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Toxicology Mechanisms and Methods May 2024Torsional stress in double-stranded DNA enables and regulates facets of chromosomal metabolism, replication, and transcription and requires regulatory enzymatic systems...
Torsional stress in double-stranded DNA enables and regulates facets of chromosomal metabolism, replication, and transcription and requires regulatory enzymatic systems including topoisomerases and histone methyltransferases. As such, this machinery may be subject to deleterious effects from reactive mutagens, including ones from carcinogenic polycyclic aromatic hydrocarbon (PAH) adduct formation with DNA. Supercoiled plasmid DNA was investigated for its torsional responses to adducts formed from PAH benzylic carbocation reactive intermediates created spontaneously by release of leaving groups. PAH sulfate esters were found to (1) unwind DNA in a concentration dependent manner, and (2) provide maximum unwinding in a pattern consistent with known carcinogenicities of the parent PAHs, that is, 6-methylbenzo[a]pyrene > 7,12-methylbenz[a]anthracene > 3-methylcholanthrene > 9-methylanthracene > 7-methylbenz[a]anthracene > 1-methylpyrene. Supercoil unwinding was demonstrated to be dependent on the presence of sulfate or chloride leaving groups such that reactive carbocations were generated by hydrolysis. modeling of intercalative complex topology showed PAH benzylic carbocation reactive functional groups in alignment with target nucleophiles on guanine bases in a 5'-dCdG-3' pocket in agreement with known formation of nucleotide adducts. Inhibitory or modulatory effects on PAH-induced supercoil unwinding were seen with ascorbic acid and an experimental antineoplastic agent Antineoplaston A10 in agreement with their known anticarcinogenic properties. In summary, the reactive PAH intermediates studied here undoubtedly participate in well-known mutational mechanisms such as frameshifts and apurinic site generation. However, they are also capable of random disruption of chromosomal supercoiling in a manner consistent with the known carcinogenicities of the parent compounds, and this mechanism may represent an additional detrimental motif worthy of further study for a more complete understanding of chemical carcinogenicity.
Topics: Polycyclic Aromatic Hydrocarbons; DNA; Anthracenes; Sulfates; Deoxyribonucleotides; DNA Adducts
PubMed: 38133498
DOI: 10.1080/15376516.2023.2297836 -
Molecular Carcinogenesis Jun 2024Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins...
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.
PubMed: 38925569
DOI: 10.1002/mc.23783 -
The Science of the Total Environment Jan 2024The initial step in the assessment of the ecological risk of pollutants is to determine the predicted no-effect concentration (PNEC). However, ecological risk...
The initial step in the assessment of the ecological risk of pollutants is to determine the predicted no-effect concentration (PNEC). However, ecological risk assessments of eight carcinogenic polycyclic aromatic hydrocarbons (PAHs), including dimethylbenz[a]anthracene (DMBA), methylcholanthrene (MCA), benzo(a)anthracene (BaA), chrysene (CHR), benzo(b)fluoranthene (BbF), benzo(k)fluoranthene (BkF), benzo(a)pyrene (BaP), and dibenzo(a,h)anthracene (DBA), are rarely conducted due to the lack of their PNECs based on test data. In this study, quantitative structure-activity relationship (QSAR) models and interspecies correlation estimation (ICE) models were combined to predict the acute toxicity of these eight target PHAs. A Kolmogorov-Smirnov analysis for species sensitivity distributions (SSDs) of native and all species was conducted. There was no significant difference between the predictions for native Chinese species and the predictions for all species by the QSAR-ICE models. In addition, the feasibility of the QSAR-ICE models was demonstrated by comparing the SSD curves constructed by measured toxicity data of BaP and those predicted by the QSAR-ICE models. The PNECs of the eight PAHs were estimated based on the SSDs and acute to chronic ratio (ACR) method; these data were 0.071 μg/L, 0.033 μg/L, 0.049 μg/L, 0.114 μg/L, 0.019 μg/L, 0.021 μg/L, 0.038 μg/L and 0.054 μg/L for DMBA, DBA, BaP, MCA, BaA, CHR, BbF, BkF, respectively. The higher PNECs of the alkylated PAHs suggested their lower ecological risks. Based on the mixed risk quotient (mRQ) of PAHs through the concentration addition (CA) model, high ecological risk watersheds, such as the Songhua River (mRQ = 1.95), the Liao River (mRQ = 4.59), and the Huai River (mRQ = 1.93), were identified.
Topics: Polycyclic Aromatic Hydrocarbons; Rivers; China; Environmental Pollutants; Anthracenes
PubMed: 37802352
DOI: 10.1016/j.scitotenv.2023.167590 -
FEBS Letters Jun 2024The aryl hydrocarbon receptor (AhR) forms a complex with the HSP90-XAP2-p23 molecular chaperone when the cells are exposed to toxic compounds. Recently,...
The aryl hydrocarbon receptor (AhR) forms a complex with the HSP90-XAP2-p23 molecular chaperone when the cells are exposed to toxic compounds. Recently, 1,4-dihydroxy-2-naphthoic acid (DHNA) was reported to be an AhR ligand. Here, we investigated the components of the molecular chaperone complex when DHNA binds to AhR. Proteins eluted from the 3-Methylcolanthrene-affinity column were AhR-HSP90-XAP2-p23 complex. The AhR-molecular chaperone complex did not contain p23 in the eluents from the DHNA-affinity column. In 3-MC-treated cells, AhR formed a complex with HSP90-XAP2-p23 and nuclear translocation occurred within 30 min, while in DHNA-treated cells, AhR formed a complex with AhR-HSP90-XAP2, and translocation was slow from 60 min. Thus, the AhR activation mechanism may differ when DHNA is the ligand compared to toxic ligands.
Topics: Receptors, Aryl Hydrocarbon; Ligands; HSP90 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Binding; Methylcholanthrene; Prostaglandin-E Synthases; Animals
PubMed: 38605276
DOI: 10.1002/1873-3468.14871