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Bioinformatics (Oxford, England) Jun 2022Molecular carcinogenicity is a preventable cause of cancer, but systematically identifying carcinogenic compounds, which involves performing experiments on animal...
MOTIVATION
Molecular carcinogenicity is a preventable cause of cancer, but systematically identifying carcinogenic compounds, which involves performing experiments on animal models, is expensive, time consuming and low throughput. As a result, carcinogenicity information is limited and building data-driven models with good prediction accuracy remains a major challenge.
RESULTS
In this work, we propose CONCERTO, a deep learning model that uses a graph transformer in conjunction with a molecular fingerprint representation for carcinogenicity prediction from molecular structure. Special efforts have been made to overcome the data size constraint, such as multi-round pre-training on related but lower quality mutagenicity data, and transfer learning from a large self-supervised model. Extensive experiments demonstrate that our model performs well and can generalize to external validation sets. CONCERTO could be useful for guiding future carcinogenicity experiments and provide insight into the molecular basis of carcinogenicity.
AVAILABILITY AND IMPLEMENTATION
The code and data underlying this article are available on github at https://github.com/bowang-lab/CONCERTO.
Topics: Animals; Carcinogens; Forecasting; Mutagens; Neural Networks, Computer
PubMed: 35758812
DOI: 10.1093/bioinformatics/btac266 -
Archives of Toxicology Sep 2022Methyl acrylate (MA) and ethyl acrylate (EA) had previously tested positive for mutagenicity in vitro, but in vivo studies were negative. One of the metabolism pathways...
Methyl acrylate (MA) and ethyl acrylate (EA) had previously tested positive for mutagenicity in vitro, but in vivo studies were negative. One of the metabolism pathways of alkyl acrylates is conjugation with glutathione. The glutathione availability is restricted in standard in vitro test systems so that they do not reflect the in vivo metabolism in this respect. We investigated whether the addition of glutathione to the in vitro L5178Y/TK mouse lymphoma mutagenicity test prevents alkyl acrylate's mutagenicity in vitro. We also investigated whether the quantitative relationships support the notion that the GSH supplemented in vitro systems reflect the true in vivo activity. Indeed, glutathione concentrations as low as 1 mM completely negate the mutagenicity of MA and EA in the L5178Y/TK mouse lymphoma mutagenicity test up to the highest concentrations of the two acrylates tested, 35 µg/ml, a higher concentration than that previously found to be mutagenic in this test (14 µg MA/ml and 20 µg EA/ml). 1 mM Glutathione reduced the residual MA and EA at the end of the exposure period in the mutagenicity tests by 96-97%, but in vivo up to 100 mg/kg body weight MA and EA left the glutathione levels in the mouse liver and forestomach completely intact. It is concluded that the in-situ levels of glutathione, 7.55 ± 0.57 and 2.84 ± 0.22 µmol/g mouse liver and forestomach, respectively, can efficiently protect against MA and EA-induced mutagenicity up to the high concentration of 100 mg MA and EA/kg body weight and that the negative in vivo mutagenicity tests on MA and EA reflect the true in vivo situation.
Topics: Acrylates; Animals; Body Weight; Glutathione; Lymphoma; Mice; Mutagenicity Tests; Mutagens
PubMed: 35704047
DOI: 10.1007/s00204-022-03322-1 -
Mutation Research. Reviews in Mutation... 2016Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally... (Review)
Review
Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.
Topics: Animals; Carcinogenicity Tests; Carcinogens; Environmental Exposure; Epigenesis, Genetic; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Mutagenicity Tests; Mutagens; Occupational Exposure
PubMed: 27234561
DOI: 10.1016/j.mrrev.2016.03.004 -
Brazilian Journal of Microbiology :... 2017Dyes are recalcitrant compounds that resist conventional biological treatments. The degradation of three textile dyes (Indigo, RBBR and Sulphur Black), and the...
Dyes are recalcitrant compounds that resist conventional biological treatments. The degradation of three textile dyes (Indigo, RBBR and Sulphur Black), and the dye-containing liquid effluent and solid waste from the Municipal Treatment Station, Americana, São Paulo, Brazil, by the cyanobacteria Anabaena flos-aquae UTCC64, Phormidium autumnale UTEX1580 and Synechococcus sp. PCC7942 was evaluated. The dye degradation efficiency of the cyanobacteria was compared with anaerobic and anaerobic-aerobic systems in terms of discolouration and toxicity evaluations. The discoloration was evaluated by absorption spectroscopy. Toxicity was measured using the organisms Hydra attenuata, the alga Selenastrum capricornutum and lettuce seeds. The three cyanobacteria showed the potential to remediate textile effluent by removing the colour and reducing the toxicity. However, the growth of cyanobacteria on sludge was slow and discoloration was not efficient. The cyanobacteria P. autumnale UTEX1580 was the only strain that completely degraded the indigo dye. An evaluation of the mutagenicity potential was performed by use of the micronucleus assay using Allium sp. No mutagenicity was observed after the treatment. Two metabolites were produced during the degradation, anthranilic acid and isatin, but toxicity did not increase after the treatment. The cyanobacteria showed the ability to degrade the dyes present in a textile effluent; therefore, they can be used in a tertiary treatment of effluents with recalcitrant compounds.
Topics: Aerobiosis; Allium; Anaerobiosis; Animals; Biotransformation; Brazil; Chlorophyta; Coloring Agents; Cyanobacteria; Hydra; Industrial Waste; Lactuca; Mutagens; Seeds; Textiles; X-Ray Absorption Spectroscopy
PubMed: 28341397
DOI: 10.1016/j.bjm.2016.09.012 -
Anais Da Academia Brasileira de Ciencias 2022Kavain is one of the main kavalactones of Piper methysticum (Piperaceae) with anxiolytic, analgesic, and antioxidant activities. Therefore, the aim of the study was to...
Kavain is one of the main kavalactones of Piper methysticum (Piperaceae) with anxiolytic, analgesic, and antioxidant activities. Therefore, the aim of the study was to evaluate the cytotoxic, mutagenic, and antimutagenic potential of kavain in Allium cepa cells. Roots of A. cepa were transferred to the negative (2% acetone) and positive (10 µg/mL of Methylmethanesulfonate, MMS) controls and to the concentrations of kavain (32, 64 and 128 µg/mL) for 48 h. A total of 5,000 meristematic cells were analyzed under an optical microscope to determine the mitotic index, mean number of chromosomal alterations and percentage of damage reduction. Data were analyzed by Kruskal-Wallis test (p <0.05). All concentrations of kavain were not cytotoxic and did not show significant chromosomal changes when compared to 2% acetone. Kavain showed a cytoprotective effect in the pre (128 μg/mL) and in the post-treatment (32 and 64 μg/mL) and reduced damage against the mutagenic action of MMS in all concentrations of the pre and simultaneous and at the highest of post (128 μg/mL). Kavain promoted a significant reduction in micronuclei, nuclear buds and chromosomal losses in relation to MMS. The observed data indicate the importance of kavain for the inhibition of damage and chemoprevention.
Topics: Acetone; Chromosome Aberrations; Meristem; Mutagens; Onions; Plant Roots; Pyrones
PubMed: 35703688
DOI: 10.1590/0001-3765202220200520 -
Journal of Applied Toxicology : JAT Oct 2014There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those... (Review)
Review
There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those involved in the process. The issue lies in the inability of the classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern. This has its origins in the early years of toxicology when it was thought that a relatively small number of chemicals would be either carcinogens or reproductive toxicants, but this has turned out not to be the case. This can cause problems in communicating to the users of chemicals, including the public, the nature of the hazard presented by chemicals. Processes have been developed within the classification system for setting specific concentration limits which assess the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. However these categories are not otherwise used in classification. It is proposed that their wider use would bring the advantages of transparency, clarity of communication, certainty of the process and would allow chemicals with a high degree of hazard to be identified and managed in an appropriate way.
Topics: Animals; Carcinogens; European Union; Humans; Mutagens; Reproduction; Risk Management; Teratogens
PubMed: 25059745
DOI: 10.1002/jat.3045 -
International Journal of Toxicology 2023Hesperetin glucosides such as hesperidin and hesperetin-7-glucoside are abundantly present in citrus fruits and have various pharmacological properties. However, the...
Hesperetin glucosides such as hesperidin and hesperetin-7-glucoside are abundantly present in citrus fruits and have various pharmacological properties. However, the potential toxicity of hesperetin glucosides remains unclear. An initial assessment of the safety of hesperetin-7-glucoside-β-cyclodextrin inclusion complex (HPTGCD) as a functional food ingredient was undertaken to assess toxicity and mutagenic potential. A bacterial reverse mutation assay (Ames test) using (strains TA98, TA1535, TA100, and TA1537) and (strain WP2 uvrA) with HPTGCD (up to 5000 µg/plate) in the absence and presence of metabolic activation was negative. In a single oral (gavage) toxicity study in male and female rats, HPTGCD at dose up to 2000 mg/kg did not produce mortality nor clinical signs of toxicity or change in body weight. In a subchronic oral (dietary admix) toxicity study in rats receiving 0, 1.5, 3, and 5% HPTGCD for 13 weeks, no adverse effects were noted and the no-observed-adverse-effect level (NOAEL) was 5% in the diet (equivalent to 3267.7 mg/kg/day for males and to 3652.4 mg/kg/day for females). These results provide initial evidence of the safety of HPTGCD.
Topics: Rats; Male; Female; Animals; Mutagens; Mutagenicity Tests; Hesperidin; Mutation
PubMed: 36280476
DOI: 10.1177/10915818221134022 -
Mutation Research. Genetic Toxicology... 2020This work investigates a completely novel and experimental concept of exposing L5178Y cells at the air-agar-interface to mainstream cigarette smoke aerosol (Kentucky...
This work investigates a completely novel and experimental concept of exposing L5178Y cells at the air-agar-interface to mainstream cigarette smoke aerosol (Kentucky reference 3R4F). This study highlights the associated challenges of combining a suspension cell line alongside an in vitro aerosol exposure system. To achieve a monolayer, cells were 'seeded' in a concentrated cell super-mix suspension onto an RPMI/agar-matrix -base. The resulting cell suspension media was adsorbed into the agar base leaving the L5178Y cells lightly suspended on the agar surface, approximating a monolayer. Cells were deemed supportable on the agar-matrix, viable and recoverable. Using Vitrocell VC 10 exposure system and the Ames 4 exposure module, L5178Y cells were successfully exposed to a dynamic cigarette smoke aerosol, recovered and assessed for mutant frequencies, using standard assay procedures. Method development included assessment of flowing air conditions, plating efficiency and recovery of L5178Y cells from the agar-matrix surface. Positive controls MMS and B[a]P were successfully incorporated into the agar-matrix and metabolic activation was achieved by S-9 incorporation into the same agar-base-matrix. B[a]P demonstrated metabolic activation and positive response, suggesting a clear cellular interaction with the agar-matrix. Whole smoke exposed cells in the presence of metabolic activation showed a clear dose response and increasing mutant frequencies, well in excess of the controls (air and incubator) and the global evaluation factor following a 2 or 3 day expression period. This experimental concept demonstrates that L5178Y cells can be exposed to cigarette smoke aerosol, using a completely novel and a previously untested approach. Although this work successfully demonstrates the approach is viable and cells can be plated and maintained on an agar-matrix, more optimisation and robustness assessment is required before it can be considered fully adapted and used alongside other whole aerosol methodologies for the assessment of cigarette smoke and other inhaled aerosols.
Topics: Aerosols; Agar; Air; Animals; Cell Line; Dose-Response Relationship, Drug; Electronic Nicotine Delivery Systems; Humans; Lymphoma; Mice; Mutagenicity Tests; Mutagens; Smoke
PubMed: 32928375
DOI: 10.1016/j.mrgentox.2020.503230 -
Toxicology Feb 2017Antarctica moss Sanionia uncinata (Hedw.) Loeske is exposed in situ to damaging levels of ultraviolet (UV) radiation. This moss has the ability to respond to UV...
Antarctica moss Sanionia uncinata (Hedw.) Loeske is exposed in situ to damaging levels of ultraviolet (UV) radiation. This moss has the ability to respond to UV radiation exposure producing secondary metabolites such as flavonoids, and has been recommended as a potential source of photoprotective compounds and antioxidants. The aim of the present paper was to investigate the free-radical scavenging activity and mutagenic and photomutagenic properties of methanolic (ME), hydroethanolic (HE) and ethanolic (EE) extracts of S. uncinata. The phenolic contents were evaluated by high-performance liquid chromatography (HPLC) and spectrophotometry. The findings showed that ME and EE presented the highest phenolic contents and inhibited free radical-scavenging activity against 2,2'-diphenyl-1 picrylhydrazyl (DPPH) and the HPLC analysis indicated several classes of phenolic acids and flavonoids. The sun protection factors (SPF) were determined by an in vitro method and the results showed significant values. The SPF values of BZ-3 at 50μg/mL increased significantly in association with ME, HE and EE. The extracts did not induce mutagenicity in auxotrophic Salmonella typhimurium histidine and photomutagenicity was not detected in the TA102 and TA104 strains after exposure to UV-A at doses of up to 6.5J/cm for the TA102 strain and up to 0.24J/cm for the TA104 strain. In addition, with the exception of ME, all the extracts induced photoprotective effects in the presence of the TA104 strain at 0.04J/cm. The present results suggest that S. uncinata extracts did not induce photomutation and showed promise for photoprotection against the photobiological and ROS-inducing effects of the UV-A radiation.
Topics: Animals; Antarctic Regions; Bryophyta; Dose-Response Relationship, Drug; Free Radical Scavengers; Mutagenicity Tests; Mutagens; Plant Extracts; Rats; Salmonella typhimurium; Sunscreening Agents; Ultraviolet Rays
PubMed: 27234318
DOI: 10.1016/j.tox.2016.05.021 -
International Journal of Environmental... Feb 2018The chemical composition of particles varies with space and time and depends on emission sources, atmospheric chemistry and weather conditions. Evidence suggesting that...
The chemical composition of particles varies with space and time and depends on emission sources, atmospheric chemistry and weather conditions. Evidence suggesting that particles differ in toxicity depending on their chemical composition is growing. This in vitro study investigated the biological effects of PM in relation to PM-associated chemicals. PM was sampled in ambient air at an urban traffic site (Borgerhout) and a rural background location (Houtem) in Flanders (Belgium). To characterize the toxic potential of PM, airway epithelial cells (Beas-2B cells) were exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) and the induction of interleukin-8 (IL-8). The mutagenic capacity was assessed using the Ames II Mutagenicity Test. The endotoxin levels in the collected samples were analyzed and the oxidative potential (OP) of PM particles was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM included tracers for biomass burning (levoglucosan, mannosan and galactosan), elemental and organic carbon (EC/OC) and polycyclic aromatic hydrocarbons (PAHs). Most samples displayed dose-dependent cytotoxicity and IL-8 induction. Spatial and temporal differences in PM toxicity were seen. PM collected at the urban site was characterized by increased pro-inflammatory and mutagenic activity as well as higher OP and elevated endotoxin levels compared to the background area. Reduced cell viability (-0.46 < < -0.35, < 0.01) and IL-8 induction (-0.62 < < -0.67, < 0.01) were associated with all markers for biomass burning, levoglucosan, mannosan and galactosan. Furthermore, direct and indirect mutagenicity were associated with tracers for biomass burning, OC, EC and PAHs. Multiple regression analyses showed levoglucosan to explain 16% and 28% of the variance in direct and indirect mutagenicity, respectively. Markers for biomass burning were associated with altered cellular responses and increased mutagenic activity. These findings may indicate a role of biomass burning in the observed adverse health effect of particulate matter.
Topics: Air Pollutants; Belgium; Carbon; Cell Survival; Dose-Response Relationship, Drug; Environmental Monitoring; Galactose; Glucose; Interleukin-8; Mannose; Mutagens; Particulate Matter; Polycyclic Aromatic Hydrocarbons; Rural Health; Urban Health
PubMed: 29439546
DOI: 10.3390/ijerph15020320