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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 -
International Journal of Molecular... Jun 2022Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments.... (Review)
Review
Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments. It is present in cigarette smoke as well as in food products, especially when smoked and grilled. Human exposure to B[]P is therefore common. Research shows growing evidence concerning toxic effects induced by this substance. This xenobiotic is metabolized by cytochrome P450 (CYP P450) to carcinogenic metabolite: 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[]pyrene (BPDE), which creates DNA adducts, causing mutations and malignant transformations. Moreover, B[]P is epigenotoxic, neurotoxic, and teratogenic, and exhibits pro-oxidative potential and causes impairment of animals' fertility. CYP P450 is strongly involved in B[]P metabolism, and it is simultaneously expressed as a result of the association of B[]P with aromatic hydrocarbon receptor (AhR), playing an essential role in the cancerogenic potential of various xenobiotics. In turn, polymorphism of genes determines the sensitivity of the organism to B[]P. It was also observed that B[]P facilitates the multiplication of viruses, which may be an additional problem with the widespread COVID-19 pandemic. Based on publications mainly from 2017 to 2022, this paper presents the occurrence of B[]P in various environmental compartments and human surroundings, shows the exposure of humans to this substance, and describes the mechanisms of its toxicity.
Topics: Animals; Benzo(a)pyrene; COVID-19; Carcinogens; Cytochrome P-450 Enzyme System; DNA Adducts; Humans; Pandemics; Polycyclic Aromatic Hydrocarbons
PubMed: 35683027
DOI: 10.3390/ijms23116348 -
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 -
Free Radical Biology & Medicine Jun 2017The genetic material of all organisms is susceptible to modification. In some instances, these changes are programmed, such as the formation of DNA double strand breaks... (Review)
Review
The genetic material of all organisms is susceptible to modification. In some instances, these changes are programmed, such as the formation of DNA double strand breaks during meiotic recombination to generate gamete variety or class switch recombination to create antibody diversity. However, in most cases, genomic damage is potentially harmful to the health of the organism, contributing to disease and aging by promoting deleterious cellular outcomes. A proportion of DNA modifications are caused by exogenous agents, both physical (namely ultraviolet sunlight and ionizing radiation) and chemical (such as benzopyrene, alkylating agents, platinum compounds and psoralens), which can produce numerous forms of DNA damage, including a range of "simple" and helix-distorting base lesions, abasic sites, crosslinks and various types of phosphodiester strand breaks. More significant in terms of frequency are endogenous mechanisms of modification, which include hydrolytic disintegration of DNA chemical bonds, attack by reactive oxygen species and other byproducts of normal cellular metabolism, or incomplete or necessary enzymatic reactions (such as topoisomerases or repair nucleases). Both exogenous and endogenous mechanisms are associated with a high risk of single strand breakage, either produced directly or generated as intermediates of DNA repair. This review will focus upon the creation, consequences and resolution of single strand breaks, with a particular focus on two major coordinating repair proteins: poly(ADP-ribose) polymerase 1 (PARP1) and X-ray repair cross-complementing protein 1 (XRCC1).
Topics: Animals; Benzopyrenes; DNA Breaks, Single-Stranded; DNA Damage; DNA Repair; Humans; Nervous System Diseases; Poly (ADP-Ribose) Polymerase-1; Radiation, Ionizing; Reactive Oxygen Species; Sunlight; X-ray Repair Cross Complementing Protein 1
PubMed: 27890643
DOI: 10.1016/j.freeradbiomed.2016.11.039 -
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 -
Molecular Microbiology Aug 2018The growing release of organic contaminants into the environment due to industrial processes has inevitably increased the incidence of their exposure to humans which... (Review)
Review
The growing release of organic contaminants into the environment due to industrial processes has inevitably increased the incidence of their exposure to humans which often results in negative health effects. Microorganisms are also increasingly exposed to the pollutants, yet their diverse metabolic capabilities enable them to survive toxic exposure making these degradation mechanisms important to understand. Fungi are the most abundant microorganisms in the environment, yet less has been studied to understand their ability to degrade contaminants than in bacteria. This includes specific enzyme production and the genetic regulation which guides metabolic networks. This review intends to compare what is known about bacterial and fungal degradation of toxic compounds using benzo(a)pyrene as a relevant example. Most research is done in the context of using fungi for bioremediation, however, we intend to also point out how fungal metabolism may impact human health in other ways including through their participation in microbial communities in the human gut and skin and through inhalation of fungal spores.
Topics: Bacteria; Benzo(a)pyrene; Biodegradation, Environmental; Environmental Pollutants; Environmental Pollution; Fungi; Humans; Soil Microbiology
PubMed: 29995976
DOI: 10.1111/mmi.14062 -
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 -
Biochemistry. Biokhimiia Nov 2022Lung cancer (LC), one of the most common malignant neoplasms, is the leading cause of high cancer mortality worldwide. Smoking is a risk factor for almost all... (Review)
Review
Lung cancer (LC), one of the most common malignant neoplasms, is the leading cause of high cancer mortality worldwide. Smoking is a risk factor for almost all histological types of LC. Benzo[a]pyrene (BaP), one of the main constituents of tobacco smoke, can cause cancer. It has been established that its toxic effects can develop in the following ways: genotoxic (formation of adducts with DNA) and non-genotoxic or epigenetic. The latter is less known, although it is known that BaP activates aryl hydrocarbon receptor (AhR), which regulate transcription of many target genes, including microRNAs, which can lead to initiation and enhancement of the malignant cell transformation. Recent studies are evaluating the role of AhR in the regulation of immune checkpoints, as cigarette smoke and BaP induce the AhR-regulated expression of PD-L1 (CD274) in lung epithelial cells in vitro and in vivo. In addition, kynurenine (a metabolite of tryptophan) has been found to stimulate the PD-1 (CD279) expression in cytotoxic T cells by activating AhR. Recent studies confirm great importance of AhR expressed in malignant cells for suppression of antitumor immunity. All this makes us rethink the role of AhR in lung carcinogenesis and investigate the mechanisms of its activation by exogenous and endogenous ligands. This review highlights the current understanding of the functional features of AhR and its role in the LC pathogenesis.
Topics: Humans; Receptors, Aryl Hydrocarbon; Benzo(a)pyrene; Lung; Carcinogenesis; Lung Neoplasms
PubMed: 36509717
DOI: 10.1134/S0006297922110013 -
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 -
Advanced Science (Weinheim,... Sep 2023Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show...
Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon-λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.
Topics: Aged; Male; Humans; Animals; Mice; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Benzo(a)pyrene; Lung; Nuclear Receptor Subfamily 4, Group A, Member 2; Serine Endopeptidases
PubMed: 37428471
DOI: 10.1002/advs.202300834