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Mutational signatures associated with exposure to carcinogenic microplastic compounds bisphenol A and styrene oxide.

ABSTRACT: Microplastic pollutants in oceans and food chains are concerning to public health. Common plasticizing compounds Bisphenol-A (BPA) and Styrene-7,8-Oxide (SO) are now labeled as carcinogens. We show that BPA and SO cause deoxyribonucleic acid damage and mutagenesis in human cells, and analyze the genome-wide point mutation and genomic rearrangement patterns associated with BPA and SO exposure. A subset of the single- and doublet base substitutions shows mutagenesis near or at guanine, consistent with these compounds' preferences to form guanosine adducts. Presence of other mutational signatures suggest additional mutagenesis probably due to complex effects of BPA and SO on diverse cellular processes. Analyzing data for 19 cancer cohorts, we find that tumors of digestive and urinary organs show relatively high similarity in mutational profiles, and the burden of such mutations increases with age. Even within the same cancer type, proportions of corresponding mutational patterns vary among the cohorts from different countries, as does the amount of microplastic waste in ocean waters. BPA and SO are relatively mild mutagens, and other environmental agents can also potentially generate similar, complex mutational patterns in cancer genomes. Nonetheless, our findings call for systematic evaluation of public health consequences of microplastic exposure worldwide.

SUBMITTER: Hu X

PROVIDER: S-EPMC7936647 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cochlear dysfunction is associated with styrene exposure in humans.

Project description:AIM:Occupational exposure to styrene has been shown to be associated with an increased probability of developing hearing loss. However, the sites of lesions in the auditory system in humans remain unknown. The aim of this study was to investigate the possible adverse effects of styrene exposure on the cochlea of human subjects. DESIGN:The hearing function of 98 styrene-exposed male workers from the glass fibre-reinforced plastics industry (mean concentration of 55 mg/m3) was evaluated bilaterally using pure-tone audiometry (1000-16000 Hz), distortion product otoacoustic emissions (DPOAEs), and auditory brainstem response (ABR). The results were compared to a group of 111 male workers exposed to noise (above 85 dBA) and 70 male white-collar workers exposed to neither noise nor solvents. Age and noise exposure levels were accounted for as confounding variables in all statistical models. RESULTS:Styrene exposure was significantly associated with poorer pure-tone thresholds (1-8 kHz), lower DPOAE amplitudes (5-6 kHz), and shorter wave V latencies in both ears compared to control-group subjects. Similar results were found among noise-exposed subjects. A further analysis with wave V latency showed that styrene-exposed subjects showed significantly shorter latencies than expected according to normative data. These results suggest that occupational exposure to styrene at moderate concentrations is associated with cochlear dysfunction, at least at high frequencies. DPOAEs may be considered a valuable diagnostic tool in hearing conservation programs in workers exposed to styrene.

| S-EPMC6974250 | biostudies-literature

Mutational signatures

Project description:Mutational signatures

| PRJEB60585 | ENA

Mutational signatures associated with tobacco smoking in human cancer.

Project description:Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.

| S-EPMC6141049 | biostudies-literature

Genomic Landscape and Mutational Signatures of Deafness-Associated Genes.

Project description:The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.

| S-EPMC6174355 | biostudies-literature

DNA nicks induce mutational signatures associated with BRCA1 deficiency

Project description:Analysis of human cancer genome sequences has revealed specific mutational signatures associated with BRCA1-deficient tumors, but the underlying mechanisms remain poorly understood. Here, we show that one-ended DNA double strand breaks (DSBs) converted from CRISPR/Cas9-induced nicks by DNA replication, not two-ended DSBs, cause more characteristic chromosomal aberrations and micronuclei in Brca1-deficient cells than in wild-type cells. BRCA1 is required for efficient homologous recombination of these nick-converted DSBs and suppresses bias towards long tract gene conversion and tandem duplication (TD) mediated by two-round strand invasion in a replication strand asymmetry. However, aberrant repair of these nick-converted one-ended DSBs, not that of two-ended DSBs in Brca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those in BRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated with BRCA1 deficiency in cancer and the underlying mechanisms. It remains unclear how BRCA1-associated mutational sigantures are generated in cancer. Here, the authors develop nCas9-based approaches to uncover that aberrant repair of one-ended DSBs converted from DNA nicks by replication, not that of two-ended DSBs, induces such mutational signatures.

| S-EPMC9314409 | biostudies-literature

Genotoxic and Carcinogenic Potential of Compounds Associated with Electronic Cigarettes: A Systematic Review.

Project description:BackgroundMany studies, comparing the health associated risks of electronic cigarettes with conventional cigarettes focus mainly on the common chemical compounds found between them.AimReview chemical compounds found exclusively in electronic cigarettes and describe their toxic effects, focusing on electronic-cigarette-only and dual electronic-cigarette and conventional cigarette users.Data sourcesLiterature search was carried out using PubMed.Study eligibility criteriaArticles related exclusively to conventional and electronic cigarettes' chemical composition. Articles which reported to be financed from tobacco or electronic cigarettes industries, not reporting source of funding, not related to the chemical composition of electronic and conventional cigarettes and not relevant to tobacco research were excluded.Methods and resultsChemical compounds reported in the selected studies were tabulated using the Chemical Abstracts Service registry number for chemical substances information. A total of 50 chemical compounds were exclusively reported to be present in electronic cigarettes. Crucial health risks identified were: eye, skin, and respiratory tract irritation, with almost 50% of incidence, an increment of 10% in cytotoxic effects, when compared to compounds in common with conventional cigarettes and around 11% of compounds with unknown effects to human health.LimitationsArticles reporting conflicts of interest.Conclusions and implications of key findingsDespite being considered as less harmful for human health, compounds found in electronic cigarettes are still a matter of research and their effects on health are yet unknown. The use of these devices is not recommended for first time users and it is considered hazardous for dual users.

| S-EPMC6948324 | biostudies-literature

Differences in exposure to toxic and/or carcinogenic volatile organic compounds between Black and White cigarette smokers.

Project description:ObjectiveIt is unclear why Black smokers in the United States have elevated risk of some tobacco-related diseases compared to White smokers. One possible causal mechanism is differential intake of tobacco toxicants, but results across studies are inconsistent. Thus, we examined racial differences in biomarkers of toxic volatile organic compounds (VOCs) present in tobacco smoke.MethodWe analyzed baseline data collected from 182 Black and 184 White adult smokers who participated in a randomized clinical trial in 2013-2014 at 10 sites across the United States. We examined differences in urinary levels of ten VOC metabolites, total nicotine equivalents (TNE), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), controlling for covariates such as cigarettes per day (CPD), as well as differences in VOCs per TNE to assess the extent to which tobacco exposure, and not metabolic factors, accounted for racial differences.ResultsConcentration of metabolites of acrolein, acrylonitrile, ethylene oxide, and methylating agents were significantly higher in Blacks compared to Whites when controlled for covariates. Other than the metabolite of methylating agents, VOCs per TNE did not differ between Blacks and Whites. Concentrations of TNE/CPD and VOCs/CPD were significantly higher in Blacks. Menthol did not contribute to racial differences in VOC levels.ConclusionsFor a given level of CPD, Black smokers likely take in higher levels of acrolein, acrylonitrile, and ethylene oxide than White smokers. Our findings are consistent with Blacks taking in more nicotine and toxicants per cigarette smoked, which may explain their elevated disease risk relative to other racial groups.

| S-EPMC7012700 | biostudies-literature

Cross-Linked Chitosan/Gelatin Beads Loaded with <i>Chlorella vulgaris</i> Microalgae/Zinc Oxide Nanoparticles for Adsorbing Carcinogenic Bisphenol-A Pollutant from Water.

Project description:Water polluted by phenolic compounds is a global threat to health and the environment; accordingly, we prepared a green novel sorbent biological system from a chitosan (CS), gelatin (GT), and Chlorella vulgaris freshwater microalgae (m-Alg) composite impregnated with zinc oxide nanoparticles (ZnO-NPs) for the remediation of bisphenol-A (BPA) from water. C. vulgaris was selected to be one of the constituents of the prepared composite because of its high capability in phytoremediation. The morphology and the structure of CS/GT*m-Alg/ZnO beads were characterized by SEM, FTIR, XRD, and TGA. Different monitoring experimental conditions, such as contact time, pH, BPA concentration, and sorbent dosage, were optimized. The optimum conditions for the adsorption process showed outstanding removal efficiency toward BPA at pH 4.0, contact time 40.0 min, and 40.0 mg L-1 BPA initial concentration. Langmuir, Freundlich, and Temkin isotherm models have been studied for adsorption equilibrium, and the best fit is described by the Langmuir adsorption isotherm. The adsorption kinetics has been studied using pseudo-first-order (PFO), pseudo-second-order (PSO), Elovich, and intraparticle diffusion (IPD) models. The pseudo-second-order kinetic model shows the optimum experimental fit. The monolayer adsorption capacity of the prepared CS/GT*m-Alg/ZnO for BPA was determined to be 38.24 mg g-1. The prepared CS/GT*m-Alg/ZnO beads show advantageous properties, such as their high surface area, high adsorption capacity, reusability, and cost-effectiveness.

| S-EPMC9366769 | biostudies-literature

Proteomic signatures associated with p53 mutational status in lung adenocarcinoma.

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| S-EPMC4403731 | biostudies-literature

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies.

Project description:Single nucleotide variants (SNVs) identified in cancer genomes can be de-convolved using non-negative matrix factorization (NMF) into discrete trinucleotide-based mutational signatures indicative of specific cancer-causing processes. The stability of NMF-generated mutational signatures depends upon the numbers of variants available for analysis. In this work, we sought to assess whether data from well-controlled mouse models can compensate for scarce human data for some cancer types. High quality sequencing data from radiotherapy-induced cancers is particularly scarce and the mutational processes defining ionizing radiation (IR)-induced mutagenesis in vivo are poorly defined. Here, we combine sequencing data from mouse models of IR-induced malignancies and human IR-induced malignancies. To determine whether the signatures identified from IR-exposed subjects can be differentiated from other mutagenic signatures, we included data from an ultraviolet radiation (UV)-induced human skin cancer and from a mouse model of urethane-induced cancers. NMF distinguished all three mutagens and in the pooled analysis IR was associated with mutational signatures common to both species. These findings illustrate the utility of pooled analysis of mouse and human sequencing data.

| S-EPMC5550450 | biostudies-literature

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