多环芳烃与乳腺癌的相关性

随着交通工具及现代工业的发展,多环芳烃(PAHs)在空气中的含量逐步增加。乳腺癌作为一种女性常见的恶性肿瘤,发病率逐年上升。部分病因学研究表明,PAHs等环境污染物与乳腺癌存在一定的相关性。PAHs进入机体后,不仅能被代谢解毒,而且也可经代谢而被活化,形成致癌物质。笔者主要从PAHs的体内代谢、关键酶和代谢产物方面进行文献整理,并对当前PAHs与乳腺癌相关性的研究进行总结,进一步探讨PAHs在乳腺癌发病中的作用,以期为乳腺癌的预防和治疗提供新途径。     

Ambient air emissions of polycyclic aromatic hydrocarbons and female breast cancer incidence in US

To examine ambient air pollutants, specifically polycyclic aromatic hydrocarbons (PAHs), as a factor in the geographic variation of breast cancer incidence seen in the US, we conducted an ecological study involving counties throughout the US to examine breast cancer incidence in relation to PAH emissions in ambient air. Age-adjusted incidence rates of female breast cancer from the surveillance, epidemiology, and end results (SEER) program of the US National Cancer Institute were collected and analyzed using SEER*Stat 8.3.2. PAH emissions data were obtained from the Environmental Protection Agency. Linear regression analysis was performed using SPSS 23 software for Windows to analyze the association between PAH emissions and breast cancer incidence, adjusting for potential confounders. Age-adjusted incidence rates of female breast cancer were found being significantly higher in more industrialized metropolitan SEER regions over the years of 1973–2013 as compared to less industrialized regions. After adjusting for sex, race, education, socioeconomic status, obesity, and smoking prevalence, PAH emission density was found to be significantly associated with female breast cancer incidence, with the adjusted β of 0.424 (95% CI 0.278, 0.570; p?<?0.0001) for emissions from all sources and of 0.552 (95% CI 0.278, 0.826; p?<?0.0001) for emissions from traffic source. This study suggests that PAH exposure from ambient air could play a role in the increased breast cancer risk among women living in urban areas of the US. Further research could provide insight into breast cancer etiology and prevention.     

Association between polycyclic aromatic hydrocarbons and human rectal tumor or liver cancer

Objective

The aim of this study was to investigate the effect of polycyclic aromatic hydrocarbons (PAHs) in rectal carcinoma and hepatocarcinoma genesis.

Methods

The PAHs in the human rectal cancer and liver cancer tissues, the adjacent tissues and homologous tissues without rectal cancer or liver cancer were extracted by ultrasonic wave. The extracts were then cleaned up and enriched by solid phase extraction, analyzed by high performance liquid chromatography (HPLC) with fluorescence spectroscopy.

Results

Four kinds of PAHs were detected in human rectal and hepatic tissues. The contents of pyrene, 2-methylanthracene and benzo (a) pyrene in both rectal cancer tissues and adjacent homologous tissues were higher than rectal tissues without rectal cancer, the differences were statistically significant (P < 0.05). The contents of phenanthrene in the three kind of tissue were not significant (P > 0.05). The differences of the content of each PAHs between rectal cancer and adjacent tissue were not significant (P > 0.05). The contents of the four PAHs in the three kinds of liver tissues were not statistically significant (P > 0.05).

Conclusion

PAHs are found in human rectal tissues or hepatic tissues. The contents of PAHs in human rectal tissue may have an effect on the occurrence of human rectal cancer while the contents of PAHs in human hepatic tissues may have not ones.     

The detection and significance of polycyclic aromatic hydrocarbons in human pancreatic cancer

Objective  

The aim of this study was to investigate the effect of polycyclic aromatic hydrocarbons (PAHs) on the occurrence of human pancreatic cancer.     

Smoking increases carcinogenic polycyclic aromatic hydrocarbons in human lung tissue

Tobacco smoke is a major source of human exposure to polycyclic aromatic hydrocarbons (PAHs). The concentration of PAHs in lung tissue would reflect an individual's dose, and its variation could perhaps reflect cancer risk. Eleven PAHs were measured in 70 lung tissue samples from cancer-free autopsy donors by gas chromatography-mass spectrometry. There were 37 smokers and 33 nonsmokers as estimated by serum cotinine concentration. The sum of PAH concentrations was higher in smokers (P = 0.01), and there was a dose-response relationship for greater smoking (P < 0.01). Smoking increased the concentration of five PAHs including benzo(a)pyrene, which increased approximately 2-fold. The risk for increasing carcinogenic PAHs (odds ratio, 8.20; 95% confidence interval, 2.39-28.09) was 3-fold compared with noncarcinogenic PAHs (odds ratio, 2.61; 95% confidence interval, 0.75-9.12). A higher concentration of PAHs was detected in the lung tissue of males, although the estimated smoking was similar in males and females. Race was not associated with PAH concentrations overall, but PAH concentrations appeared to be higher in African-American males than in any other group. Age was weakly correlated with an increase in fluoranthene and pyrene. The measurement of PAHs in human lung tissue can be used to estimate the actual dose to the target organ.     

Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons

The association between occupational exposure to polycyclic aromatic hydrocarbons (PAH) and bladder cancer development was investigated in a population-based case-control study carried out in the Bormida valley, Italy. One hundred and twenty-one male cases and 342 male controls, matched age, were collected from local hospitals. Occupational exposure to PAH and aromatic amines (AA) was evaluated by means of a job exposure matrix, constructed specifically for this study. Subjects considered as sharing a "definite exposure to PAH" showed an increased risk even after adjustment for cigarette smoking and exposure to AA (OR = 2.14, 95% CL 0.82-5.60). No elevation in risk was found for the category "possible exposure to PAH" (OR = 1.05, 95% CL 0.45-2.44). The findings of this study are consistent with previous studies indicating PAH as a risk factor for bladder cancer. A possible residual confounding effect due to AA impurities is discussed.     

多环芳烃水平与人类直肠癌发生相关性的研究

目的:探讨多环芳烃(PAHs)在人类直肠癌发生过程中的作用。方法:直肠癌组织、癌旁组织和非直肠癌患者的直肠组织中的PAHs分别经超声提取,固相萃取净化和高效液相色谱荧光分析。结果:3组标本中共检出4种PAHs,分别是菲、芘、2-甲基蒽和苯并(a)芘。其中芘、2-甲基蒽和苯并(a)芘在直肠癌组织和癌旁组织中的含量均高于非直肠癌患者的直肠组织,差异有统计学意义,P<0.05;菲在3组标本中的含量差异无统计学意义,P>0.05;4种PAHs在直肠癌组织与癌旁组织中的含量差异均无统计学意义,P>0.05。结论:人类直肠组织中存在PAHs;人类直肠组织中PAHs的含量与直肠癌的发生有一定的相关性。     

乳腺癌患者术前外周血ＶＥＧＦ-Ａ与术后癌组织ＭＶＤ的相关性研究

目的：探讨乳腺癌患者术前外周血中血管内皮生长因子-Ａ（ＶＥＧＦ-Ａ）、术后肿瘤组织微血管密度（ＭＶＤ）的水平及其与临床病理学特征的关系,分析两者与肿瘤血管生成的关系。方法：采用ＥＬＩＳＡ法检测术前外周血ＶＥＧＦ-Ａ水平,免疫组化ＳＰ法检测乳腺癌术后肿瘤组织ＣＤ３４的表达,并计数肿瘤组织ＭＶＤ,进行对比分析。结果：乳腺癌患者术前外周血ＶＥＧＦ-Ａ水平为（２９２.２０±８９.００）ｐｇ／ｍｌ,显著高于乳腺良性病患者的（１０２.７０±３１.０４）ｐｇ／ｍｌ和正常健康女性的（９４.８５±２５.７２）ｐｇ／ｍｌ,且与临床分期（Ｐ＜０.０５）、淋巴结转移（Ｐ＝０.０２１）有关;ＣＤ３４染色显示乳腺癌组织中有大量的新生血管形成,同时ＭＶＤ阳性的乳腺癌患者术前外周血ＶＥＧＦ-Ａ水平为（３１６.６８±６１.５１）ｐｇ／ｍｌ,显著高于ＭＶＤ阴性患者的（２３２.０９±７１.８３）ｐｇ／ｍｌ（Ｐ＝０.０２７）。结论：乳腺癌患者术前外周血ＶＥＧＦ-Ａ显著升高,术前外周血ＶＥＧＦ-Ａ水平与术后肿瘤组织ＭＶＤ密切相关。     

The association between glutathione S-transferase M1 genotype and polycyclic aromatic hydrocarbon-DNA adducts in breast tissue.

A major goal in molecular epidemiology is to identify preventable environmental risk factors and susceptible subpopulations. In a hospital-based molecular epidemiological case-control study of breast cancer, we investigated the relationship between DNA damage from exposure to polycyclic aromatic hydrocarbons (PAHs) and susceptibility attributable to inherited deletion of the xenobiotic detoxifying gene, glutathione S-transferase M1 (GSTM1). Prior to breast surgery, women (n = 227) were enrolled and interviewed and donated a blood sample. PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples retrieved from pathology blocks, and GSTM1 genotype was determined by PCR using WBC DNA. The GSTM1 analysis included 95 cases and 87 benign breast disease controls. GSTM1 genotype was not associated with breast cancer case-control status (odds ratio = 0.73; 95% confidence interval, 0.37-1.44). However, the GSTM1 null genotype predicted PAH-DNA adduct levels in malignant (beta = 0.407; P = 0.003) and nonmalignant (beta = 0.243; P = 0.05) breast tissue from cases. This relationship was not seen in tissue from controls (beta = 0.095; P = 0.341). When tissue from controls was compared with tumor tissue from cases, there was a significant case-control difference in PAH-DNA adduct levels among women who were GSTM1 null. There was no such case-control difference among women who were homozygous or heterozygous for GSTM1. There was an interaction between GSTM1 and case-control status on adduct levels in breast tissue (P = 0.002). The results suggest that genetic susceptibility to the formation of PAH-DNA adducts in breast tissue may play a role in breast cancer development.     

The metabolism and activation of polycyclic aromatic hydrocarbons in epithelial cell aggregates and fibroblasts prepared from rat mammary tissue

The metabolism of 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene(BP) and benz[a]anthracene (BA) by epithelial cell aggregatesand fibroblasts in culture has been investigated using mammarytissue obtained from female Wistar rats. The results show that:(a) both types of mammary cells metabolise all three hydrocarbonsinto ether- and water-soluble derivatives; (b) the patternsof metabolites produced by epithelial cells and fibroblastsare similar but that fibroblasts form more of the water-solublematerials; (c) the major dihydrodiols formed are the 8,9-dihydrodiolsof BA and DMBA and the 7,8- and 9,10-dihydrodiols of BP; (d)all three hydrocarbons are metabolised to form products thatbind covalently to protein but only the potent carcinogens BPand DMBA are metabolised to form derivatives that react covalentlywith DNA; and (e) the chromatographic profiles of the hydrocarbon- deoxyribonudeoside adducts formed in epithelial cells treatedwith either BP or DMBA are similar to those obtained in analogousexperiments with fibroblasts.     

Human breast cell-mediated mutagenesis of mammalian cells by polycyclic aromatic hydrocarbons

A system has been developed in which human breast cells activate chemical procarcinogens to mutagenic compounds. The degree of activation is quantitated by the estimation of induction of 6-thioguanine-resistant specific locus mutants in a cocultured Chinese hamster V-79 cell population which does not activate carcinogens. Both mammary stromal and parenchymal cells could activate the procarcinogen 7,12-dimethylbenz(a)anthracene. In addition, it is shown that the two mammary cell populations converted both 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene to water-soluble metabolites. The stromal cells produced substantial amounts of glucuronic acid conjugates, but the parenchymal cells did not. Both cell types metabolize benzo(a)pyrene to the organic-soluble metabolites 9,10- and 7,8-dihydrodiol and both 9- and 3-hydroxybenzo(a)pyrene. These results suggest that the human breast may be a target for polycyclic aromatic hydrocarbon carcinogenesis.     

Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in combustion products of organic matter, including cigarette smoke. Metabolically activated diol epoxides of these compounds, including benzo[a]pyrene diol epoxide (B[a]PDE), have been suggested as causative agents in the development of lung cancer. We previously mapped the distribution of B[a]PDE adducts within the p53 tumor suppressor gene (also known as TP53), which is mutated in 60% of human lung cancers, and found that B[a]PDE adducts preferentially form at lung cancer mutational hotspots (codons 154, 157, 158, 245, 248, and 273). Other PAHs may be important in lung cancer as well. METHODS: Here we have mapped the distribution of adducts induced by diol epoxides of additional PAHs: chrysene (CDE), 5-methylchrysene (5-MCDE), 6-methylchrysene (6-MCDE), benzo[c]phenanthrene (B[c]PDE), and benzo[g]chrysene (B[g]CDE) within exons 5, 7, and 8 of the p53 gene in human bronchial epithelial cells. RESULTS: CDE exposure produced only low levels of adducts. Exposure of cells to the other activated PAHs resulted in DNA damage patterns similar to those previously observed with B[a]PDE but with some distinct differences. 5-MCDE, 6-MCDE, B[g]CDE, and B[c]PDE efficiently induced adducts at guanines within codons 154, 156, 157, 158, and 159 of exon 5, codons 237, 245 and 248 of exon 7, and codon 273 of exon 8, but the relative levels of adducts at each site varied for each compound. B[g]CDE, B[c]PDE, and 5-MCDE induced damage at codon 158 more selectively than 6-MCDE or B[a]PDE. The sites most strongly involved in PAH adduct formation were also the sites of highest mutation frequency (codons 157, 158, 245, 248, and 273). CONCLUSION: The data suggest that PAHs contribute to the mutational spectrum in human lung cancer.     

Occupation, exposure to polycyclic aromatic hydrocarbons and laryngeal cancer risk

Primary risk factors for laryngeal cancer are smoking and alcohol. The relevance of occupational exposures in the etiology of laryngeal cancer is not yet clarified. Some studies have suggested various occupational agents as additional causal risk factors. A population-based case-control study 1:3 frequency matched by age and gender on laryngeal cancer was carried out in southwest Germany with 257 cases (236 males and 21 females between the ages of 37-80, histologically confirmed and diagnosed between January 5, 1998 and December 31, 2000) and 769 population controls (702 males, 67 females). Occupational exposures and other risk factors were obtained with face-to-face interviews using a detailed standardized questionnaire. The complete individual work history was assessed. A detailed assessment of work conditions was obtained by job-specific questionnaires for selected jobs known to be associated with exposure to potential carcinogens. A specific substance list was used as second method for exposure assessment. Blood samples were taken from all individuals for genotype analysis. A strong effect of polycyclic aromatic hydrocarbons exposure on laryngeal cancer risk after adjustment for smoking and alcohol (odds ratio [OR] = 5.2, 95% confidence interval [CI] = 1.6-17.1) was observed for concordant exposure classified with both methods, and a clear dose-response (p < 0.01 for linear trend) for exposure duration. Our findings are supported by risks associated with occupational groups in which this exposure is a priori considered likely. A differential effect by glutathione-S-transferases-M1 genotype was found, however, small numbers do not allow firm conclusions on effect modification. Our study contributes to classifying polycyclic aromatic hydrocarbons as a risk factor for laryngeal cancer.     

Immunohistochemical analysis of polycyclic aromatic hydrocarbon-DNA adducts in breast tumor tissue

Environmental carcinogens may play a role in the etiology of breast cancer, but the extent of their contribution is not yet defined. The aims of this study were to determine whether polycyclic aromatic hydrocarbon (PAH)-DNA adducts could be detected in stored paraffin blocks of breast tumor tissue (n=147) with an immunoperoxidase technique and whether they correlated with smoking history and/or mutant p53 protein expression. There was no significant difference in mean relative nuclear staining intensity in non-smokers (444+/-90, n=75), ever smokers (435+/-91, n=72), and current smokers (456+/-98, n=35). In either current or ever smokers, PAH-DNA adducts were non-significantly elevated in those with greater compared with lower exposure in relation to age at started smoking, years of smoking, cigarettes per day, and pack years. DNA damage levels were not elevated in tissues with compared with those without mutant p53 protein expression. These data demonstrate that immunohistochemical methods can be used to monitor DNA damage levels in archived breast tissues.     

Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons

Epidemiologic evidence on the relationship between polycyclic aromatic hydrocarbons (PAH) and cancer is reviewed. High occupational exposure to PAHs occurs in several industries and occupations. Covered here are aluminum production, coal gasification, coke production, iron and steel foundries, tar distillation, shale oil extraction, wood impregnation, roofing, road paving, carbon black production, carbon electrode production, chimney sweeping, and calcium carbide production. In addition, workers exposed to diesel engine exhaust in the transport industry and in related occupations are exposed to PAHs and nitro-PAHs. Heavy exposure to PAHs entails a substantial risk of lung, skin, and bladder cancer, which is not likely to be due to other carcinogenic exposures present in the same industries. The lung seems to be the major target organ of PAH carcinogenicity and increased risk is present in most of the industries and occupations listed above. An increased risk of skin cancer follows high dermal exposure. An increase in bladder cancer risk is found mainly in industries with high exposure to PAHs from coal tars and pitches. Increased risks have been reported for other organs, namely the larynx and the kidney; the available evidence, however, is inconclusive. The results of studies addressing environmental PAH exposure are consistent with these conclusions.     

The presence of aflatoxin and some polycyclic aromatic hydrocarbons in human foods

An analysis of several common food items (fish, meat, crops and spices) as sold in the Nigerian markets has shown the presence of (a) benzo[a]pyrene and benz[a]anthracene in fish and meat samples, and (b) aflatoxin in crops and spices. These results are discussed in relation to the relatively high incidence of cancer in tropical Africa.     

Immunoperoxidase detection of polycyclic aromatic hydrocarbon-DNA adducts in breast tissue sections.

Although the etiology of the majority of human breast cancers is unknown, environmental carcinogens are suspected to play a role. In this study, we investigated polycyclic aromatic hydrocarbon-DNA adducts in 78 breast cancer patients and benign breast disease patients with lifetime environmental exposure to polycyclic aromatic hydrocarbon (PAH) compounds. Adducts were detected in paraffin sections by immunoperoxidase method using polyclonal antiserum and were quantitated by the image-analyzing system. A significantly higher level of adducts was found in benign breast disease as compared to cancer patients (P < .001; Mann-Whitney U test). Neither smoking nor genetic polymorphisms in glutathione S-transferase and cytochrome P450 influenced the level of adducts. This exploratory study demonstrates the usefulness of the immunoperoxidase method to detect PAH-DNA adducts in stored breast tissue and suggests further research on a larger population, including patients from both high- and low-pollution environments.     

趋化因子与乳腺癌

趋化因子参与乳腺癌细胞的生长、血管生成及远处转移过程。然而,近年来单靶点趋化因子受体拮抗剂的临床试验多以失败告终,彰显了肿瘤微环境中趋化因子网络的复杂性,因此基于多向药理学原理确立多靶点调控策略势在必行。多靶点非典型性趋化因子受体(ACR)作为内源性和生理性的调节分子,有可能成为捕获高表达的多种促肿瘤性趋化因子、有效控制乳腺癌的利器。