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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 -
Tumour Biology : the Journal of the... 2023Epithelial-mesenchymal transition (EMT) is associated with altered cellular adhesion. We previously demonstrated that cellular adhesion influences Low-dose...
BACKGROUND
Epithelial-mesenchymal transition (EMT) is associated with altered cellular adhesion. We previously demonstrated that cellular adhesion influences Low-dose Hyper-Radiosensitivity (HRS) in a variety of tumor cells. However, the relationship of low-dose HRS with the phenotypic plasticity incurred by EMT during the neoplastic transformation remains to be elucidated.
OBJECTIVE
To investigate whether acquisition of EMT phenotype during progressive neoplastic transformation may affect low-dose radiation sensitivity.
METHODS
Primary thyroid cells obtained from a human cystic thyroid nodule were first subjected to nutritional stress. This yielded immortalized INM-Thy1 cell strain, which was further treated with either multiple γ-radiation fractions (1.5 Gy each) or repetitive cycles of 3-methylcholanthrene and phorbol-12-myristate-13-acetate, yielding two progressive transformants, viz., INM-Thy1R and INM-Thy1C. Morphological alterations, chromosomal double-minutes, cell adhesion proteins, anchorage dependency, tumorigenicity in nude mice and cellular radiosensitivity were studied in these strains.
RESULTS
Both transformants (INM-Thy1R, INM-Thy1C) displayed progressive tumorigenic features, viz., soft agar colony growth and solid tumor growth in nude mice, coupled with features of epithelial-mesenchymal transition and activated Wnt pathway. Incidentally, the chemical-induced transformant (INM-Thy1C) displayed a prominent HRS (αs/αr = 29.35) which remained unaffected at high cell density. However, the parental (INM-Thy1) cell line as well as radiation-induced transformant (INM-Thy1R) failed to show this hypersensitivity.
CONCLUSION
The study shows that induction of EMT in thyroid follicular cells may accompany increased susceptibility to low-dose ionizing radiation, which was attenuated by adaptive resistance acquired during radiation-induced transformation.
Topics: Animals; Mice; Humans; Cell Adhesion; Epithelial-Mesenchymal Transition; Mice, Nude; Thyroid Epithelial Cells; Carcinogenesis
PubMed: 37742670
DOI: 10.3233/TUB-220027 -
Bioscience, Biotechnology, and... Nov 2023We focused on Piper longum L., a herbal drug produced in Myanmar, which has a renoprotective effect. Thus, we attempted to isolate and identify compounds that enhance...
We focused on Piper longum L., a herbal drug produced in Myanmar, which has a renoprotective effect. Thus, we attempted to isolate and identify compounds that enhance the expression of the ABCG2 gene from the aerial parts of the plant except for the fruit. Among the various P. longum extracts, we isolated and identified the components. Using Caco-2 cells, the hABCG2 mRNA expression-enhancing effects of the isolated compounds were compared with the positive reference compound (3-methylcholanthrene [3MC]) using real-time polymerase chain reaction. Six compounds were isolated and identified from the methanol extract of P. longum. Among the isolated compounds, licarin A and neopomatene had lower toxicity and higher hABCG2 mRNA expression-enhancing effects in Caco-2 cells. Suppression of hAhR expression by siRNA reduced the activity of licarin A and neopomatene, as well as the hAhR agonist 3MC, suggesting that these 2 compounds may act as hAhR agonists to promote hABCG2 expression.
Topics: Humans; Piper; Plant Extracts; Caco-2 Cells; Lignans; Gene Expression; RNA, Messenger; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 37709570
DOI: 10.1093/bbb/zbad132 -
Genes and Environment : the Official... Aug 2023Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP...
Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.
PubMed: 37544994
DOI: 10.1186/s41021-023-00275-4 -
Toxicology Aug 2023Aryl hydrocarbon receptor (AHR) is a ligand-dependent receptor that belongs to the superfamily of basic helix-loop-helix (bHLH) transcription factors. The activation of... (Review)
Review
Aryl hydrocarbon receptor (AHR) is a ligand-dependent receptor that belongs to the superfamily of basic helix-loop-helix (bHLH) transcription factors. The activation of the canonical AHR signaling pathway is known to induce the expression of cytochrome P450 enzymes, facilitating the detoxification metabolism in the human body. Additionally, AHR could interact with various signaling pathways such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1α (HIF-1α), nuclear factor ekappa B (NF-κβ), estrogen receptor (ER), and androgen receptor (AR) signaling pathways. Over the past 30 years, several studies have reported that various chemical, physical, or biological agents, such as tobacco, hydrocarbon compounds, industrial and agricultural chemical wastes, drugs, UV, viruses, and other toxins, could affect AHR expression or activity, promoting cancer development. Thus, it is valuable to overview how these factors regulate AHR-mediated carcinogenesis. Current findings have reported that many compounds could act as AHR ligands to drive the expressions of AHR-target genes, such as CYP1A1, CYP1B1, MMPs, and AXL, and other targets that exert a pro-proliferation or anti-apoptotic effect, like XIAP. Furthermore, some other physical and chemical agents, such as UV and 3-methylcholanthrene, could promote AHR signaling activities, increasing the signaling activities of a few oncogenic pathways, such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Understanding how various factors regulate AHR-mediated carcinogenesis processes helps clinicians and scientists plan personalized therapeutic strategies to improve anti-cancer treatment efficacy. As many studies that have reported the roles of AHR in regulating carcinogenesis are preclinical or observational clinical studies that did not explore the detailed mechanisms of how different chemical, physical, or biological agents promote AHR-mediated carcinogenesis processes, future studies should focus on conducting large-scale and functional studies to unravel the underlying mechanism of how AHR interacts with different factors in regulating carcinogenesis processes.
Topics: Humans; Receptors, Aryl Hydrocarbon; Phosphatidylinositol 3-Kinases; Basic Helix-Loop-Helix Transcription Factors; Extracellular Signal-Regulated MAP Kinases; Cytochrome P-450 CYP1A1; Biological Factors; Carcinogenesis
PubMed: 37480978
DOI: 10.1016/j.tox.2023.153596 -
International Journal of Molecular... Mar 20233-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian...
3-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian dysfunction. However, the effects of 3-MC exposure on oocyte maturation and embryo development remain unclear. This study revealed the toxic effects of 3-MC exposure on oocyte maturation and embryo development. 3-MC with different concentrations of 0, 25, 50, and 100 μM was applied for in vitro maturation of porcine oocytes. The results showed that 100 μM 3-MC significantly inhibited cumulus expansion and the first polar body extrusion. The rates of cleavage and blastocyst of embryos derived from 3-MC-exposed oocytes were significantly lower than those in the control group. Additionally, the rates of spindle abnormalities and chromosomal misalignments were higher than those in the control group. Furthermore, 3-MC exposure not only decreased the levels of mitochondria, cortical granules (CGs), and acetylated α-Tubulin, but also increased the levels of reactive oxygen species (ROS), DNA damage, and apoptosis. The expression of cumulus expansion and apoptosis-related genes was abnormal in 3-MC-exposed oocytes. In conclusion, 3-MC exposure disrupted the nuclear and cytoplasmic maturation of porcine oocytes through oxidative stress.
Topics: Animals; Swine; Methylcholanthrene; Oogenesis; Oocytes; Oxidative Stress; Reactive Oxygen Species; Embryonic Development; In Vitro Oocyte Maturation Techniques
PubMed: 36982641
DOI: 10.3390/ijms24065567 -
American Journal of Cancer Research 2023The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to...
The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of β-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.
PubMed: 36895984
DOI: No ID Found -
Aquatic Toxicology (Amsterdam,... Mar 2023Oil spills that occur in high traffic coastal environments can have profound consequences for the health of marine ecosystems and the commercial and social interests...
Dynamic cyp1a1 transcript responses in the caudal fin of coho salmon (Oncorhynchus kisutch) smolts to low sulfur marine diesel water accommodated fraction exposures and depuration.
Oil spills that occur in high traffic coastal environments can have profound consequences for the health of marine ecosystems and the commercial and social interests that are dependent upon these habitats. Given that the global reliance on marine fuels is not abating, it is imperative to develop sensitive and robust tools to monitor oil contamination and remediation in a timely manner. Such tools are increasingly important for ascertaining the immediate and long-term effects of oil contamination on species of interest and local habitats as water-soluble components of oils, such as polycyclic aromatic hydrocarbons (PAHs), can persist post-remediation. We previously demonstrated that 3-methylcholanthrene responsive cytochrome P450-1a (cyp1a1) transcript abundance in the liver and caudal fin of coho salmon smolts (Onchorhynchus kisutch) was sensitive to exposure to low sulfur marine diesel (LSMD) seawater accommodated fractions (seaWAF) in cold water. We expanded upon this paradigm by assessing the utility of the cyp1a1 transcript to track both exposure to LSMD seaWAF and recovery from exposure by measuring cyp1a1 abundance in coho smolts using quantitative polymerase chain reaction (qPCR). Smolts were exposed to either 100 mg/L LSMD seaWAF or clean seawater (control) for 4 days. Fish were then transferred to clean seawater for depuration and tissues sampled at 0, 1, 2, 4, and 8 days from both treatments. Livers and caudal fins were dissected from 40 smolts per group (n = 400 smolts). The LSMD seaWAF-induced cyp1a1 transcript levels significantly decreased one day after depuration in the liver and caudal fin in a sex-independent manner in genotyped females and males. After four days of depuration, cyp1a1 transcript abundance decreased to baseline control levels, regardless of tissue or sex. The present study demonstrates the value of using the caudal fin as a reliable, sensitive, and non-lethal sampling and monitoring tool.
Topics: Animals; Male; Female; Water; Oncorhynchus kisutch; Ecosystem; Water Pollutants, Chemical; Cytochrome P-450 Enzyme System; Sulfur
PubMed: 36716652
DOI: 10.1016/j.aquatox.2023.106412 -
Food Science and Biotechnology Jan 2023The objective of this study was to quantify four polycyclic aromatic hydrocarbons (PAH4) in herbal medicine products in Korea. The PAH4 (benzo[]anthracene,...
The objective of this study was to quantify four polycyclic aromatic hydrocarbons (PAH4) in herbal medicine products in Korea. The PAH4 (benzo[]anthracene, benzo[]fluoranthene, chrysene, and benzo[]pyrene) were analyzed in 70 popularly used herbal medicine products without containing essential oil and containing essential oil matrices, using 3-methylcholanthrene as the internal standard. Ultrasonication and liquid-liquid extraction were followed by HPLC-FLD analysis. Satisfactory linearity ( = 0.99), limit of detection (0.05-0.18 μg/kg), limit of quantification (0.14-0.54 μg/kg), recovery (85.72-112.18%), and precision (0.22-2.90%) of PAH4 were acquired. PAH contamination was detected in all herbal medicine products without containing essential oil and containing essential oil matrices types. In 44 samples of herbal medicine products, all PAH4 were detected, and in two samples of the other herbal medicine products, only benzo[]fluoranthene was detected. The average concentration of PAH4 was 3.88 μg/kg. The validated analytical method was used for preventing human health risks related to the consumption of herbal medicines.
PubMed: 36606095
DOI: 10.1007/s10068-022-01168-y -
Toxicology Reports 2023Diazinon (DZN) is an insecticide extensively used to control pests in crops and animals. However, its indicriminated use may lead to liver damage in animals and humans....
Diazinon (DZN) is an insecticide extensively used to control pests in crops and animals. However, its indicriminated use may lead to liver damage in animals and humans. This study aimed to evaluate the toxicity of DZN (25-150 µM) on human hepatoblastoma (HepG2) cells after 24 and 48 h of exposure and the role of its biotransformation on the toxicological potential. We also tested the protective effect of tetrahydrocurcumin (THC), an antioxidant agent, in the DZN-induced citotoxicity. DZN caused cytotoxicity in the HepG2 cells, inhibiting cell proliferation and reducing cell viability in a dose- and time-dependent manner. The pre-incubation of HepG2 cells with chemical inducers of cytochrome P450 monooxygenase 3-methylcholanthrene and phenobarbital resulted in a further decrease of cell viability associated with DZN exposure. In addition, the metabolite diazoxon was more toxic than DZN. Our results also revealed that THC alleviated DZN-induced cytotoxicity and reactive oxygen and nitrogen species (RONS) generation in HepG2 cells. In conclusion, our data provide novel insights into the involvement of biotransformation in the mechanisms of DZN-induced cytotoxicity and suggest that amelioration of RONS accumulation might be involved in the protective effect of THC on DZN-induced liver injury.
PubMed: 36578673
DOI: 10.1016/j.toxrep.2022.12.005