meats, chicken, or fish) in relation to hypertension risk among men and women who consumed meat regularly (≥2 servings/week). Methods: Study population consisted of 32,925 women from the Nurses’ Health Study (NHS 1996-2012), 53,852 women from the NHSII (2001-2013), and 17,104 men from the Health Professionals Follow-Up Study (HPFS 1996-2012), who were free of hypertension, diabetes, cardiovascular disease, and cancer at baseline. Results: We documented 37,123 incident hypertension cases during 1.06 million person-years of follow-up. After multivariate adjustments of covariates including total consumption of red meats, chicken, and fish, a higher frequency of open-flame and/or high-temperature cooking and a preference for higher meat doneness level were both independently associated with an increased hypertension risk. When comparing open-flame and/or high-temperature cooking >15 times/month with <4 times/month, the pooled hazard ratio (HR) and 95% confidence interval (CI) of hypertension was 1.17 (1.12, 1.21; P trend <0.001). When comparing the extreme quartiles of meat doneness level score, the pooled HR (95% CI) of hypertension was 1.15 (1.12, 1.19; P trend <0.001). The associations persisted when data were analyzed by individual meat groups: comparing extreme groups, for red meats, the pooled HR (95% CI) of hypertension was 1.18 (1.13, 1.23; P trend <0.001) for open-flame and/or high-temperature cooking and 1.15 (1.12, 1.19; P trend <0.001) for high meat doneness level; for white meats (chicken and fish), the pooled HR (95% CI) of hypertension was 1.12 (1.08, 1.16; P trend <0.001) for open-flame and/or high-temperature cooking and 1.10 (1.07, 1.14; P trend <0.001) for high meat doneness level. Moreover, levels of estimated intake of heterocyclic aromatic amines (HAAs) were also independently associated with an increased risk of hypertension. Comparing extreme quintiles of HAAs, the pooled HR (95% CI) of hypertension was 1.16 (1.13, 1.21; P trend <0.001). These associations were attenuated but remained significant when further adjusting for baseline body mass index. Conclusions: Our results suggest that, independent of the amount of meat consumption, open-flame and/or high-temperature cooking and high doneness level for both red meats and white meats are associated with an increased risk of hypertension.

Meat Cooking Methods and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies.

To examine open-flame and/or high-temperature cooking (grilling/barbecuing, broiling, or roasting) and doneness preferences (rare, medium, or well done) for red meat, chicken, and fish in relation to type 2 diabetes (T2D) risk among U.S. adults who consumed animal flesh regularly (≥2 servings/week). The prospective studies included 52,752 women from the Nurses' Health Study (NHS) (followed during 1996-2012), 60,809 women from NHS II (followed during 2001-2013), and 24,679 men from the Health Professionals Follow-Up Study (HPFS) (followed during 1996-2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. Incident cases of T2D were confirmed by validated supplementary questionnaires. We documented 7,895 incident cases of T2D during 1.74 million person-years of follow-up. After multivariate adjustments including baseline BMI and total consumption of red meat, chicken, and fish, higher frequency of open-flame and/or high-temperature cooking was independently associated with an elevated T2D risk. When comparing open-flame and/or high-temperature cooking >15 times/month with <4 times/month, the pooled hazard ratio (HR) (95% CI) of T2D was 1.28 (1.18, 1.39; Ptrend <0.001). When comparing the extreme quartiles of doneness-weighted frequency of high-temperature cooking, the pooled HR (95% CI) of T2D was 1.20 (1.12, 1.28; Ptrend <0.001). These associations remained significant when red meat and chicken were examined separately. In addition, estimated intake of heterocyclic aromatic amines was also associated with an increased T2D risk. Independent of consumption amount, open-flame and/or high-temperature cooking for both red meat and chicken is associated with an increased T2D risk among adults who consume animal flesh regularly.

Distribution of serum levels of persistent organic pollutants, heterocyclic aromatic amine theoretical intake and nutritional cofactors in a semi-rural island population.

Persistent organic pollutant (POP) exposure is strongly associated with negative health effects in humans. Heterocyclic aromatic amines (HAAs) are formed during high temperature cooking of foods (i.e. meat and fish). Human exposure to HAA is through food consumption and from similar food groups to POPs. A study of serum samples for POPs in a non-occupational exposed population (n=149, age range 18-80years, recruited in 2012) and comparison with estimated HAA daily intake calculations based on food diaries were undertaken. Three different age groups (group 1, 18-29years; group 2, 30-44years; and group 3, 45-80years) were used to explore possible relationships between POP levels present in blood, HAA intake and nutritional cofactors. Significant differences (p<0.05) between groups (1 and 3) for POP levels were found for p,p'-DDE, polychlorinated biphenyl (PCB) 153, PCB 138 and the sum of PCBs. A similar trend was found between groups 2 and 3 for PCB 153 and sum of PCBs. Significant differences were found between groups 1 and 3 and groups 2 and 3 for HAA intake., i.e. HAA intake was lowest in those of middle age, which may well reflect a different pathway of human exposure between HAA and POPs through the diet preferences.

Acid-labile protein-adducted heterocyclic aromatic amines in human blood are not viable biomarkers of dietary exposure: A systematic study

Heterocyclic aromatic amines (HCA) are carcinogenic mutagens formed during cooking of protein-rich foods. HCA residues adducted to blood proteins have been postulated as biomarkers of HCA exposure. However, the viability of quantifying HCAs following hydrolytic release from adducts in vivo and correlation with dietary intake are unproven. To definitively assess the potential of labile HCA-protein adducts as biomarkers, a highly sensitive UPLC-MS/MS method was validated for four major HCAs: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx). Limits of detection were 1–5 pg/ml plasma and recoveries 91–115%. Efficacy of hydrolysis was demonstrated by HCA-protein adducts synthesised in vitro. Plasma and 7-day food diaries were collected from 122 fasting adults consuming their habitual diets. Estimated HCA intakes ranged from 0 to 2.5 mg/day. An extensive range of hydrolysis conditions was examined for release of adducted HCAs in plasma. HCA was detected in only one sample (PhIP, 9.7 pg/ml), demonstrating conclusively for the first time that acid-labile HCA adducts do not reflect dietary HCA intake and are present at such low concentrations that they are not feasible biomarkers of exposure. Identification of biomarkers remains important. The search should concentrate on stabilised HCA-peptide markers and use of untargeted proteomic and metabolomic approaches.

Heterocyclic Aromatic Amines in Cooked Meat Products: Causes, Formation, Occurrence, and Risk Assessment

Meat products are sources of protein with high biological value and an essential source of other nutrients, such as vitamins and minerals. Heating processes cause food to become more appetizing with changes in texture, appearance, flavor, and chemical properties by the altering of protein structure and other ingredients. During heat treatment, heterocyclic aromatic amines (HAAs), potent mutagens/carcinogens, are formed due to the Maillard reaction. The HAAs are classified in at least 2 groups: thermic HAAs (100 to 300 °C) and pyrolytic HAAs (>300 °C). This review focuses on the parameters and precursors which affect the formation of HAAs: preparation, such as the marinating of meat, and cooking methods, including temperature, duration, and heat transfer, as well as levels of precursors. Additionally, factors are described subject to pH, and the type of meat and ingredients, such as added antioxidants, types of carbohydrates and amino acids, ions, fat, and other substances inhibiting or enhancing the formation of HAAs. An overview of the different analytical methods available is shown to determine the HAAs, including their preparation to clean up the sample prior to extraction. Epidemiological results and human daily intake of HAAs obtained from questionnaires show a relationship between the preference for very well-done meat products with increased HAA levels and an enhanced risk of the incidence of cancer, besides other carcinogens in the diet. The metabolic pathway of HAAs is governed by the activity of several enzymes leading to the formation of DNA adducts or HAA excretion and genetic sensitivity of individuals to the impact of HAAs on human cancer risk.

Abstract A10: Exposure to heterocyclic aromatic amines, genetic susceptibility and bulky DNA adduct levels in blood leukocytes

Abstract Background: There is compelling evidence to suggest that aspects of diet influence cancer risk; specifically, high meat consumption is associated with elevated risks. Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, is a hypothesized explanation for the meat-cancer relationship. Reactive HAA metabolites form adducts with DNA; left unrepaired, adducts can induce mutations which may initiate/promote carcinogenesis. Genetic differences in the ability to biotransform HAAs (as conferred by polymorphisms in CYP1A1, CYP1A2, CYP1B1, NAT1 and NAT2) and repair DNA adducts (as conferred by polymorphisms in XPA, XPD and XRCC1) is postulated to modify the dietary HAAs-DNA adduct relationship. Methods: In a cross-sectional study of 99 healthy volunteers recruited from Kingston, Ontario, Canada, dietary exposure to HAAs and bulky DNA adduct levels in blood leukocytes was investigated. A detailed questionnaire was used in combination with a mutagen database to estimate average intake of dietary HAAs. Specifically, the detailed questionnaire obtained the average frequency of consumption, usual level of doneness and usual serving size of nine commonly consumed meats items with high HAA content. Bulky DNA adduct levels were measured in blood collected after an overnight fast using 32P-postlabelling. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. Results: No main effects of dietary exposure to HAAs on bulky DNA adduct levels were observed. However, polymorphisms in NAT1 were found to associate with bulky DNA adduct levels. Specifically, those with the putative NAT1*10 rapid acetylator phenotype had a lower adduct level than those with the slow acetylator phenotype (p=0.02). Furthermore, having five or more ‘at-risk’ genotypes was associated with higher bulky DNA adduct levels (p=0.03). Gene-diet interactions were also observed between the NAT1*10 allele and dietary HAAs (p&amp;lt;0.05); specifically, among the slow acetylator phenotype, higher intakes of dietary HAAs were associated with an increase in DNA adduct levels compared to lower intakes. Conclusions: This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. The lack of a strong independent association between dietary HAAs and DNA adducts suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this Canadian population; future studies should consider relevant gene-diet interactions to clarify the potential role of HAAs in carcinogenesis. Citation Format: Vikki Ho, Sarah Peacock, Thomas E. Massey, Roger W. L. Godschalk, Frederik-Jan van Schooten, Jian Chen, Will D. King. Exposure to heterocyclic aromatic amines, genetic susceptibility and bulky DNA adduct levels in blood leukocytes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A10.

Validity of a self-administered food frequency questionnaire in the estimation of heterocyclic aromatic amines.

Clarification of the putative etiologic role of heterocyclic aromatic amines (HAAs) in the development of cancer requires a validated assessment tool for dietary HAAs. This study primarily aimed to evaluate the validity of a food frequency questionnaire (FFQ) in estimating HAA intake, using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) level in human hair as the reference method. We first updated analytical methods of PhIP using liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-ESI/MS/MS) and measured 44 fur samples from nine rats from a feeding study as part-verification of the quantitative performance of LC-ESI/MS/MS. We next measured PhIP level in human hair samples from a validation study of the FFQ (n = 65). HAA intake from the FFQ was estimated using information on intake from six fish items and seven meat items and data on HAA content in each food item. Correlation coefficients between PhIP level in human hair and HAA intake from the FFQ were calculated. The animal feeding study of PhIP found a significant dose-response relationship between dosage and PhIP in rat fur. Mean level was 53.8 pg/g hair among subjects with values over the limit of detection (LOD) (n = 57). We found significant positive correlation coefficients between PhIP in human hair and HAA intake from the FFQ, with Spearman rank correlation coefficients of 0.35 for all subjects, 0.21 for subjects with over LOD values, and 0.34 for subjects with over limit of quantification. Findings from the validation study suggest that the FFQ is reasonably valid for the assessment of HAA intake.

Heterocyclic Aromatic Amine Contents of Kavurma Commercially Cooked in Steam and Copper Cauldron

Kavurma is a traditional coarsely diced and cooked meat product in Turkey. Heterocyclic aromatic amines (HCAs), carcinogenic and/or mutagenic compounds in commercial kavurma samples cooked in steam and copper cauldron were determined. Varying levels of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (up to 0.07 ng/g), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (up to 15.60 ng/g), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) (up to 0.10 ng/g), 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8-DiMeIQx) (up to 0.36 ng/g) were detected in commercially cooked kavurma, whereas 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC) were not detected in any of the analyzed samples. Total HCA amounts in kavurma cooked in steam and copper cauldron were 16.01 and 12.56 ng/g, respectively. Practical Applications Heterocyclic aromatic amines (HCAs) are compounds that are formed naturally during cooking of proteinaceous foods such as meat. Epidemiologic studies have shown that most HCAs are highly mutagenic and almost all of them are also carcinogenic. Therefore, determination of the HCA content in cooked meat is very important to estimation of daily HCAs intake and furthermore to evaluate the relationship between nutrition and cancer. In this respect, kavurma is a commonly consumed meat dish in Turkey and this study provides valuable data that will help estimation of daily HCA intake and exposure.

Effect of Thermal Treatments on the Formation of Heterocyclic Aromatic Amines in Various Meats

Heterocyclic aromatic amines (HAAs), the potential mutagens/carcinogens, are formed during cooking meat at higher temperature. The current study was designed to evaluate the effects of various cooking methods, i.e., pan frying, deep frying, charcoal grilling and roasting, on the formation of HAAs in three different types of meat, i.e., beef, chicken and mutton. Physicochemical analysis of thermally treated meat was carried out. Mineral profile such as Na, K, Fe, Cu, Zn and Mg was also determined. Two mutagenic HAAs, i.e., 1-methyl-9H-pyrido [4,3-b]indole (Harman) and 9H-pyrido-[4,3-b]indole (Norharman), were formed during cooking and extracted by solid phase extraction technique and analyzed by high-performance liquid chromatography using internal standards. The results showed that the amounts of Harman were higher than Norharman. Generally, the type and content of HAAs in cooked meat varies with cooking methods and conditions. Practical Applications Diet is one of the major factors that influence the tumor formation in humans. Epidemiologic and experimental evidence indicates that proteinaceous foods, especially meat cooked at higher temperatures, may lead to the formation of heterocyclic aromatic amines (HAAs). HAAs are the potential mutagens and contribute toward the carcinogenicity depending on many factors, including type of meat and cooking method. They vary in their chemical nature, mechanism of formation, amounts in different types of meat and meat products. They also show a variable range of metabolic behavior and carcinogenic potential. The exact identification of major risk factors, especially dietary carcinogens, could play a vital role in reducing cancer incidence and mortality. The present study was designed to investigate the influence of different cooking methods (pan frying, deep frying, charcoal grilling and roasting) on the formation of HAAs in various meats (chicken, beef and mutton). It is also evident from the results that the content of HAAs in cooked meat varied with cooking methods and cooking conditions, and data from this study could be used to assess the human intake of HAAs and also to identify conditions that minimize the formation and intake of HAAs.

Intake of heterocyclic aromatic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort

Heterocyclic amines (HCA) are positively associated with prostate cancer risk in animal models. Because of mostly inconsistent results of epidemiological studies, we examined the association between intake of HCA and prostate cancer risk. In the EPIC-Heidelberg cohort, detailed information on diet, anthropometry, and lifestyle was assessed between 1994 and 1998. Dietary HCA intake was estimated using information on meat consumption, cooking methods, and preferred degree of browning. During 104,195 person-years of follow-up, 337 incident cases of prostate cancer (123 advanced cases) were identified among 9,578 men with valid dietary information. Multivariate Cox proportional hazards regression was used to examine the association between intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and prostate cancer. Men in the highest quartiles of PhIP, MeIQx, and DiMeIQx intake, respectively, had no increased risk of prostate cancer compared with men in the lowest quartiles (HR=0.89, 95% CI 0.66-1.22 [PhIP]; 1.06, 0.77-1.45 [MeIQx]; 0.98, 0.72-1.34 [DiMeIQx]). There were no associations between HCA intake and advanced prostate cancer or between high consumption of strongly browned meat and prostate cancer. Our data do not support the hypothesis that HCA intake as consumed in a regular diet is a risk factor for prostate cancer.

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are two of the most common heterocyclic aromatic amines (HAA) produced during cooking of meat, fish and poultry. Both HAA produce different tumor profiles in rodents and are suspected to be carcinogenic in humans. In order to better understand the molecular basis of HAA toxicity, we have analyzed gene expression profiles in the metabolically competent human HepaRG cells using pangenomic oligonucleotide microarrays, after either a single (24-h) or a repeated (28-day) exposure to 10 μM PhIP or MeIQx. The most responsive genes to both HAA were downstream targets of the arylhydrocarbon receptor (AhR): CYP1A1 and CYP1A2 after both time points and CYP1B1 and ALDH3A1 after 28 days. Accordingly, CYP1A1/1A2 induction in HAA-treated HepaRG cells was prevented by chemical inhibition or small interference RNA-mediated down-regulation of the AhR. Consistently, HAA induced activity of the CYP1A1 promoter, which contains a consensus AhR-related xenobiotic-responsive element (XRE). In addition, several other genes exhibited both time-dependent and compound-specific expression changes with, however, a smaller magnitude than previously reported for the prototypical AhR target genes. These changes concerned genes mainly related to cell growth and proliferation, apoptosis, and cancer. In conclusion, these results identify the AhR gene battery as the preferential target of PhIP and MeIQx in HepaRG cells and further support the hypothesis that intake of HAA in diet might increase human cancer risk.

Abstract B105: Intake of heterocyclic aromatic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort

Abstract Background: Heterocyclic amines are mutagens formed in meat prepared at high temperatures. These compounds are associated with prostate cancer risk in animal models. Because of mostly inconsistent results of the published studies it was the aim of this study to examine the association between intake of heterocyclic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort study. Methods: Within the EPIC-Heidelberg cohort, detailed information on diet, anthropometry, and lifestyle was assessed between 1994 and 1998. Dietary HCA intake was assessed using information on amount of meat consumption, cooking methods, and degree of browing. After excluding men with prevalent cancer or with missing information on food preparation methods and preferred degree of browning our study population comprises a total of 9578 men (80.2% of the total cohort). Until July 31, 2009, 337 incident cases of prostate cancer have been identified. One-hundred twenty-three advanced prostate cancer cases, defined as Gleason sum score equal or higher than 7, TNM staging score of T3/T4, N1–N3, or M1 or prostate cancer as the underlying cause of death, were identified. Cox proportional hazards regression was used to examine the association between intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and prostate cancer risk taking into account age, smoking status, participation in prostate cancer screening, family history of prostate cancer, and intake of milk and milk products. Results: Men in the highest quartiles of PhIP, MeIQx, and DiMeIQx intake, respectively, did not have an increased risk of prostate cancer compared with men in the lowest quartiles (HR=0.89, 95% CI 0.66–1.22 [PhIP]; 1.06, 0.77–1.45 [MeIQx]; 0.98, 0.72–1.34 [DiMeIQx]). There were also no indications of positive associations between HCA intake and risk of advanced prostate cancer (HR=0.89, 95% CI 0.51–1.56 [PhIP]; 0.91, 0.53–1.57 [MeIQx];1.05, 0.61–1.82 [DiMeIQx]). Further adjustment for other potential confounders did not materially modify these associations. In addition to HCAs, we also observed no association between high consumption of strongly browned meat and prostate cancer. Conclusions: Previous epidemiological studies on the association between HCA intake and prostate cancer risk have led to inconclusive results. Our data do not support the hypothesis that HCA intake as consumed in a regular diet is a risk factor for prostate cancer. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B105.

Development of a quantitative food frequency questionnaire for assessing food, nutrient, and heterocyclic aromatic amines intake in Japanese Brazilians for a colorectal adenoma case–control study

Primary objective To develop of a quantitative food frequency questionnaire (QFFQ) to assess intake of specific foods, nutrients and heterocyclic aromatic amines (HAAs) in a case–control study of colorectal adenoma.Methods and procedures A cross-sectional survey conducted in a hospital in São Paulo, Brazil. A trained dietitian collected 24-h recalls from 60 Japanese Brazilian outpatients (29 men and 31 women; mean age 58 years and 57 years, respectively).Main outcomes and results Fruit, vegetable and legume intake was high, with mean daily servings consumed in men and women of 8.2 and 6.9, respectively. The QFFQ contains 161 food items presented in 15 food groupings, with particular emphasis paid to the HAA content of meat, fish and chicken items.Conclusions We have developed a QFFQ appropriate for Japanese Brazilians that will allow us to estimate HAA intake and will be used to examine our hypotheses related to foods, nutrients and HAAs, and diet–gene interactions in colorectal neoplasia in this population.

Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue

It was the aim of this study to examine the association of the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in the breast tissue of women undergoing reduction mammoplasty. Dietary intake of meat and HCA were assessed via questionnaire in 44 women undergoing reduction mammoplasty. DNA adduct analysis in breast tissue was performed by (32)P-postlabelling analysis. Spearman rank correlation coefficients (r) were calculated to examine the association of meat consumption and dietary HCA intake with tissue DNA adduct levels. A median DNA adduct level of 18.45 (interquartile range 12.81-25.65) per 10(9) nucleotides in breast tissue was observed; median HCA intake was 40.43 ng/day (interquartile range 19.55-102.33 ng/day). Total HCA intake (r = 0.33, P = 0.03), consumption of fried meat (r = 0.39, P = 0.01), beef (r = 0.32, P = 0.03) and processed meat (r = 0.51, P = 0.0004) were statistically significantly correlated with the level of DNA adducts in breast tissue. The detected DNA adducts could not be confirmed to be specific HCA-derived DNA adducts by comparison with external standards, using the (32)P-postlabelling assay. We observed strong correlations of dietary HCA intake and consumption of fried and processed meat with DNA adduct levels in breast tissue of 44 women. Since the detected DNA adducts were not necessarily specific only for HCA, it is possible that HCA intake is a surrogate of other genotoxic substances, such as polycyclic aromatic hydrocarbons, in meat prepared at high temperatures.

Metabolism and toxicology of heterocyclic aromatic amines when consumed in diet: Influence of the genetic susceptibility to develop human cancer. A review

There is not sufficient scientific evidence to support the hypothesis that human cancer risk is specifically due to the intake of heterocyclic aromatic amines (HAAs) in diet. Epidemiological evidence appears to imply two main factors in the HAAs carcinogenicity. These factors are the very high frequency of consumption of red meats, and very darkly browned meats from cooking, which are HAAs-containing foods. The present review focuses on the fact that the cancer risk is notably enhanced when certain genotypes related to HAAs metabolism are present. Thus, genetic predisposition seems to be the main factor in cancer development related to HAAs, and possibly the co-presence of other mutagenic compounds in diet.

Intake of heterocyclic aromatic amines from meat in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort

It was the aim of the present study to estimate the intake of heterocyclic aromatic amines (HCA) from meat, which have been associated with cancer risk in several epidemiological studies, of 21 462 subjects who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) in Heidelberg. This was accomplished by using a detailed dietary questionnaire that assessed meat consumption, cooking methods, and degree of browning of the respective food items. Median total HCA intake from meat was 31 ng/d (mean 69 ng/d), which was lower than results observed in previous studies. 2-Amino-1-methyl-6-phenylimidazo[4,5b]pyridine was the most common HCA in this cohort (median 17; mean 48 ng/d). The present study offers the opportunity of a detailed examination of the associations between meat cooking as well as HCA intake from meat and cancer risk in a prospective way.

Exposure to heterocyclic aromatic amines from the consumption of cooked red meat and its effect on human cancer risk: A review

This review covers the bibliographic data from the last 10 years on the possible carcinogenicity of heterocyclic aromatic amines (HAAs) in humans. Aspects such as red meat intake, cooking methods applied to red meat, and doneness of cooking are discussed from an epidemiological point of view. The role in the carcinogenicity of the HAAs has been assigned to two main factors: first, the very high frequency of consumption of red meat; and, second, very darkly browned meats from cooking. However, there are some uncertainties associated with epidemiological results such as the presence of other carcinogens, co-carcinogens and anti-carcinogens in the diet, analytical results on the content of HAAs in foods, food frequency questionnaires, and mainly genetic susceptibility to HAAs. It is concluded that there is not sufficient scientific evidence to support the hypothesis that human cancer risk is due specifically to the intake of HAAs in the diet.