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International Journal of Molecular... Dec 2021Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes,... (Review)
Review
Epigenetic changes constitute one of the processes that is involved in the mechanisms of carcinogenicity. They include dysregulation of DNA methylation processes, disruption of post-translational patterns of histone modifications, and changes in the composition and/or organization of chromatin. Benzo(a)pyrene (BaP) influences DNA methylation and, depending on its concentrations, as well as the type of cell, tissue and organism it causes hypomethylation or hypermethylation. Moreover, the exposure to polyaromatic hydrocarbons (PAHs), including BaP in tobacco smoke results in an altered methylation status of the offsprings. Researches have indicated a potential relationship between toxicity of BaP and deregulation of the biotin homeostasis pathway that plays an important role in the process of carcinogenesis. Animal studies have shown that parental-induced BaP toxicity can be passed on to the F1 generation as studied on marine medaka (), and the underlying mechanism is likely related to a disturbance in the circadian rhythm. In addition, ancestral exposure of fish to BaP may cause intergenerational osteotoxicity in non-exposed F3 offsprings. Epidemiological studies of lung cancer have indicated that exposure to BaP is associated with changes in methylation levels at 15 CpG; therefore, changes in DNA methylation may be considered as potential mediators of BaP-induced lung cancer. The mechanism of epigenetic changes induced by BaP are mainly due to the formation of CpG-BPDE adducts, between metabolite of BaP-BPDE and CpG, which leads to changes in the level of 5-methylcytosine. BaP also acts through inhibition of DNA methyltransferases activity, as well as by increasing histone deacetylases HDACs, i.e., HDAC2 and HDAC3 activity. The aim of this review is to discuss the mechanism of the epigenetic action of BaP on the basis of the latest publications.
Topics: 5-Methylcytosine; Animals; Benzo(a)pyrene; Biotin; Carcinogenesis; DNA Methylation; Epigenesis, Genetic; Epigenomics; Female; Histone Deacetylases; Humans; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34948252
DOI: 10.3390/ijms222413453 -
Environment International Oct 2023Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic...
Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes.
Topics: Mice; Animals; Pregnancy; Humans; Female; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Ferroptosis; Abortion, Spontaneous; Benzo(a)pyrene; Endothelial Cells; Placenta; Proteins
PubMed: 37802009
DOI: 10.1016/j.envint.2023.108237 -
Journal of Hazardous Materials Aug 2023Environmental Benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are typical persistent organic pollutants and endocrine...
Environmental Benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are typical persistent organic pollutants and endocrine disrupting chemicals. BaP/BPDE exposure might cause human trophoblast cell dysfunctions and induce miscarriage. However, the underlying mechanisms remain largely elusive. In this study, we found that BPDE exposure induced human trophoblast cell pyroptosis by up-regulating NLRP3/Caspase1/GSDMD pathway. We also identified that lnc-HZ14 was highly expressed in BPDE-exposed trophoblast cells and in recurrent miscarriage (RM) vs healthy control (HC) villous tissues. Lnc-HZ14 promoted trophoblast cell pyroptosis by promoting IRF1-mediated ZBP1 transcription, increasing METTL3-mediated m6A methylation on NLRP3 mRNA and its stability, and also enhancing ZBP1/NLRP3 protein interactions. Knockdown of lnc-HZ14/ZBP1/NLRP3 axis could efficiently alleviate BPDE-induced trophoblast cell pyroptosis. Higher level of pyroptosis, as indicated by the up-regulation of lnc-HZ14/ZBP1/NLRP3 axis, was found in RM vs HC villous tissues. In BaP-exposed mouse model, BaP exposure induced placental tissue pyroptosis and miscarriage by up-regulating murine Zbp1/Nlrp3 axis, and knockdown of Nlrp3 could efficiently reduce placenta pyroptosis and alleviate BaP-induced mouse miscarriage. Serum IL-1β protein level might act as a promising indicator to predict the risk of miscarriage. These findings provided new insights into BaP/BPDE-induced trophoblast cell pyroptosis and miscarriage and might be helpful for further assessment of the toxicological effects of BaP/BPDE on the female reproduction.
Topics: Pregnancy; Humans; Female; Mice; Animals; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Trophoblasts; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Abortion, Spontaneous; Benzo(a)pyrene; Placenta; Methyltransferases; RNA-Binding Proteins
PubMed: 37167865
DOI: 10.1016/j.jhazmat.2023.131543 -
Photochemistry and Photobiology 2023Polycyclic aromatic hydrocarbons (PAHs) are a group of organic compounds derived mostly from the incomplete combustion of fossil fuels and biomass. Human skin can absorb...
Polycyclic aromatic hydrocarbons (PAHs) are a group of organic compounds derived mostly from the incomplete combustion of fossil fuels and biomass. Human skin can absorb PAHs and the uptake increases with their molar mass and lipophilicity. Benzopyrene is high molecular weight PAH frequently appearing in ambient pollution. It exists in two isomeric forms: benzo[a]pyrene (BaP) and benzo[e]pyrene (BeP), which exhibit different biological activity. Although certain properties of benzopyrenes suggested photoreactivity of the compounds, no direct measurements were previously conducted to characterize their photochemical activity. In this study, quantum yield and action spectra of singlet oxygen photogeneration by BaP and BeP were measured by time-resolved near-infrared phosphorescence, and the ability of both compounds to photogenerate superoxide anion was assessed by electron paramagnetic resonance (EPR) spin-trapping. The measurements revealed high efficiency of benzopyrenes to photogenerate singlet oxygen and their ability to photogenerate superoxide anion. Using HaCaT cells as single-layer skin model, we demonstrated concentration-dependent and light-dependent cytotoxicity of BaP and BeP. The compounds induced damage to the cell mitochondria and elevated the levels of intracellular reactive oxygen species.
Topics: Humans; Benzo(a)pyrene; Superoxides; Singlet Oxygen; Benzopyrenes; Keratinocytes; Polycyclic Aromatic Hydrocarbons
PubMed: 36117444
DOI: 10.1111/php.13721 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self-antigen, autoantibody production, and abnormal immune response....
BACKGROUND
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self-antigen, autoantibody production, and abnormal immune response. Cuproptosis is a recently reported cell death form correlated with the initiation and development of multiple diseases. This study intended to probe cuproptosis-related molecular clusters in SLE and constructed a predictive model.
METHODS
We analyzed the expression profile and immune features of cuproptosis-related genes (CRGs) in SLE based on GSE61635 and GSE50772 datasets and identified core module genes associated with SLE occurrence using the weighted correlation network analysis (WGCNA). We selected the optimal machine-learning model by comparing the random forest (RF) model, support vector machine (SVM) model, generalized linear model (GLM), and the extreme gradient boosting (XGB) model. The predictive performance of the model was validated by nomogram, calibration curve, decision curve analysis (DCA), and external dataset GSE72326. Subsequently, a CeRNA network based on 5 core diagnostic markers was established. Drugs targeting core diagnostic markers were acquired using the CTD database, and Autodock vina software was employed to perform molecular docking.
RESULTS
Blue module genes identified using WGCNA were highly related to SLE initiation. Among the four machine-learning models, the SVM model presented the best discriminative performance with relatively low residual and root-mean-square error (RMSE) and high area under the curve (AUC = 0.998). An SVM model was constructed based on 5 genes and performed favorably in the GSE72326 dataset for validation (AUC = 0.943). The nomogram, calibration curve, and DCA validated the predictive accuracy of the model for SLE as well. The CeRNA regulatory network includes 166 nodes (5 core diagnostic markers, 61 miRNAs, and 100 lncRNAs) and 175 lines. Drug detection showed that D00156 (Benzo (a) pyrene), D016604 (Aflatoxin B1), D014212 (Tretinoin), and D009532 (Nickel) could simultaneously act on the 5 core diagnostic markers.
CONCLUSION
We revealed the correlation between CRGs and immune cell infiltration in SLE patients. The SVM model using 5 genes was selected as the optimal machine learning model to accurately evaluate SLE patients. A CeRNA network based on 5 core diagnostic markers was constructed. Drugs targeting core diagnostic markers were retrieved with molecular docking performed.
Topics: Humans; Aflatoxin B1; Autoimmune Diseases; Benzo(a)pyrene; Lupus Erythematosus, Systemic; MicroRNAs; Molecular Docking Simulation; Copper; Apoptosis
PubMed: 37313407
DOI: 10.3389/fimmu.2023.1157196 -
Biochimie Aug 2019Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers.... (Review)
Review
Despite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants, notably chemicals like polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread pollutants in our environment resulting from incomplete combustion or pyrolysis of organic material, and thus produced by both natural and anthropic sources; notably benzo[a]pyrene (B[a]P), i.e. the prototypical molecule of this family, that can be detected in cigarette smoke, diesel exhaust particles, occupational-related fumes, and grilled food. This molecule is a well-recognized carcinogen belonging to group 1 carcinogens. Indeed, it can target the different steps of the carcinogenic process and all cancer hallmarks. Interestingly, H dynamics have been described as key parameters for the occurrence of several, if not all, of these hallmarks. However, information regarding the role of such parameters during environmental carcinogenesis is still very scarce. The present review will thus mainly give an overview of the impact of B[a]P on H dynamics in liver cells, and will show how such alterations might impact different aspects related to the finely-tuned balance between cell death and survival processes, thereby likely favoring environmental carcinogenesis. In total, the main objective of this review is to encourage further research in this poorly explored field of environmental molecular toxicology.
Topics: Animals; Benzo(a)pyrene; Carcinogenesis; Carcinogens; Environmental Exposure; Humans; Liver; Neoplasms; Protons
PubMed: 31228544
DOI: 10.1016/j.biochi.2019.06.013 -
Environmental Health Perspectives Jan 2023Recurrent miscarriage (RM) affects 1%-3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene...
BACKGROUND
Recurrent miscarriage (RM) affects 1%-3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene [B(a)P], a representative of polycyclic aromatic hydrocarbons (PAHs), is correlated with miscarriage. However, the underlying mechanisms of B(a)P/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-induced trophoblast cell dysfunctions and miscarriage remain largely unknown.
OBJECTIVE
The objective was to discover the role(s) of a novel lncRNA, , in the regulation of BPDE-inhibited migration and invasion of trophoblast cells and the occurrence of miscarriage.
METHOD
Human trophoblast cells were treated with 0, 0.25, 0.5, BPDE with or without corresponding silencing or overexpression. Using these cells, we evaluated cell migration and invasion, the mRNA and protein levels of members of the PLD1/RAC1/CDC42 pathway, the regulatory roles of lnc-HZ09 in PLD1 transcription and mRNA stability, and lnc-HZ09 transcription and stability. Human villous tissues were collected from RM () group and their matched healthy control (HC, ) group. We evaluated the levels of BPDE-DNA adducts, lnc-HZ09, and the mRNA and protein expression of members of the PLD1/RAC1/CDC42 pathway, and correlated their relative expression levels. We further constructed 0, 0.05 or B(a)P-induced mouse miscarriage model (each ), in which the mRNA and protein expression of members of the Pld1/Rac1/Cdc42 pathway were measured.
RESULTS
We identified a novel . Human trophoblast cells treated with exhibited less cell migration and invasion. In addition, the levels of this lncRNA were higher in villous tissues from women with recurrent miscarriage than those from healthy individuals. SP1-mediated PLD1 mRNA levels were lower, and HuR-mediated PLD1 mRNA stability was less in trophoblast cells overexpressing . However, trophoblast cells treated with MSX1 had higher levels of , and METTL3-mediated m6A methylation on resulted in greater RNA stability. In BPDE-treated human trophoblast cells and in RM villous tissues, MSX1-mediated transcription and METTL3-mediated stability were both greater. In our mouse miscarriage model, B(a)P-treated mice had lower mRNA and protein levels of members of the Pld1/Rac1/Cdc42 pathway.
DISCUSSION
These results suggest that in human trophoblast cells, BPDE exposure up-regulated level, suppressed PLD1/RAC1/CDC42 pathway, and inhibited migration and invasion, providing new insights in understanding the causes and mechanisms of unexplained miscarriage. https://doi.org/10.1289/EHP10477.
Topics: Pregnancy; Humans; Female; Mice; Animals; Trophoblasts; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; RNA, Long Noncoding; Benzo(a)pyrene; Abortion, Habitual; RNA, Messenger; Methyltransferases
PubMed: 36719213
DOI: 10.1289/EHP10477 -
Chemical Research in Toxicology Dec 2022Benzo[]pyrene (BaP) is known to form DNA adduct following metabolic activation, which causes phosphorylation of histone H2AX (γ-H2AX). Recent studies have shown that...
Benzo[]pyrene (BaP) is known to form DNA adduct following metabolic activation, which causes phosphorylation of histone H2AX (γ-H2AX). Recent studies have shown that histone deacetylase (HDAC) inhibitors enhanced BaP-induced gene expression. In this study, we examined the relationship between the HDAC inhibitor-augmented metabolic activation and BaP-induced γ-H2AX. Sodium butyrate (SB), a typical HDAC inhibitor, enhanced BaP-induced γ-H2AX. The enhanced DNA damage was further confirmed by biased sinusoidal field gel electrophoresis, which detects DNA double-strand breaks. SB remarkably augmented BaP-induced gene expression, and -overexpressing cells showed elevated generation of γ-H2AX. Furthermore, SB enhanced intracellular oxidation after treatment with BaP. These results suggested that SB-induced CYP1A1 upregulation facilitated BaP metabolism, which might result in excess DNA adducts or oxidative DNA damages, leading to augmentation of γ-H2AX.
Topics: Benzo(a)pyrene; Cytochrome P-450 CYP1A1; Histone Deacetylase Inhibitors; DNA Adducts; Butyric Acid
PubMed: 36399157
DOI: 10.1021/acs.chemrestox.2c00238 -
Journal of Food Science Apr 2022Cachaça is a beverage of great cultural and economic importance for Brazil. It is made up of several substances that are responsible for the flavor of the beverage.... (Review)
Review
Cachaça is a beverage of great cultural and economic importance for Brazil. It is made up of several substances that are responsible for the flavor of the beverage. Countless substances of a toxic nature can also be present, such as polycyclic aromatic hydrocarbons (PAHs). These contaminants are commonly found in beverages and food. They have been studied because their toxicity is related to their mutagenic and carcinogenic properties, and they pose a risk to human health. The PAHs can be formed in cachaça during different stages of processing. In this work, the presence of PAHs (naphthalene, acenaphene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benzo[a]anthracene, acephenylene, and benzo[a]pyrene) was investigated during the storage of the beverage in plastic containers. Thus, samples from five producers of cachaça in the state of Minas Gerais were stored for up to 8 months in polyethylene terephthalate (PET) packaging from three different manufacturers. Samples stored for 4 and 8 months were analyzed by high-performance liquid chromatography, and 10 PAHs (naphthalene, acenaphene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benzo[a]anthracene, acephenylene, and benzo[a]pyrene) were identified and quantified. An increase in PAH concentration in cachaça samples with the storage time in plastic containers was observed. The three different packages contributed to the contamination of the cachaça samples with different PAHs. The highest concentration (approximately 11.0 µg L ) of fluorene was observed in sample A from the three packages and during the two storage times. Thus, it can be inferred that the storage of cachaça in bottles of PET is inadequate for maintaining the quality of the beverage. PRACTICAL APPLICATION: Therefore, it can be inferred from the results of the analysis that PET packages are sources of PAHs, and the storage time in these packages contributed to the increase in the concentration of these contaminants in the beverage. These results suggest that a review of the legislation regarding the use of PET packaging for beverage storage is necessary, as these compounds are carcinogenic.
Topics: Benzo(a)pyrene; Carcinogens; Humans; Plastics; Polycyclic Aromatic Hydrocarbons; Polyethylene Terephthalates
PubMed: 35275405
DOI: 10.1111/1750-3841.16095 -
Environmental Science and Pollution... Apr 2022Stormwater results from precipitation events and melting snow running off urban landscapes and typically being released into receiving water bodies with little to no...
Stormwater results from precipitation events and melting snow running off urban landscapes and typically being released into receiving water bodies with little to no treatment. Despite evidence of its deleterious impacts, snowmelt (SM) management and treatment are limited, partly due to a lack of quality and loading data. This study examines snowmelt quality during the spring for a cold climate, semi-arid Canadian city (Saskatoon, Saskatchewan). Four snow storage facilities receiving urban snow plowed from roads in mixed land use urban catchments (228 km) were sampled including snow piles (five events) and SM (twelve events) runoff in 2019 and 2020. Samples were analyzed for pH, EC, TDS, TSS, COD, DOC, metals, chloride, PAHs, and Raphidocelis subcapitata and Vibrio fischeri toxicity. Notable event-specific TSS spikes occurred on April 13, 2019 (3,513 mg/L), and April 24, 2019 (3,838 mg/L), and TDS, chloride, and manganese on March 26, 2020 (15,000 mg/L, 5,800 mg/L, 574 mg/L), April 17, 2020 (5,200 mg/L, 2,600 mg/L, 882 mg/L), and April 23, 2020 (5,110 mg/L, 2,900 mg/L, 919 mg/L), though chloride remained elevated through May 1, 2020, samples (1,000 mg/L). Additionally, at two sites sampled April 13, 2019, pulses of aluminum (401 mg/L) and PAHs (pyrene, phenanthrene, anthracene; 71 µg/L, 317 µg/L, 182 µg/L) were detected. Concentrations of fluorene, benzo[a]pyrene, pyrene, phenanthrene, and anthracene in almost all SP samples exceeded national aquatic toxicity guideline thresholds, while 50% of SM samples exceeded guideline thresholds for benzo[a]pyrene and pyrene, and almost all exceeded the threshold for anthracene. Nevertheless, the EC for R. subcapitata and V. fischeri was observed, if at all, above expected toxicity thresholds.
Topics: Benzo(a)pyrene; Chlorides; Environmental Monitoring; Polycyclic Aromatic Hydrocarbons; Saskatchewan; Snow
PubMed: 34984614
DOI: 10.1007/s11356-021-18340-2