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Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015.

Eur J Epidemiol

Background: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. Objectives: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother–child study. Methods: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006–2010. Maternal diet was estimated through food-frequency questionnaires. Results: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was –132 g (95% CI: –207, –56); the corresponding difference for head circumference was –0.33 cm (95% CI: –0.61, –0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. Conclusions: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women. The NewGeneris (Newborns and Genotoxic exposure risks) study was funded by the European Union (EU Contract FOOD-CT-2005-016320). The study was also supported by grants obtained locally, including the Swedish Cancer and Allergy Foundation and the Swedish Research Council Formas, the National Institute for Health Research, UK (programme grant RP-PG-0407-10044), the Norwegian Ministry of Health, the Norwegian Ministry of Education and Research, the Norwegian Research Council/FUGE (grant 151918/S10), the EU funded HiWATE (contract Food-CT-2006-036224), the U.S. National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (contract NO-ES-75558), and the U.S. NIH/National Institute of Neurological Disorders and Stroke (grant 1 UO1 NS 047537-01). M.P. holds a Juan de la Cierva postdoctoral fellowship awarded from the Spanish Ministry of Science and Innovation (JCI-2011-09479)

Differences in biological responses to exposure to hazardous airborne substances between children and adults have been reported, suggesting children to be more susceptible. Aim of this study was to improve our understanding of differences in susceptibility in cancer risk associated with air pollution by comparing genome-wide gene expression profiles in peripheral blood of children and their parents. Gene expression analysis was performed in blood from children and parents living in two different regions in the Czech Republic with different levels of air pollution. Data were analyzed by two different approaches: one method first selected significantly differentially expressed genes and analyzed these gene lists for overrepresented biological processes, whereas the other applied the T-profiler tool to directly perform pathway analyses on the total gene set without preselection of significantly modulated gene expressions. In addition, gene expressions in both children and adults were investigated for associations with micronuclei frequencies. Both analysis approaches returned considerably more genes or gene groups and pathways that significantly differed between children from both regions than between parents. Very little overlap was observed between children and adults. The two most important biological processes or molecular functions significantly modulated in children, but not in adults, are nucleosome and immune response related. Our study suggests differences between children and adults in relation to air pollution exposure at the transcriptome level. The findings underline the necessity of implementing environmental health policy measures specifically for protecting children's health. © The Author 2008. Published by Oxford University Press. All rights reserved.

The goal of the mitotic cell division is the faithful transmission of chromosomes to the daughter cells. To fulfil a correct separation of sister chromatids, kinetochores of all chromosomes should be correctly attached to spindle microtubules of opposite poles and should all be under tension. These events are monitored by the spindle checkpoint, which delays mitotic progression allowing time for corrections when errors occur in the dynamic interactions between chromosomes and microtubules. The G(1) post-mitotic checkpoint constitutes an additional checkpoint preventing further proliferation of cells that have undergone massive spindle damage. This review concentrates on the key structural and protein components which are pivotal for an accurate segregation of chromosomes during anaphase: the chromosome scaffold, sister chromatid cohesion and segregation and the kinetochores in higher eukaryotes. Furthermore, recent advances in understanding spindle and G(1) post-mitotic checkpoint and how they prevent aneuploidization and polyploidization are presented. In a last part the impact of aneuploidy and polyploidy on human health and in particular on cancer development is highlighted.

The influence of genetic polymorphisms in GSTM1 and GSTT1 genes on micronucleus frequencies in human peripheral blood lymphocytes was assessed through a pooled analysis of data from seven laboratories that did biomonitoring studies using the in vivo cytokinesis-block micronucleus assay. A total of 301 nonoccupationally exposed individuals (207 males and 94 females) and 343 workers (237 males and 106 females) occupationally exposed to known or suspected genotoxic substances were analyzed by Poisson regression. The results of the pooled analysis indicate that the GSTT1 null subjects had lower micronucleus frequencies than their positive counterparts in the total population (frequency ratio, 0.55; 95% confidence interval, 0.33-0.89). The protective effect of this genotype is reversed with increasing age, with a frequency ratio of 1.33 (95% confidence interval, 1.06-1.68) in subjects aged 60 years. A significant overall increase in micronucleus frequency with age and gender (P

Cytogenetic biomarkers are by far the most frequently used endpoints in human population studies. Their sensitivity for measuring exposure to genotoxic agents and their role as early predictors of cancer risk have contributed to this success. In this article, we present an overview of the last 25 years of population studies with cytogenetic biomarkers, describing the evolution of this research and addressing the most promising innovations for the future. The evaluation has been restricted to the most popular assays, i.e., chromosomal aberrations (CAs) and micronucleus (MN), which are considered to be causally related to early stages of chronic diseases, especially cancer, and may therefore play a major role in prevention. An extensive literature search covering the period 1 January 1980 to 31 December 2003 was performed using the Medline/PubMed database. A total of 833 population studies using CAs and 434 using matched MN inclusion criteria were included in the analysis. We report the distribution of selected papers by year of publication, country, language, agents investigated, and methods employed. The state of the art and future prospects regarding cytogenetic techniques and epidemiologic and statistical methods are discussed. The role of susceptibility and its potential impact on genotoxic damage are discussed with special attention to the effect of major genetic polymorphisms on the baseline frequency of CAs and micronuclei.

Aneugenic and clastogenic agents are good inducers of both micronuclei and apoptosis. In its turn, apoptosis may modify the threshold values for the induction of micronuclei. This is of major concern for accurate assessment of hazard related to exposure to mutagens. In the present work we studied the influence of caspases, the key regulators of the apoptotic process, on the induction of micronuclei in the cytokinesis block micronucleus assay. For this, we applied a combined approach in which both human peripheral blood mononucleated cells (PBMC) and the paired human breast carcinoma cell lines MCF-7, which is caspase-3 deficient, and the caspase-3 transfected MCF-7 (MCF-7casp-3) were used to study the influence of caspase activity on micronuclei. When nocodazole induced apoptosis was inhibited by the use of inhibitors of the two main apical caspases-8 and -9 in PBMC, the frequencies of micronucleated binucleates (MNCB) increased with inhibition of these caspases confirming that apoptosis can eliminate micronucleated cells. On the contrary when caspase-3 was inhibited, the frequencies of MNCB was lower, suggesting a role of caspase-3, also in micronuclei formation. To verify this hypothesis, we compared the induction of apoptosis and micronuclei by the aneugen nocodazole, the clastogen methyl methane sulfonate (MMS) and the non-mutagenic apoptogen staurosporin in MCF-7 and MCF-7casp-3 cells. The results showed that when caspase-3 activity was impaired, in the parental MCF-7 cell line or in the MCF-7casp-3 cells in the presence of the caspase-3 inhibitor, the frequencies of nocodazole or MMS induced micronuclei decreased. These results suggest that caspase- 3, besides its function as an effector caspase in the apoptotic pathway, is also involved in the formation of micronuclei.

The present study aimed at comparing in vitro the apoptogenic properties of metallic cobalt (Co), tungsten carbide (WC) and tungsten carbide-cobalt (WC-Co) in conditions known to cause genotoxicity. Human peripheral blood mononucleated cells were incubated with 2.0-6.0 microg/ml of Co alone or mixed with WC particles and 33.3-100.0 microg/ml WC alone for up to 24 h. Under these culture conditions the majority (60%) of the cobalt metal particles were almost immediately solubilised in the culture medium, while WC remained under the form of particles that were progressively phagocytosed by monocytes. Apoptosis was assessed by Annexin-V staining, flow cytometry and analysis of DNA fragmentation by ELISA. Metallic Co-particles induced apoptosis in vitro. Furthermore, although so far considered as biologically inert, WC particles also induced apoptosis. When compared with its individual components WC-Co displayed an additive apoptotic effect in the DNA fragmentation assay. Apoptosis induced by WC particles was found largely dependent on caspase-9 activation and occurred presumably in monocytes, while that induced by Co involved both caspase-9 and -8 activation. The data suggest that apoptosis induced by the tested WC-Co mixture results from the additive effects of WC apoptosis induced in monocytes and Co-specific apoptosis in both monocytes and lymphocytes. The apoptogenic properties of these metals may be important in the mechanism of lung pathologies induced by the cobalt-containing particles.

One of the objectives of the HUman MicroNucleus (HUMN) project is to identify the methodological variables that have an important impact on micronucleus (MN) or micronucleated (MNed) cell frequencies measured in human lymphocytes using the cytokinesis-block micronucleus assay, In a previous study we had shown that the scoring criteria used were likely to be an important variable. To determine the extent of residual variation when laboratories scored cells from the same cultures using the same set of standard scoring criteria, an inter-laboratory slide-scoring exercise was performed among 34 laboratories from 21 countries with a total of 51 slide scorers involved. The results of this StUdy show that even under these optimized conditions there is a great variation in the MN frequency or MNed cell frequency obtained by individual laboratories and scorers. All laboratories ranked correctly the MNed cell frequency in cells from cultures that were unirradiated, or exposed to 1 or 2 Gy of gamma rays. The study also estimated that the intra-scorer median coefficient of variation for duplicate MNed cell frequency scores is 29% for unexposed cultures and 14 and 11% for cells exposed to I and 2 Gy, respectively, These values can be used as a standard for quality or acceptability of data in future studies. Using a Poisson regression model it was estimated that radiation dose explained 67% of the variance, while staining method. cell sample, laboratory, and covariance explained 0.6, 0.3, 6.5. and 25.6% of the variance, respectively, leaving only 3.1% of the variance unexplained. As part of this exercise. nucleoplasmic bridges were also estimated by the laboratories however, inexperience in the use of this biomarker of chromosome rearrangement was reflected in the much greater heterogeneity in the data and the unexplained variation estimated by the Poisson model. The results of these studies indicate clearly that even after standardizing culture and scoring conditions it will be necessary to calibrate scorers and laboratories if MN, MNed cell and nucleoplasmic bridge frequencies are to be reliably compared among laboratories and among populations. (C) 2002 Elsevier Science B.V. All rights reserved.

Two major mechanisms responsible for chromosome segregation errors are non- disjunction and chromosome loss, both leading to aneuploidy. Previous studies in our laboratory showed the existence of thresholds for the induction of chromosome non-disjunction and chromosome loss and the induction of apoptosis by microtubule inhibitors. From a mechanistic point of view one can expect that apoptosis contributes to the elimination of cells with premutagenic/mutagenic lesions. If aneuploid cells were eliminated by the induction of apoptosis below the threshold concentrations for chromosome loss and non-disjunction, the defined thresholds would not be applicable to cells unable to undergo apoptosis. The aim of this study was to investigate whether apoptosis was induced directly or indirectly as a response to aberrant chromosome segregation below the thresholds for the induction of chromosome loss and non- disjunction, as previously defined by us. Therefore, human lymphocytes were exposed in vitro to five concentrations of nocodazole and five concentrations of carbendazim representing the threshold concentrations for chromosome non-disjunction and chromosome loss, two concentrations below the lowest threshold and one concentration between the two threshold values. After 48 h exposure to the aneugens, induction of apoptosis was analysed by the annexin-V test. The frequencies of chromosome non- disjunction and chromosome loss were estimated in cytokinesis-blocked human lymphocytes in combination with FISH; this methodology was applied to whole cell cultures as well as to apoptotic and viable cell fractions obtained using magnetic annexin microbead cell sorting. Our results suggest that elimination of aneuploid cells does occur. However, the efficiency of disappearance of micronucleated cells is higher than for cells presenting chromosome non-disjunction. The correlation found between early apoptotic events and micronucleus formation could account, at least in part, for the specific elimination of aneuploid cells.

Polychaetes, because of their bioturbation capacity, play an important role in the distribution of anthropogenic contaminants (including polycyclic aromatic hydrocarbons [PAHs]) throughout the sediments. In this work the use of Nereis virens (Annelida: Polychaeta) as a bioindicator to assess the genotoxic risk of PAH exposure for the environment was evaluated. For this purpose the alkaline single cell gel electrophoresis [comet] assay was applied on the coelomocytes of in vivo exposed Nereis virens. Benzo[a]pyrene (B[a]P) was chosen because it is classified by the IARC (International Agency for Research on Cancer) as "probably carcinogenic to humans" and because its mechanisms of action are well-known. Nereis virens was exposed to B[a]P in concentrations of 0.3, 0.6, 10, 20, 35 and 45 mg/ml by an intracoelomic injection of B[a]P (20 microliters) dissolved in dimethyl sulphoxide (DMSO). A solvent control with DMSO, a positive control with ethyl methane sulphonate (EMS) (12.1 mg/ml) and a negative control were included in each experiment. For each treatment four animals were analysed. After 1 hr treatment coelomocytes were harvested by puncturing the coelomic cavity with a sharpened Pasteur pipette, mixed with 0.5% low melting point agarose and sandwiched between two other gel layers. Ethidium bromide stained nuclei were analysed for tail length and tail moment. 12.1 mg/ml EMS, pure DMSO (98.9%) and B[a]P in all tested concentrations induced a statistically significant increase of DNA single strand breaks in the comet assay. The effect of B[a]P, however, was only at the highest concentration (45 mg/ml) significantly stronger than the effect of DMSO alone. Although a relatively large heterogeneity in the results could be observed, these experiments clearly showed that Nereis virens is not suited as a sentinel species for the assessment of the genotoxic risk of PAH exposure because this species seems to be very resistant to benzo[a]pyrene.