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Population aging is one of the most important demographic transformations of our time. Increasing the "health span"-the proportion of life spent in good health-is a global priority. Biological aging comprises molecular and cellular modifications over many years, which culminate in gradual physiological decline across multiple organ systems and predispose to age-related illnesses. Cardiovascular disease is a major cause of ill health and premature death in older people. The rate at which biological aging occurs varies across individuals of the same age and is influenced by a wide range of genetic and environmental exposures. The authors review the hallmarks of biological cardiovascular aging and their capture using imaging and other noninvasive techniques and examine how this information may be used to understand aging trajectories, with the aim of guiding individual- and population-level interventions to promote healthy aging., Competing Interests: Funding Support and Author Disclosures Dr Raisi-Estabragh recognizes the National Institute for Health and Care Research Integrated Academic Training Programme, which supports her academic clinical lectureship post. Dr Szabo has received support from the Barts Charity (G-002389). Dr Schuermans has received support from the Belgian American Educational Foundation. Dr Vágó was supported by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund (Project no. TKP2021-NKTA- 46). Dr Ng was supported by the British Heart Foundation. Dr Pavanello has received support of “PE8 Ageing Well in an Ageing Society—AGE-IT,” funded by the European Union—Next Generation EU–NRRP M6C2—Investment 2.1 Enhancement and Strengthening of Biomedical Research in the NHS. Dr Marwick has received funding by an investigator grant (2008129) from the National Health and Medical Research Council of Australia. Dr Petersen acknowledges the SmartHeart Engineering and Physical Sciences Research Council program grant (EP/P001009/1); and provides consultancy to Cardiovascular Imaging. Drs Petersen and Szabo have received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 825903 (euCanSHare project). The authors acknowledge the support of the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330), a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St. George’s University Hospitals NHS Foundation Trust, and St. George’s University of London. Drs Salih and Petersen acknowledge support from the Barts Charity (G-002523) and the British Heart Foundation (PG/21/10619). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Several toxicological and epidemiological studies were published during the last five decades on non-sugar sweeteners (NSS) and cancer. Despite the large amount of research, the issue still continues to be of interest. In this review, we provided a comprehensive quantitative review of the toxicological and epidemiological evidence on the possible relation between NSS and cancer. The toxicological section includes the evaluation of genotoxicity and carcinogenicity data for acesulfame K, advantame, aspartame, cyclamates, saccharin, steviol glycosides and sucralose. The epidemiological section includes the results of a systematic search of cohort and case-control studies. The majority of the 22 cohort studies and 46 case-control studies showed no associations. Some risks for bladder, pancreas and hematopoietic cancers found in a few studies were not confirmed in other studies. Based on the review of both the experimental data on genotoxicity or carcinogenicity of the specific NSS evaluated, and the epidemiological studies it can be concluded that there is no evidence of cancer risk associated to NSS consumption., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Melete srl provided financial support through a grant form ISA (International Sweeteners Association). The conclusions are those of the authors; the sponsors did not have any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes., Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span., Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity., Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed., Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

Background: Continuous exposure to particulate air pollution (PM) is a serious worldwide threat to public health as it coherently links with increased morbidity and mortality of cardiorespiratory diseases (CRD), and of type 2 diabetes (T2D). Extracellular vesicles (EVs) are circular plasma membrane fragments released from human cells that transfer microRNAs between tissues. In the present work it was explored the hypothesis that EVs with their encapsulated microRNAs (EVmiRNAs) contents might mediate PM effects by triggering key pathways in CRD and T2D., Methods: Expression of EVmiRNAs analyzed by real-time PCR was correlated with oxidative stress, coagulation and inflammation markers, from healthy steel plant workers (n=55) with a well-characterized exposure to PM and PM-associated metals. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways regulated by PM-associated EVmiRNAs., Results: Increased expression in 17 EVmiRNAs is associated with PM and metal exposure (p<0.01). Mir-196b that tops the list, being related to 9 different metals, is fundamental in insulin biosynthesis, however three (miR-302b, miR-200c, miR-30d) out of these 17 EVmiRNAs are in turn also related to disruptions (p<0.01) in inflammatory and coagulation markers., Conclusions: The study's findings support the hypothesis that adverse cardiovascular and metabolic effects stemming from inhalation exposures in particular to PM metallic component may be mediated by EVmiRNAs that target key factors in the inflammation, coagulation and glucose homeostasis pathways., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Cytochrome P4501A2 (CYP1A2) is a key enzyme for lung carcinogen activation and lung inflammation. We studied the interactions of the CYP1A2 functional variants -3860G/A(rs2069514),-2467T/delT(rs3569413),-163C/A(rs762551)] with occupational/environmental carcinogenic exposures in the development of lung cancer in a case-control study nested in the Danish prospective cohort "Diet, Cancer and Health." At enrollment (1993-1997), blood samples for genotype analyses and information on lifestyle were collected 5 (mean value) years before the onset of the disease. The study population included 425 lung cancer cases and 786 subcohort members, who were gender- and age-matched. We found that -163A carriers were at increased risk of lung cancer (P=0.035) in a multivariate COX regression model, which was adjusted for personal habits (i.e., cumulative smoking, passive smoke at home, alcohol intake, and fruit intake) and occupational exposure. Additionally, the interaction between -2467delT and smoking increases lung cancer risk in males, especially light smokers (<21.5 pack-years, P=0.004). The increased lung cancer risk found in -163C carriers, independent of smoking status, and in -2467delT male smokers, suggests that these variants could influence lung cancer development through different mechanisms (i.e. lung carcinogen activation and lung inflammation)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim of the study was the assessment of exposure of coke-oven workers to polycyclic aromatic hydrocarbons (PAHs) by determination of urinary profiles of hydroxylated and unmetabolized PAHs. Fifty-five Polish coke-oven workers were investigated by measurement of 12 hydroxylated metabolites of PAHs (OHPAHs) (1-, 2-hydroxynaphthalene; 2-, 9-hydroxyfluorene; 1-, 2-, 3-, 4-, 9-hydroxyphenanthrene; 1-hydroxyypyrene, 6-hydroxychrysene and 3-hydroxybenzo[a]pyrene) and 13 unmetabolized PAHs (U-PAHs) (from naphthalene to benzo[a]pyrene), in spot urine samples collected at the end of the workshift. U-PAHs with four or less rings were detected in all samples. In particular, median levels for urinary naphthalene, phenanthrene, pyrene, chrysene and benz[a]anthracene were 0.806, 0.721, 0.020, 0.032 and 0.035 microg/L. OHPAHs up to 1-hydroxypyrene were found in all samples, while high molecular-weight OHPAHs were always below quantification limit. Median level of 1-hydroxyypyrene was 15.4 microg/L. In all subjects significant correlations between OHPAHs and U-PAHs were observed (0.27 < r < 0.70, p < 0.01). Our results suggest that both hydroxylated metabolites and unmetabolized PAHs in urine are useful biomarkers of exposure to PAHs. Moreover, the simultaneous determination of several biomarkers permits to obtain specific excretion profiles that might help in exposure characterization and in better defining the excretion patterns.

Aims: In this study, the effects of four single nucleotide polymorphisms (SNPs), -3860G>A, -2467delT, -739T>G and -163C>A, of CYP1A2 gene on lung cancer were evaluated in Tunisian population., Main Methods: Four polymorphisms of CYP1A2 gene were analysed in 109 healthy smokers and in 101 lung cancer cases, including 63 with squamous cell carcinoma (SCC) and 41 with adenocarcinoma (AD). The genotyping for the SNPs -3860 G>A, -2467delT, -739T>G and -163C>A was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis., Key Findings: The results showed that smokers with CYP1A2 gene polymorphisms were associated with an increased risk for the development of lung AD. There was however no significant increased risk of developing lung SCC in smokers having CYP1A2 gene polymorphisms. An increased risk of developing AD was observed in smokers who are carriers of at least one copy of -3680A or -739G giving a significant odds ratio (OR) of 6.02 (CI=2.91-12.9) and 3.01 (CI=1.54-5.98), respectively., Significance: These genotyping data are consistent with the hypothesis that tobacco-specific-N-nitrosamines (TSN) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major contributors to the development of lung AD and that CYP1A2 gene product plays an important role in the metabolic activation of NNK. This study suggests that SNPs of CYP1A2 could be considered as promising biomarkers in the aetiology of lung AD in smokers.

The influence of low-activity NER genotypes (XPC PAT-/+, XPA-A23G, XPD Asp312Asn, XPD Lys751Gln) and GSTM1 (active or null) was evaluated on anti-benzo[a]pyrene diol epoxide-(B[a]PDE)-DNA adduct formed in the lymphocyte plus monocyte fraction (LMF). The sample population consisted of 291 healthy subjects with low exposure to polycyclic aromatic hydrocarbons (PAHs) (B[a]P) through their smoking (n=126 smokers) or dietary habits (n=165 non-smokers with high (>or=52 times/year) consumption of charcoaled meat or pizza). The bulky anti-B[a]PDE-DNA adduct levels were detected by HPLC/fluorescence analysis and genotypes by PCR. Anti-B[a]PDE-DNA was present (>or=0.5 adducts/10(8) nucleotides) in 163 (56%) subjects (median (range) 0.77 (0.125-32.0) adducts/10(8) nucleotides), with smokers showing a significantly higher adduct level than non-smokers with high consumption of PAH-rich meals (P<0.01). Our exposed-sample population with unfavourable XPC PAT+/- or +/+ and GSTM1 null genotypes has the significantly highest adduct level (P<0.01). Taking into account tobacco smoke and diet as sources of exposure to B[a]P, low-activity XPC PAT+ shows a major role in smokers (P<0.05) and GSTM1 null in non-smokers with frequent consumption of PAH-rich meals (P<0.01). The modulation of anti-B[a]PDE-DNA adduct in the LMF by GSTM1 null and low-activity XPC PAT+ polymorphisms may be considered as potential genetic susceptibility factors that can modify individual responses to low PAH (B[a]P) genotoxic exposure, with the consequent risk of cancer in the general population.

We evaluated determinants of anti-benzo[a]pyrenediolepoxide-(B[a]PDE)-DNA adduct formation (adduct induced by the ultimate carcinogenic metabolite of B[a]P) in lymphomonocytes of subjects environmentally exposed to low doses of polycyclic aromatic hydrocarbons (PAHs) (B[a]P). Our study population consisted of 585 Caucasian subjects, all municipal workers living in North-East Italy and recruited during their periodic check-ups after informed consent. PAH (B[a]P) exposure was assessed by questionnaire. Anti-B[a]PDE-DNA levels were measured by HPLC fluorescence analysis. We found that cigarette smoking (smokers (22%) versus non-smokers, p<0.0001), dietary intake of PAH-rich meals (> or =52 (38%) versus <52 times/year, p<0.0001), and outdoor exposure (> or =4 (19%) versus <4h/day; p=0.0115) significantly influenced adduct levels. Indoor exposure significantly increased the frequency of positive subjects (> or =0.5 adducts/10(8) nucleotides; chi(2) for linear trend, p=0.051). In linear multiple regression analysis the major determinants of increased DNA adduct levels (ln values) were smoking (t=6.362, p<0.0001) and diet (t=4.035, p<0.0001). In this statistical analysis, indoor and outdoor exposure like other factors of PAH exposure had no influence. In non-smokers, the influence of diet (p<0.0001) and high indoor exposure (p=0.016) on anti-B[a]PDE-DNA adduct formation became more evident, but not that of outdoor exposure, as was confirmed by linear multiple regression analysis (diet, t=3.997, p<0.0001 and high indoor exposure, t=2.522, p=0.012). This study indicates that anti-B[a]PDE-DNA adducts can be detected in the general population and are modulated by PAH (B[a]P) exposure not only with smoking - information already known from studies with limited number of subjects - but also with dietary habits and high indoor exposure. In non-smokers, these two factors are the principal determinants of DNA adduct formation. The information provided here seems to be important, since DNA adduct formation in surrogate tissue is an index of genotoxic exposure also in target organs (e.g., lung) and their increase may also be predictive of higher risk for PAH-related cancers.

The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined. The influence of three polymorphisms of the cytochrome P450 1A2 gene (CYP1A2) (-3860 G-->A (allele *1C), -2467 T-->delT (allele *1D), -163C-->A (allele *1F)), located in the 5'-noncoding promoter region of the gene, on CYP1A2 activity (measured as caffeine metabolic ratio, CMR), was studied in Caucasian current smokers (n=95). Tobacco smoke intake was calculated from the number of cigarettes/day. Also, studied was the influence of these CYP1A2 genotypes on smoking-associated urinary mutagenicity, detected in Salmonella typhimurium strain YG1024 with S9 mix, considering the urinary excretion of nicotine plus its metabolites as an internal indicator of tobacco smoke exposure. Smokers with at least one of the variant alleles CYP1A2 -3860A and -2467 delT showed a significantly increased CYP1A2 CMR (-3860 G/A versus G/G, p<0.05; -2467 delT/delT versus T/delT and T/T, p<0.01). Multiple regression analysis showed that the increase in CYP1A2 CMR (ln values) was again significantly related to the presence of CYP1A2 variants -2467delT and also to variant -163A (p<0.05), but moderately to -3860A (p=0.084). No influence of the number of cigarettes smoked per day by each subject was found. Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in smokers, -2467 T-->delT having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility factors in exposure to carcinogens.

We examined the urinary mutagenicity in the YG1024 Salmonella typhimurium strain in the presence of S9 mix, of 31 male non-smoking coke oven workers and an equal number of controls matched for gender and dietary habits. Occupational PAH exposure to the workers was assessed by means of the individual urinary post-shift excretion of 1-pyrenol (mean +/- S.D.: 5.41 +/- 6.06 micromole/mol creatinine). Eleven urinary extracts of workers (35.5%) were clearly mutagenic (with at least a doubling of the number of spontaneous revertants), against only two samples in the control group (6.5%) (chi2-test; chi2 = 7.883; P < 0.01). Moreover, the mean mutagenic activity level corrected for dilution/concentration of the urine was about three times higher in coke oven workers than in matched controls (mean +/- S.D. (range) 495 +/- 407 (89.7-1603) versus 186 +/- 113 (14.2-524) net revertants/mmol creatinine; Mann-Whitney U-test, z = 3.86, P < 0.001). Simple linear regression analysis showed that the coke workers' urinary mutagenic activity is associated with the PAH occupation-related urinary excretion of 1-pyrenol (r = 0.41, P = 0.0215). This study definitely demonstrates an occupation-related exposure of coke oven workers' bladder epithelium to mutagenic PAH metabolites. This factor, mainly in the case of high exposure studied here, may account for a higher bladder cancer risk in coke oven workers.

The influence of the genetic deletion polymorphism of glutathione S-transferase micro 1 (GSTM1 *0/*0) on levels of anti (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-DNA) adduct in the peripheral blood lymphocyte plus monocyte fraction (LMF) of coke-oven workers was investigated. A total of 95 male Polish coke-oven workers (60% current smokers) from two different plants comprised the sample population. Polycyclic aromatic hydrocarbons (PAH) exposure was assessed by means of the individual post-shift urinary excretion of 1-pyrenol (mean +/- S.D.: 6.93 +/- 7.20 micromol/mol creatinine; 70% of the subjects exceeded the proposed biological exposure index (BEI) 2.28 micromol/mol creatinine). Anti-BPDE-DNA adduct levels were detected by high performance liquid chromatography (HPLC)/fluorescence analysis of the anti-BPDE tetrol I-1 released after acid hydrolysis of DNA samples. Genotypes were determined by polymerase chain reaction (PCR) on the genomic DNA of each subject. Coke-oven workers without active GSTM1 (GSTM1 *0/*0, 33%) had significantly higher adduct levels than those with active GSTM1 (GSTM1*1/*1 and *1/*0) (5.90 +/- 5.59 versus 3.25 +/- 2.01 adducts/10(8) bases, Mann-Whitney U-test, z = 2.53, P = 0.011), PAH exposure in the two subgroups being similar (7.06 +/- 6.83 versus 6.67 +/- 8.00 1-pyrenol micromol/mol creatinine). The highest number of GSTM1 null subjects (12/23, 39%) belonged to the quartile with the highest adduct levels (i.e., >4.67 adducts/10(8) nucleotides). That is, coke-oven workers with GSTM1 *0/*0 genotype had a significantly higher risk of having high adduct levels than individuals with active GSTM1 genotype (Fisher exact test P = 0.0355; odds ratio (OR) = 4.145, 95% CI 1.0-18.8). Multiple linear regression analysis showed that the increase in anti-BPDE-DNA adduct levels in LMF was significantly related to the high occupational exposure to PAHs (benzo[a]pyrene (BaP)) of coke-oven workers (t = 3.087, P < 0.01) and to the lack of GSTM1 activity (t = 3.512, P < 0.001), rather than to the two other confounding factors of PAH intake, i.e. charcoal-broiled meat consumption and smoking habits. In conclusion, our results indicate the clear influence of the GSTM1 detoxifying genotype on anti-BPDE-DNA adduct formation in the LMF of coke-oven workers. This is invaluable for future environmental-occupational studies using this biomarker of PAH exposure.

In this study, the correlation of indicators of external (i.e. mean daily intake of condensate, nicotine, tobacco and tobacco proteins, and daily number of cigarettes smoked) and of internal tobacco-smoke exposure (i.e. urinary 1-pyrenol, nicotine and its metabolites and trans,trans-muconic acid) with urinary mutagenicity, detected on YG1024 Salmonella typhimurium strain with S9, were examined in 118 smokers. An increase in urinary mutagenicity was clearly significantly correlated with each external and internal indicators of exposure to tobacco smoke (correlation coefficient (r) ranging between 0.22 and 0.54, P<0.01), with a greater extent in the case of indicators of internal dose. In multiple regression analysis, among the indicators of external exposure, daily tobacco intake was the only variable significantly associated with urinary mutagenicity (t=2.47, P=0.015, with partial contribution to r(2)=5.15%). Instead, when all indicators of exposure (external and internal) were considered in the analysis, the influence of urinary 1-pyrenol on urinary mutagenicity was predominant, followed by those of urinary trans,trans-muconic acid and nicotine plus metabolites (t=4.63, 2.73 and 2.08, P<0.001, P=0.002 and 0.04, with partial contribution to r(2)=17.0, 6.66 and 3.96%, respectively), with no influence at all of external tobacco-smoke exposure indicators. In conclusion, our results show that indicators of internal dose are better correlated with formation of mutagens in urine of smokers. Among these, the best indicator was urinary 1-pyrenol and this result designates the combustion processes of tobacco as the determining step for the formation of urinary mutagens. However, as these biomarkers cannot be analysed the amount of daily tobacco intake represent the best valuable index of external (presumptive) exposure to tobacco-smoke genotoxins.

International scientific publications on the influence of metabolic genotypes on biological indicators of genotoxic risk in environmental or occupational exposure are reviewed. Biomarkers of exposure (substance or its metabolites in biological fluids, urinary mutagenicity, protein and DNA adducts) and of effects (chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (Mn), COMET assay, HPRT mutants) have been evaluated according to different genotypes (or phenotypes) of several activating/detoxifying metabolic activities. In less than half the studies (43 out of 95), the influence of genotype on the examined biological indicator was found, of which four report poorly reliable results (i.e., with scarce biological plausibility, because of the inconsistency of modulated effect with the type of enzymatic activity expressed). As regards urinary metabolites, the excretion of mercapturic acids (MA) is greater in subjects with high GST activity, that of 1-pyrenol and other PAH metabolites turns out to be significantly influenced by genotypes CYP1A1 or GSTM1 null, and that of exposure indicators to aromatic amines (AA) (acetylated and non-acetylated metabolites) is modulated by NAT2. In benzene exposure, preliminary results suggest an increase in urinary t, t-muconic acid (t,t-MA) in subjects with some genotypes. On urinary mutagenicity of PAH-exposed subjects, the effects of genotype GSTM1 null, alone or combined with NAT2 slow are reported. When DNA adduct levels are clearly increased in PAH-exposed group (18 out of 22), 7 out of 18 studies report the influence of GSTM1 null on this biomarker, and of the five studies which also examined genotype CYP1A1, four report the influence of genotype CYP1A1, alone or in combination with GSTM1 null. A total of 25 out of 41 publications (61%) evaluating the influence of metabolic polymorphisms on biomarkers of effect (cytogenetic markers, COMET assay, HPRT mutants) do not record any increase in the indicator due to exposure to the genotoxic agents studied, confirming the scarce sensitivity of these indicators (mainly HPRT mutants, Mn, COMET assay) for assessing environmental or occupational exposure to genotoxic substances. Concluding, in determining urinary metabolites for monitoring exposure to genotoxic substances, there is sufficient evidence that genetically-based metabolic polymorphisms must be taken into account in the future. The unfavourable association for the activating/detoxifying metabolism of PAH is also confirmed as a risk factor due to the formation of PAH-DNA adducts. The clearly protective role played by GSTT1 on DEB (and/or related compound)-induced sister chromatid exchanges (SCEs) should be noted. The modulating effects of genotypes on protein adduct levels in environmental and occupational exposure have not yet been documented, and most studies on the influence of genotype on biological indicators of early genotoxic effects report negative results.

Fifteen hospitalized, non-smoking, dermatological patients were treated with ointment containing 2% coal tar (CT) in order to assess the influence of metabolic genotype GSTM1 on urinary mutagen levels. Urinary 1-pyrenol, the main metabolite of pyrene, was used to check the high exposure to PAH of this population. The mean levels of urinary 1-pyrenol found in the 24-h urine of our patients were 467. 8+/-211.0 nmoles-24 h (range 94.6-890.1 nmoles-24 h). Mutagenicity was assessed on urine samples collected over a period of 24 h, after three consecutive days of topical application, using the bacterial mutagenesis test on Salmonella typhimurium strains TA98 and YG1024 in the presence of microsomal enzymes. The latter strain turned out to be more sensitive than the former in revealing urinary mutagens in these patients (42 693+/-30 867 vs. 6877+/-6040 net revertants-24 h). The mutagenicity on YG1024 strain and 1-pyrenol levels of urine samples were correlated (Spearman's rank correlation coefficient=0. 6678, P<0.01, z=2.795). The influence of genotype GSTM1 on urinary mutagen levels was assessed on strain YG1024. The values of urinary mutagenicity of subjects with genotype GSTM1-null (n=6) were on average higher than those of GSTM1-positive subjects (n=9) (55 498+/-45 957 vs. 34 156+/-11 933 net rev.-24 h), a non-significant statistical difference. The mean total excretion of mutagens corrected for PAH exposure (net rev./nmoles of urinary 1-pyrenol) in GSTM1-null patients was double that of GSTM1-positive ones (136. 8+/-34.7 vs. 70.8+/-23.3 net rev./nmoles of urinary 1-pyrenol; one-tailed Mann-Whitney U-test, U=11.5, P<0.05). These results indicate a greater body burden of promutagens, resulting from skin application of CT, in GSTM1-null subjects., (Copyright 1999 Elsevier Science B.V.)

Mutant p53 is frequently detected in endometrial and ovarian carcinoma, but it is rare in cervical cancers. Previous reports focused on cervical squamous cell carcinoma, whereas cervical adenocarcinoma was given little attention. We searched for p53 gene mutations in 74 primary cervical adenocarcinomas with known human papillomavirus (HPV) status. Our aim was to evaluate the prevalence of p53 mutations and to investigate their possible role as an independent prognostic factor. We found mutations in 13.5% with a high rate of G:C --> A:T transitions as observed in endometrial adenocarcinoma. As p53 mutations are more frequently detected in malignancies of high grade, high stage, and large size, this molecular event seems to play a role in the progression rather than in the induction of cervical adenocarcinoma. In our series, patients with HPV-negative tumors and patients with mutated neoplasms, irrespective of HPV infection, had a shorter survival. Yet the absence of HPV infection and presence of p53 mutations are not independent risk factors for tumor-related death after adjustment for clinicopathological confounders. The only significant and independent predictors of survival are age of patient, stage of disease, tumor grade, and presence of lymph node metastases.

Human PBL were treated in vitro with the ultimate reactive metabolites of BaP anti- and syn-BaPDE and DNA damage and repair were measured. The incorporation of radioactivity into DNA due to UDS was higher after treatment with anti-BaPDE. Radioactive DNA adduct dosimetry applied to PBL treated with tritiated syn- and anti-BaPDE demonstrated that anti-BaPDE gave more DNA adducts, which were more efficiently removed than syn adducts in the 24 h following the treatment. HPLC analysis of deoxynucleosides obtained from the enzymatic digestion of DNA showed that in treated PBL the major DNA adduct involved deoxyguanosine. DNA strand breaks, detected by FADU, were induced at comparable levels by anti- and syn-BaPDE (0.1-0.4 micrograms/ml), and persisted after 20 h of post-treatment incubation. Only in the case of syn-BaPDE did the percentage of double-stranded DNA tend to increase with time after the treatment.

An enzyme-linked immunosorbent assay (ELISA) was used to detect BPDE-DNA adducts in white blood cells of 23 psoriatic patients undergoing clinical coal tar therapy. Ten of these patients were reanalyzed 2-5 months after the end of the coal tar treatments. The results show that the mean adduct level during the treatment period was 0.26 +/- 0.16 fmole BPDE/micrograms DNA (7.7 +/- 4.9 adducts/10(8) nucleotides), while 2-5 months later the mean adduct level had decreased significantly (P less than 0.005) to 0.11 +/- 0.08 fmole BPDE/micrograms DNA (3.3 +/- 2.4 adducts/10(8) nucleotides). No relationship could be ascertained between the level of exposure and the amount of BPDE-DNA adducts. In addition, no difference in the level of DNA adducts was found between smoking and non-smoking patients.