Search

Many drugs in common use possess pleiotropic properties that make them capable of interfering with carcinogenesis mechanisms. We discuss here the ability of pharmacological agents to mitigate the pulmonary carcinogenicity of mainstream cigarette smoke. The evaluated agents include anti-inflammatory drugs (budesonide, celecoxib, aspirin, naproxen, licofelone), antidiabetic drugs (metformin, pioglitazone), antineoplastic agents (lapatinib, bexarotene, vorinostat), and other drugs and supplements (phenethyl isothiocyanate, myo-inositol, N -acetylcysteine, ascorbic acid, berry extracts). These drugs have been evaluated in mouse models mimicking interventions either in current smokers or in ex-smokers, or in prenatal chemoprevention. They display a broad spectrum of activities by attenuating either smoke-induced preneoplastic lesions or benign tumors and/or malignant tumors. Together with epidemiological data, these findings provide useful information to predict the potential effects of pharmacological agents in smokers. [ABSTRACT FROM AUTHOR]

Juveniles (50 days post hatch) of a native cyprinid fish ( Barbus plebejus ) were exposed for 7 months to sediments from the River Lambro, a polluted tributary impairing the quality of the River Po for tens of kilometers from their confluence. Sediments were collected upstream of the city of Milan and downstream at the closure of the drainage basin of the River Lambro. Chemical analyses revealed the presence of a complex mixture of bioavailable endocrine-active chemicals, with higher exposure levels in the downstream section of the tributary. Mainly characterized by brominated flame retardants, alkylphenols, polychlorinated biphenyls, and minor co-occurring personal care products and natural hormones, the sediment contamination induced reproductive disorders, as well as other forms of endocrine disruption and toxicity. In particular, exposed male barbel exhibited higher biliary PAH-like metabolites, overexpression of the cyp1a gene, vitellogenin production in all specimens, the presence of oocytes (up to 22% intersex), degenerative alterations in their testis, liver fat vacuolization, a marked depression of total thyroxine (T4) and triiodothyronine (T3) plasma levels, and genotoxic damages determined as hepatic DNA adducts. These results clearly demonstrate that Lambro sediments alone are responsible for recognizable changes in the structure and function of the reproductive and, in general, the endocrine system of a native fish species. In the real environment, exposure to waterborne and food-web sources of chemicals are responsible for additional toxic loads, and the present findings thus provide evidence for a causal role of this tributary in the severe decline observed in barbel in recent decades and raise concern that the fish community of the River Po is exposed to endocrine-mediated health effects along tens of kilometres of its course. [ABSTRACT FROM AUTHOR]

Although the adverse effects of active smoking on sperm quality and fertilization ability are well established, little is known about possible effects of involuntary exposures to cigarette smoke (CS). We designed an experimental study aimed at evaluating the induction of possible noxious effects on testicular morphology and functions in A/J mice exposed whole-body to CS during the first 70 days of life, from birth to early adulthood. Twenty-five sham-exposed neonatal mice and 23 CS-exposed neonatal mice were used. Exposure to CS caused a variety of interconnected alterations in male gonads, including loss of weight and histomorphological alterations of testis, accompanied by a significant increase in abnormalities affecting epidydimal spermatozoa. Induction of oxidative stress was demonstrated by significantly increased concentrations of both reactive oxygen species and lipid peroxidation products in sperm cells. Occurrence of DNA damage in the same cells was documented by using the single cell gel electrophoresis (comet) assay, which showed a remarkable increase in DNA single- and double-strand breaks in CS-exposed mice, as compared with sham-exposed mice. Since biochemical and molecular alterations of sperm cells are known to be associated with impaired sperm quality, our findings suggest that involuntary smoking is potentially able to impair fertility in subjects exposed early in life. [ABSTRACT FROM AUTHOR]

Abstract: We identify trends over the past decades in membership in societies affiliated with the International Association of Environmental Mutagen Societies (IAEMS), and we also highlight findings in a recent review by Claxton et al. [Environ Health Perspect, in press] regarding the numbers of papers published per year using genetic toxicology assays. These analyses reveal a decline or at best a static level of membership in IAEMS-affiliated societies, as well as a decline in the number of papers published per year using genetic toxicology assays—with the exception of those using comet assays, which already have begun to plateau. In contrast, toxicogenomics and computational toxicology are becoming increasingly prominent relative to environmental mutagenesis research in most research institutes, reflecting the ascendancy of these areas of environmental toxicology. We conclude that changing the name of IAEMS and its affiliated societies to reflect these changes might enhance membership and publication by welcoming a broader range of scientists into these societies. Although various names are possible, we think that changing the name of these societies to “Environmental Genomics Society” may help to make our societies more attractive to a broader range of scientists, resulting in an increase in membership and an acceleration of the incorporation of genomic methods into environmental research. [ABSTRACT FROM AUTHOR]

Abstract: Genomic and postgenomic changes are extensively investigated in cancer research. Similar alterations, affecting genome, transcriptome, mirnome and/or proteome end-points, have been detected in a variety of other chronic degenerative diseases, such as atherosclerosis, degenerative heart diseases, chronic obstructive pulmonary diseases, neurological disorders, eye diseases, diabetes, metabolic syndrome, skin ageing and alopecia. No generalization can be made due to the myriad of diverse clinical entities classified as chronic degenerative diseases. Moreover, the detection of molecular changes does not automatically imply their causal role. Nevertheless, common mechanisms, such as DNA damage, epigenetic alterations, oxidative stress, and chronic inflammation, in addition to genetic predisposition, are often involved in noncancer diseases. We debate here in more detail the subjects of cardiovascular diseases and of skin diseases. Moreover, we discuss our experimental studies suggesting that genomic and postgenomic changes do also occur during critical periods of life, including the prenatal life, the perinatal period, and ageing. In addition, we comment on the finding that stem-derived cells are more susceptible to molecular damage than more differentiated cells. All these data are viewed in the perspective of preventive medicine. In fact, there is evidence that the genomic and postgenomic alterations occurring not only in several pathological conditions but also in paraphysiological situations that affect critical periods of life can be modulated by means of dietary and pharmacological agents. The discovery that chemopreventive agents are also able to attenuate nucleotide damage in stem-derived cells warrants further studies in view of possible clinical applications. [Copyright &y& Elsevier]

Abstract: Our recent studies have shown that both cigarette smoke and UV-containing light, which are the most widespread and ubiquitous mutagens and carcinogens in the world, cause systemic genotoxic damage in hairless mice. Further studies were designed with the aim of evaluating the induction of genotoxic and carcinogenic effects in Swiss albino mice exposed to smoke and/or light since birth. We observed that a 4-month whole-body exposure of mice to mainstream cigarette smoke, starting at birth, caused an early and potent carcinogenic response in the lung and other organs. Our further experiments showed that exposure of mice to environmental cigarette smoke, during the first 5 weeks of life, resulted in a variety of significant alterations of intermediate biomarkers, including cytogenetic damage in bone marrow and peripheral blood, formation of lipid peroxidation products, increase of bulky DNA adduct levels, induction of oxidative DNA damage, and overexpression of OGG1 gene in lung, stimulation of apoptosis, hyperproliferation and loss of Fhit protein in pulmonary alveolar macrophages and/or bronchial epithelial cells, and early histopathological alterations in the respiratory tract. Moreover, exposure of mice to UV-containing light, mimicking solar irradiation, significantly enhanced oxidative DNA damage and bulky DNA adduct levels in lung, and synergized with smoke in inducing molecular alterations in the respiratory tract. The baseline OGG1 expression in lung was particularly high at birth and decreased in post-weanling mice. Oxidative DNA damage and other investigated end-points exhibited differential patterns in post-weanling mice and adult mice. The findings of these studies provide a mechanistic clue to the general concept that the neonatal period and early stages of life are critical in affecting susceptibility to carcinogens. [Copyright &y& Elsevier]

Abstract: Chromium(VI) is genotoxic when tested in vitro or injected parenterally in such a way to escape detoxification mechanisms. However, its genotoxicity and potential carcinogenicity are lost, depending on dose and administration route, due to efficient reduction in body fluids and nontarget cells. Chromium(VI) is a Group 1 IARC carcinogen, but only in the respiratory tract and in well-defined occupational settings that involved heavy exposures. Recently, concern has been expressed that oral chromium(VI) may be a gastric carcinogen. We demonstrated that administration of very high doses of chromium(VI) with the drinking water does not induce any clastogenic effect in hematopoietic cells of adult mice and their fetuses. Thereafter, we investigated whether administration of chromium(VI) with the drinking water may induce local genotoxic effects in the gastrointestinal tract. Sodium dichromate dihydrate was administered to mice for 9 consecutive months, at doses corresponding to 5 and 20mg chromium(VI)/l, which exceed drinking water standards by 100 and 400 times, respectively. Under these conditions, chromium(VI) failed to enhance the frequency of DNA–protein crosslinks and did not cause oxidative DNA damage, measured in terms of 8-oxo-2′-deoxyguanosine, in the forestomach, glandular stomach and duodenum. When cells from the same organs were isolated and challenged in vitro with chromium(VI), as positive controls, the same genotoxicity biomarkers were evidently affected. Thus, consistently with the knowledge accumulated in 50 years of research on chromium(VI) kinetics and metabolism, oral chromium(VI) appears to be devoid of genotoxicity in the gastrointestinal tract. After 9 months, we did not observe any variation of tumor yield in skin, lung, forestomach, glandular stomach, and duodenum of chromium(VI)-treated mice. These results are discussed in the light of literature data, also including a recent 2-year carcinogenicity study performed by the National Toxicology Program. [Copyright &y& Elsevier]

Abstract: Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an intracellular second messenger releasing Ca2+ from intracellular stores in different cell types. In addition, it is also active in triggering [Ca2+]i increase when applied extracellularly and various underlying mechanisms have been proposed. Here, we used hP2Y11-transfected 1321N1 astrocytoma cells to unequivocally establish whether extracellular NAADP+ is an agonist of the P2Y11 receptor, as previously reported for β-NAD+ [I. Moreschi, S. Bruzzone, R.A. Nicholas, et al., Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes, J. Biol. Chem. 281 (2006) 31419–31429]. Extracellular NAADP+ triggered a concentration-dependent two-step elevation of [Ca2+]i in 1321N1-hP2Y11 cells, but not in wild-type 1321N1 cells, secondary to the intracellular production of IP3, cAMP and cyclic ADP-ribose (cADPR). Specifically, the transient [Ca2+]i rise proved to be related to IP3 overproduction and to consequent Ca2+ mobilization, while the sustained [Ca2+]i elevation was caused by the cAMP/ADP-ribosyl cyclase (ADPRC)/cADPR signalling cascade and by influx of extracellular Ca2+. In human granulocytes, endogenous P2Y11 proved to be responsible for the NAADP+-induced cell activation (as demonstrated by the use of NF157, a selective and potent inhibitor of P2Y11), unveiling a role of NAADP+ as a pro-inflammatory cytokine. In conclusion, we provide unequivocal evidence for the activation of a member of the P2Y receptor subfamily by NAADP+. [Copyright &y& Elsevier]

Abstract: Atherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N 6-ethenodeoxyadenine (ɛdA) and 3,N 4-ethenodeoxycytosine (ɛdC). By applying an ultrasensitive 32P-postlabeling-immunoaffinity method, ɛdA and ɛdC were quantified in abdominal aorta SMCs from 13 atherosclerotic patients and 3 non-smoking subjects without atherosclerotic lesions. The levels of etheno-adducts ranged for ɛdA from 2.3 to 39.6/108 dA and for ɛdC from 10.7 to 157.7/108 dC, with a high correlation between ɛdA and ɛdC (r =0.84, P =0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both ɛdA (means 15.2 versus 7.3, P =0.06) and ɛdC (71.9 versus 51.6, not significant). ɛdC levels were higher in either ex-smokers (P =0.03) or smokers (P =0.07) than in non-smokers. There was a poor correlation between either ɛdA or ɛdC and 8-hydroxy-2′-deoxyguanosine, whereas significant positive correlations were detected with the levels of several postlabeled bulky aromatic DNA adducts. In conclusion, two different types of DNA damage may be involved in atherosclerotic plaque formation and progression: (i) bulky aromatic compounds, to which aorta SMCs are chronically exposed in smokers, can either covalently bind to DNA, induce redox-cycling via quinone intermediates and/or activate local chronic inflammatory processes in the arterial wall; ii) this in turn leads to a self perpetuating generation of reactive oxygen species, LPO-products and increasing DNA-damage, as documented by the presence of high levels of miscoding etheno-DNA adducts in human aorta SMCs. [Copyright &y& Elsevier]

Abstract: Although no generalization can be made, it is of interest that cancer, cardiovascular diseases, and other chronic conditions often share common risk factors and common protective factors as well as common pathogenetic determinants, such as DNA damage, oxidative stress, and chronic inflammation. Atherosclerosis is the most important cause of vascular forms representing the major cause of death in the population of many geographical areas. A great deal of studies support the “response-to-injury” theory. A variety of experimental and epidemiological findings are also in favor of the somatic mutation theory, which maintains that the earliest event in the atherogenic process is represented by mutations in arterial smooth muscle cells, akin to formation of a benign tumor. These two theories can be harmonized, also taking into account the highly diversified nature of atherosclerotic lesions. Molecular epidemiology studies performed in our laboratory and other laboratories have shown that DNA adducts are systematically present in arterial smooth muscle cells, and their levels are correlated with atherogenic risk factors known from traditional epidemiology. Oxidative DNA damage was also consistently detected in these cells. The role of glutathione S-transferase polymorphisms on the frequency of the above molecular alterations and of arterial diseases is rather controversial. Prevention of both cancer and atherosclerosis is based on avoidance of exposure to risk factors and on fortification of the host defense mechanisms by means of dietary principles and chemopreventive drugs. [Copyright &y& Elsevier]

Abstract: Epidemiological data provide evidence that it is possible to prevent cancer and other chronic diseases, some of which share common pathogenetic mechanisms, such as DNA damage, oxidative stress, and chronic inflammation. An obvious approach is avoidance of exposure to recognized risk factors. As complementary strategies, it is possible to render the organism more resistant to mutagens/carcinogens and/or to inhibit progression of the disease by administering chemopreventive agents. In a primary prevention setting, addressed to apparently healthy individuals, it is possible to inhibit mutation and cancer initiation by triggering protective mechanisms either in the extracellular environment or inside cells, e.g., by modifying transmembrane transport, modulating metabolism, blocking reactive species, inhibiting cell replication, maintaining DNA structure, modulating DNA metabolism and repair, and controlling gene expression. Tumor promotion can be counteracted by inhibiting genotoxic effects, favoring antioxidant and anti-inflammatory activity, inhibiting proteases and cell proliferation, inducing cell differentiation, modulating apoptosis and signal transduction pathways, and protecting intercellular communications. In a secondary prevention setting, when a premalignant lesion has been detected, it is possible to inhibit tumor progression via the same mechanisms, and in addition by affecting the hormonal status and the immune system in various ways, and by inhibiting tumor angiogenesis. Although tertiary prevention, addressed to cancer patients after therapy, is outside the classical definition of chemoprevention, it exploits similar mechanisms. It is also possible to affect cell-adhesion molecules, to activate antimetastasis genes, and to inhibit proteases involved in basement membrane degradation. [Copyright &y& Elsevier]

The epidemic of lung cancer and the increase of other tumours and chronic degenerative diseases associated with tobacco smoking have represented one of the most dramatic catastrophes of the 20th century. The control of this plague is one of the major challenges of preventive medicine for the next decades. The imperative goal is to refrain from smoking. However, chemoprevention by dietary and/or pharmacological agents provides a complementary strategy, which can be targeted not only to current smokers but also to former smokers and passive smokers. This article summarises the results of studies performed in our laboratories during the last 10 years, and provides new data generated in vitro, in experimental animals and in humans. We compared the ability of 63 putative chemopreventive agents to inhibit the bacterial mutagenicity of mainstream cigarette smoke. Modulation by ethanol and the mechanisms involved were also investigated both in vitro and in vivo. Several studies evaluated the effects of dietary chemopreventive agents towards smoke-related intermediate biomarkers in various cells, tissues and organs of rodents. The investigated end-points included metabolic parameters, adducts to haemoglobin, bulky adducts to nuclear DNA, oxidative DNA damage, adducts to mitochondrial DNA, apoptosis, cytogenetic damage in alveolar macrophages, bone marrow and peripheral blood erytrocytes, proliferation markers, and histopathological alterations. The agents tested in vivo included N-acetyl-l-cysteine, 1,2-dithiole-3-thione, oltipraz, phenethyl isothiocyanate, 5,6-benzoflavone, and sulindac. We started applying multigene expression analysis to chemoprevention research, and postulated that an optimal agent should not excessively alter per se the physiological background of gene expression but should be able to attenuate the alterations produced by cigarette smoke or other carcinogens. We are working to develop an animal model for the induction of lung tumours following exposure to cigarette smoke. The most encouraging results were so far obtained in models using A/J mice and Swiss albino mice. The same smoke-related biomarkers used in animal studies can conveniently be applied to human chemoprevention studies. We participated in trials evaluating the effects of N-acetyl-l-cysteine and oltipraz in smokers from Italy, The Netherlands, and the People’s Republic of China. We are trying to develop a pharmacogenomic approach, e.g. based on genetic metabolic polymorphisms, aimed at predicting not only the risk of developing cancer but also the individual responsiveness to chemopreventive agents. [Copyright &y& Elsevier]

While disinfection processes have been central for public health protection, new concerns have been raised with respect to their ability to control the spread of antibiotic resistance in the environment. In this study, we report the inactivation kinetics by peracetic and performic acids of a typical indicator, Escherichia coli and its corresponding antibiotic-resistant subpopulation, in secondary settled wastewater effluent. Performic acid always showed greater inactivation efficiency than peracetic acid, whether or not the indicator was Ampicillin-resistant. Observed inactivation data, fitted with an exposure-based inactivation model, predicted very well the inactivation profile of both total and ampicillin resistant Escherichia coli. Notably, the antibiotic resistance percentage decreased significantly in treated wastewater compared to untreated wastewater thus making the peracid-based disinfection processes beneficial in controlling antibiotic resistance in secondary settled wastewater. Moreover, the minimum inhibitory concentration values remained unchanged. Finally, antibiotic-resistant-specific inactivation kinetics were used to predict the disinfection efficiency in continuous-flow reactors under ideal and non-ideal hydraulics thus providing useful information for future design and operation of disinfection process in antibiotic-resistance controlling mode. • Disinfection kinetics by peracetic and performic acids have been studied in wastewater effluent. • Antibiotic-resistant E. coli were less resistant to inactivation than total E. coli. • Performic acid showed greater inactivation efficiency than peracetic acid. • Antibiotic resistance decreased after disinfection treatment. • Simulation of bacteria inactivation through modeling of batch experimental data. [ABSTRACT FROM AUTHOR]

Abstract: This is the eighth special issue of ‘Mutation Research’ to focus on antimutagenesis and anticarcinogenesis. It covers a wide range of mechanisms from prevention of cancer initiation by antimutagens through to inhibition of tumour angiogenesis and selective estrogen receptor modulators. New screening methods and new biomarkers are also elucidated. There is increasing reason to believe that the long-term use of a combination of anticarcinogens, over an extended time span, may provide a realistic prospect of reducing the current burden of human cancers. [Copyright &y& Elsevier]

Lanthionine synthetase component C-like protein 2 (LANCL2) has been identified as the mammalian receptor mediating the functional effects of the universal stress hormone abscisic acid (ABA) in mammals. ABA stimulates insulin independent glucose uptake in myocytes and adipocytes via LANCL2 binding in vitro , improves glucose tolerance in vivo and induces brown fat activity in vitro and in vivo . The emerging role of the ABA/LANCL2 system in glucose and lipid metabolism makes it an attractive target for pharmacological interventions in diabetes mellitus and the metabolic syndrome. The aim of this study was to investigate the presence of ABA binding site(s) on LANCL2 and identify the amino acid residues involved in ABA binding. Equilibrium binding assays ([ 3 H]-ABA saturation binding and surface plasmon resonance analysis) suggested multiple ABA-binding sites, prompting us to perform a computational study that indicated one putative high-affinity and two low-affinity binding sites. Site-directed mutagenesis (single mutant R118I, triple mutants R118I/R22I/K362I and R118I/S41A/E46I) and equilibrium binding experiments on the mutated LANCL2 proteins identified a high-affinity ABA-binding site involving R118, with a K D of 2.6 nM ± 1.2 nM, as determined by surface plasmon resonance. Scatchard plot analysis of binding curves from both types of equilibrium binding assays revealed a Hill coefficient >1, suggesting cooperativity of ABA binding to LANCL2. Identification of the high-affinity ABA-binding site is expected to allow the design of ABA agonists/antagonists, which will help to understand the role of the ABA/LANCL2 system in human physiology and disease. [ABSTRACT FROM AUTHOR]

Abscisic acid (ABA) is a plant hormone also present in animals, where it is involved in the regulation of innate immune cell function and of glucose disposal, through its receptor LANCL2. ABA stimulates glucose uptake by myocytes and pre-adipocytes in vitro and oral ABA improves glycemic control in rats and in healthy subjects. Here we investigated the role of the ABA/LANCL2 system in the regulation of glucose uptake and metabolism in adipocytes. Silencing of LANCL2 abrogated both the ABA- and insulin-induced increase of glucose transporter-4 expression and of glucose uptake in differentiated 3T3-L1 murine adipocytes; conversely, overexpression of LANCL2 enhanced basal, ABA- and insulin-stimulated glucose uptake. As compared with insulin, ABA treatment of adipocytes induced lower triglyceride accumulation, CO 2 production and glucose-derived fatty acid synthesis. ABA per se did not induce pre-adipocyte differentiation in vitro, but stimulated adipocyte remodeling in terminally differentiated cells, with a reduction in cell size, increased mitochondrial content, enhanced O 2 consumption, increased transcription of adiponectin and of brown adipose tissue (BAT) genes. A single dose of oral ABA (1 μg/kg body weight) increased BAT glucose uptake 2-fold in treated rats compared with untreated controls. One-month-long ABA treatment at the same daily dose significantly upregulated expression of BAT markers in the WAT and in WAT-derived preadipocytes from treated mice compared with untreated controls. These results indicate a hitherto unknown role of LANCL2 in adipocyte sensitivity to insulin-stimulated glucose uptake and suggest a role for ABA in the induction and maintenance of BAT activity. [ABSTRACT FROM AUTHOR]