2,408 research outputs found
Biological indicators of genotoxic risk and metabolic polymorphisms
No full textInternational 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
Epidemiological and mechanistic links between PM2.5 exposure and type 2 diabetes: focus on the TRPV1 receptor
No full textThe growing global burden of type 2 diabetes (T2D) has prompted increasing attention to environmental factors that may contribute to its development. Among these, exposure to fine particulate matter (PM2.5) has emerged as a significant yet often overlooked risk factor. This systematic review conducted according to the PRISMA guidelines, provides a comprehensive and critical appraisal of the epidemiological evidence and discusses mechanisms linking PM2.5 exposure to the onset and progression of T2D. Long-term exposure to PM2.5 has been consistently associated with increased T2D risk in epidemiological studies, particularly among vulnerable groups such as individuals with obesity, metabolic syndrome, or advanced age. In addition, evidence from animal models suggests that acute exposure can exacerbate insulin resistance and impair glucose metabolism. Mechanistic studies highlight the roles of oxidative stress, systemic inflammation, endothelial dysfunction, and autonomic imbalance. Notably, recent findings implicate the transient receptor potential vanilloid 1 (TRPV1) in neurogenic inflammation and metabolic disruption, offering novel insights into how PM2.5 may influence glycemic control. Experimental evidence in humans indicates that traffic-related PM2.5, including diesel exhaust particles (DEPs), activates TRPV1, supporting its role as a molecular interface between environmental insults and metabolic disruption. Given its central role in neurogenic inflammation and metabolic regulation, TRPV1 has emerged as a promising therapeutic target. Preclinical studies have shown that pharmacological modulation of TRPV1 improves glucose tolerance and reduces inflammation. Currently, XEN-D0501, a TRPV1 antagonist, is undergoing clinical trials to assess its efficacy in regulating blood glucose and mitigating T2D-related inflammatory complications. These mechanistic insights are further supported by animal studies demonstrating that PM2.5 exposure induces metabolic dysfunction consistent with TRPV1 activation and inflammation-related pathways. Animal models corroborate human data, revealing that PM2.5 exposure promotes visceral adiposity, impairs hepatic insulin signaling, and triggers tissue-specific inflammation. Despite the strength of the overall evidence, heterogeneity in exposure assessment, driven by spatial and temporal variations in PM2.5 sources and composition, and in study design persists. Given the ubiquity of PM2.5 in urban environments, even modest increases in diabetes risk may translate into substantial public health burdens. Targeted policies to reduce air pollution, together with intensified research into biological susceptibility and prevention strategies, are essential. Addressing PM2.5 as a modifiable determinant of T2D represents a timely and actionable priority in environmental health
[Dosimetry of DNA and protein adducts in occupational health]
No full textGenotoxic carcinogenic compounds react chemically with DNA and proteins to form covalent adducts which, in the case of DNA adducts, are strongly believed to be the first step in cancer process (biologically effective dose). The paper reviews the main studies on the dosimetry of adducts in the biological monitoring of occupational exposure to mutagens and carcinogens. Dosimetry of DNA adducts has been used to assess exposure to polycyclic aromatic hydrocarbons in environments such as foundries, coke ovens and the aluminium industry. In many cases, adduct levels higher than those of control populations were found in exposed workers. Only one study reported increased levels of DNA adducts in workers exposed to styrene. Dosimetry of hemoglobin adducts has been used to identify occupational exposure to ethylene oxide, styrene, BaP and arylamines. The results obtained in the last few years confirm the usefulness of dosimetry of DNA and protein adducts in assessing occupational exposure to genotoxic carcinogens occurring in working environments, even at very low exposure levels, but the methods in question require high standardization and validation if systematic errors in measurement are to be avoided. In the coming years, dosimetry of adducts, together with evaluation of individual genetic sensitivity to mutagens and carcinogens, will be one of the new frontiers in research on the prevention of occupational cancer. Current research already makes use of sophisticated analytical techniques such as mass spectrometry, and both specificity and sensitivity in the determination of adducts have been considerably improved. In the future, therefore, dosimetry of adducts may also be applied to industrial health practices
Valori di riferimento nel monitoraggio biologico dell'esposizione professionale ad agenti mutageni e cancerogeni
No full text[CYP1A2, NAT2, and GSTM1 phenotype/genotype modulate human exposure and various environmental mutagens: our experience]
No full textSince some years in our research group has been studied the influence of metabolic genotypes on two biomarkers of genotoxic risk (BPDE-DNA adducts and urinary mutagenicity) in humans exposed to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. The aim was to identify possible genetic susceptible factors capable of modulating individual response to these carcinogens. Humans exposed to PAHs: dermatological patients therapeutically treated with coal tar based ointments (CT), coke oven workers and chimney sweeps. People exposed to aromatic amines will be volunteers after a meal of pan-fried hamburgers and smokers. An overview of the results we found until now will be presented
[Reference values in biological monitoring of occupational exposure to mutagens and carcinogens]
No full textThis work reports values of biological markers indicating mutagenic/carcinogenic risk in professionally non-exposed populations. The main confounding factors for most of these biomarkers are tobacco smoke, diet and air pollution. With the sole exception of compounds specifically present in work environments, in which determination in biological fluids of unchanged substances or their metabolites has high sensitivity and specificity (e.g., some aromatic amines), other biomarkers (urinary mutagenicity, DNA adducts and cytogenetic analyses), in order to be used properly as reference values, require ad hoc study of suitable control groups paired for the main confounding factors. Analytical determination of some protein adducts appears to be promising, due to its sensitivity and specificity
[New perspectives in monitoring of exposures to carcinogens]
No full textBiomonitoring occupational and environmental exposures to carcinogens is a common practice and several biomarkers have been developed for risk assessment. However, in particular, because of the lack of prospective studies, the place of these biomarkers within the complex scenario of the gene-environment interactions leading to cancer cannot be defined. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome, from the results of genomewide association and omic studies. Based on these premises it is possible to envisage personalized biomonitoring procedures, as those already actuated in nutrition and clinical oncology, allowing a better predictivity of biomarkers in the preventive settings
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