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Reproductive Toxicology (Elmsford, N.Y.) Apr 2024E-cigarettes use constitutes a source of thirdhand nicotine exposure. The increasing use of electronic cigarettes in homes and public places increases the risk of...
E-cigarettes use constitutes a source of thirdhand nicotine exposure. The increasing use of electronic cigarettes in homes and public places increases the risk of exposure of pregnant women to thirdhand nicotine. The effects of exposure of pregnant women to very low levels of nicotine have not been studied in humans but detrimental in experimental animals. The objective of this study is to investigate the effect of nanomolar concentrations of nicotine and its metabolite cotinine on the proliferation of JEG-3, a human trophoblast cell line. We also studied the proliferative effect of nanomolar concentrations of benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon in tobacco smoke, for comparison. We treated JEG-3 cells in culture with nanomolar concentrations of nicotine, cotinine, and B[a]P. Their effect on cell proliferation was determined, relative to untreated cells, by MTT assay. Western blotting was used to assess the mitogenic signaling pathways affected by nicotine and cotinine. In contrast to the inhibitory effects reported with higher concentrations, we showed that nanomolar concentrations of nicotine and cotinine resulted in significant JEG-3 cell proliferation and a rapid but transient increase in levels of phosphorylated ERK and AKT, but not STAT3. Biphasic, non-monotonic effect on cell growth is characteristic of endocrine disruptive chemicals like nicotine. The mitogenic effects of nicotine and cotinine potentially contribute to increased villous epithelial thickness, seen in placentas of some smoking mothers. This increases the diffusion distance for oxygen and nutrients between mother and fetus, contributing to intrauterine growth restriction in infants of smoking mothers.
Topics: Infant; Animals; Humans; Female; Pregnancy; Nicotine; Cotinine; Benzo(a)pyrene; Electronic Nicotine Delivery Systems; Cell Line, Tumor; Cell Proliferation; Trophoblasts; Tobacco Smoke Pollution
PubMed: 38453095
DOI: 10.1016/j.reprotox.2024.108572 -
Ecotoxicology and Environmental Safety Mar 2024Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to...
Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to mainly target airway epithelial cells, whereas its potential impact on alveolar cells remains inadequately explored. Metformin, a first-line drug for diabetes, has been shown to exert anti-inflammatory and tissue repair-promoting effects under various injurious conditions. Here, we explored the effect of chronic B[a]P exposure on alveolar cells and the impact of metformin on B[a]P-induced lung injury by examining the various parameters including lung histopathology, inflammation, fibrosis, and related signal pathway activation. MLKL knockout (Mlkl) and AT2-lineage tracing mice (Sftpc;LSL-tdTomato) were used to delineate the role of necroptosis in B[a]P-induced alveolar epithelial injury and repair. Mice receiving weekly administration of B[a]P for 6 weeks developed a significant alveolar damaging phenotype associated with pulmonary inflammation, fibrosis, and activation of the necroptotic cell death pathway. These effects were significantly relieved in MLKL null mice. Furthermore, metformin treatment, which were found to promote AMPK phosphorylation and inhibit RIPK3, as well as MLKL phosphorylation, also significantly alleviated B[a]P-induced necroptosis and lung injury phenotype. However, the protective efficacy of metformin was rendered much less effective in Mlkl null mice or by blocking the necroptotic pathway with RIPK3 inhibitor. Our findings unravel a potential protective efficacy of metformin in mitigating the detrimental effects of B[a]P exposure on lung health by inhibiting necroptosis and protecting AT2 cells.
Topics: Mice; Animals; Benzo(a)pyrene; Protein Kinases; Necroptosis; Lung Injury; Fibrosis; Red Fluorescent Protein
PubMed: 38364759
DOI: 10.1016/j.ecoenv.2024.116094 -
International Journal of Molecular... Feb 2024Light and atmospheric pollution are both independently implicated in cancer induction and premature aging. Evidence has been growing more recently on the toxic synergy...
Light and atmospheric pollution are both independently implicated in cancer induction and premature aging. Evidence has been growing more recently on the toxic synergy between light and pollutants. Polycyclic aromatic hydrocarbons (PAHs) originate from the incomplete combustion of organic matter. Some PAHs, such as the Benzo[a]pyrene (BaP), absorb ultraviolet A (UVA) wavelengths and can act as exogenous chromophores, leading to synergistic toxicity through DNA damage and cytotoxicity concomitant to ROS formation. In this study, we shed light on the mechanism underlying the toxic synergy between PAHs and UVA. Using dermal fibroblasts co-exposed to UVA and BaP, we have demonstrated that the photosensitization reaction causes mortality, which is most likely caused by ROS accumulation. We have shown that these ROS are concentrated in the lipids, which causes an important induction of lipid peroxidation and malondialdehyde, by-products of lipid peroxidation. We have also shown the accumulation of bulky DNA damage, most likely generated by these by-products of lipid peroxidation. To our knowledge, this study represents the first one depicting the molecular effects of photo-pollution on dermal skin.
Topics: Lipid Peroxidation; Polycyclic Aromatic Hydrocarbons; Reactive Oxygen Species; Ultraviolet Rays; Sunlight; Benzo(a)pyrene; Fibroblasts
PubMed: 38339182
DOI: 10.3390/ijms25031905 -
International Journal of Molecular... Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by lipid accumulation within the liver. The pathogenesis underlying its development is poorly...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is caused by lipid accumulation within the liver. The pathogenesis underlying its development is poorly understood. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and a group 1 carcinogen. The aryl hydrocarbon receptor activation by B[a]P induces cytochrome P450 (CYP) enzymes, contributing to hepatic lipid accumulation. However, the molecular mechanism through which the B[a]P-mediated induction of CYP enzymes causes hepatic lipid accumulation is unknown. This research was conducted to elucidate the role of CYP1B1 in regulating B[a]P-induced lipid accumulation within hepatocytes. B[a]P increased hepatic lipid accumulation, which was mitigated by CYP1B1 knockdown. An increase in the mammalian target of rapamycin (mTOR) by B[a]P was specifically reduced by CYP1B1 knockdown. The reduction of mTOR increased the expression of autophagic flux-related genes and promoted phagolysosome formation. Both the expression and translocation of TFE3, a central regulator of lipophagy, were induced, along with the expression of lipophagy-related genes. Conversely, enhanced mTOR activity reduced TFE3 expression and translocation, which reduced the expression of lipophagy-related genes, diminished phagolysosome production, and increased lipid accumulation. Our results indicate that B[a]P-induced hepatic lipid accumulation is caused by CYP1B1-induced mTOR and the reduction of lipophagy, thereby introducing novel targets and mechanisms to provide insights for understanding B[a]P-induced MASLD.
Topics: Benzo(a)pyrene; Cytochrome P-450 CYP1B1; Liver; Cytochrome P-450 Enzyme System; TOR Serine-Threonine Kinases; Receptors, Aryl Hydrocarbon; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Lipids; Cytochrome P-450 CYP1A1
PubMed: 38279324
DOI: 10.3390/ijms25021324 -
Environment International Feb 2024Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been... (Meta-Analysis)
Meta-Analysis
Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERβ) regulated by PAHs in CRC as well as the underlying mechanisms of ERβ-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERβ expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E had the opposite effects. Additionally, this study mapped ERβ genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERβ binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERβ by PAHs and endogenous E may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERβ and its downstream targets for CRC prevention and treatment.
Topics: Humans; Estrogen Receptor beta; Benzo(a)pyrene; Genome-Wide Association Study; Tandem Mass Spectrometry; Polycyclic Aromatic Hydrocarbons; Estrogens; Colorectal Neoplasms
PubMed: 38277997
DOI: 10.1016/j.envint.2024.108443 -
Nutrients Jan 2024Exposure to B[a]P, the most characterized polycyclic aromatic hydrocarbon, significantly increases breast cancer risk. Our lab has previously reported that diallyl...
The Garlic Compound, Diallyl Trisulfide, Attenuates Benzo[a]Pyrene-Induced Precancerous Effect through Its Antioxidant Effect, AhR Inhibition, and Increased DNA Repair in Human Breast Epithelial Cells.
Exposure to B[a]P, the most characterized polycyclic aromatic hydrocarbon, significantly increases breast cancer risk. Our lab has previously reported that diallyl trisulfide (DATS), a garlic organosulfur compound (OSC) with chemopreventive and cell cycle arrest properties, reduces lipid peroxides and DNA damage in normal breast epithelial (MCF-10A) cells. In this study, we evaluated the ability of DATS to block the B[a]P-induced initiation of carcinogenesis in MCF-10A cells by examining changes in proliferation, clonogenic formation, reactive oxygen species (ROS) formation, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, and protein expression of ARNT/HIF-1β, CYP1A1, and DNA POLβ. The study results indicate that B[a]P increased proliferation, clonogenic formation, ROS formation, and 8-OHdG levels, as well as increasing the protein expression of ARNT/HIF-1β and CYP1A1 compared to the control. Conversely, DATS/B[a]P co-treatment (CoTx) inhibited cell proliferation, clonogenic formation, ROS formation, and 8-OHdG levels compared to B[a]P alone. Treatment with DATS significantly inhibited ( < 0.0001) AhR expression, implicated in the development and progression of breast cancer. The CoTx also attenuated all the above-mentioned B[a]P-induced changes in protein expression. At the same time, it increased DNA POLβ protein expression, which indicates increased DNA repair, thus causing a chemopreventive effect. These results provide evidence for the chemopreventive effects of DATS in breast cancer prevention.
Topics: Humans; Female; Garlic; Antioxidants; Benzo(a)pyrene; Cell Line, Tumor; Reactive Oxygen Species; Cytochrome P-450 CYP1A1; Apoptosis; Sulfides; Epithelial Cells; Anticarcinogenic Agents; DNA Repair; Breast Neoplasms; DNA; Precancerous Conditions; Allyl Compounds
PubMed: 38276538
DOI: 10.3390/nu16020300 -
Ecotoxicology and Environmental Safety Feb 2024Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the...
Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the relationship is still unclear. Plasma microRNA (miRNA) is a typical epigenetic biomarker that was linked to environment exposure and lung cancer development. We aimed to reveal the mediation effect of plasma miRNAs on BaP-related lung cancer. We designed a lung cancer case-control study including 136 lung cancer patients and 136 controls, and measured the adducts of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) and sequenced miRNA profiles in plasma. The relationships between BPDE-Alb adducts, normalized miRNA levels and the risk of lung cancer were assessed by linear regression models. The mediation effects of miRNAs on BaP-related lung cancer were investigated. A total of 190 plasma miRNAs were significantly related to lung cancer status at Bonferroni adjusted P < 0.05, among which 57 miRNAs showed different levels with |fold change| > 2 between plasma samples before and after tumor resection surgery at Bonferroni adjusted P < 0.05. Especially, among the 57 lung cancer-associated miRNAs, BPDE-Alb adducts were significantly related to miR-17-3p, miR-20a-3p, miR-135a-5p, miR-374a-5p, miR-374b-5p, miR-423-5p and miR-664a-5p, which could in turn mediate a separate 42.2%, 33.0%, 57.5%, 36.4%, 48.8%, 32.5% and 38.2% of the relationship of BPDE-Alb adducts with the risk of lung cancer. Our results provide non-invasion biomarker candidates for lung cancer, and highlight miRNAs dysregulation as a potential intermediate mechanism by which BaP exposure lead to lung tumorigenesis.
Topics: Humans; MicroRNAs; Lung Neoplasms; Benzo(a)pyrene; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Case-Control Studies; Lung; Biomarkers; China
PubMed: 38262095
DOI: 10.1016/j.ecoenv.2024.115980 -
Environmental Health Perspectives Jan 2024The association between alcohol and certain cancers is well established, yet beyond ethanol and its metabolite acetaldehyde, little is known about the presence of other... (Review)
Review
BACKGROUND
The association between alcohol and certain cancers is well established, yet beyond ethanol and its metabolite acetaldehyde, little is known about the presence of other carcinogenic compounds in alcoholic beverages, including polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (a Group I carcinogen).
OBJECTIVES
We summarized the published literature on PAH levels in alcoholic beverages to identify potential gaps in knowledge to inform future research.
METHODS
Medline and Scopus were searched for primary research published from January 1966 to November 2023 that quantified PAH levels among various types of alcoholic beverages, including whisky, rum, brandy, gin, vodka, wine, and beer. Studies that were not primary literature were excluded; only studies that quantified PAH content in the specified alcoholic beverages were included.
RESULTS
Ten studies published from 1966 to 2019 met the criteria for review. Other than beverage type, no publication reported selection criteria for their samples of tested alcohol products. Studies used a variety of analytical methods to detect PAHs. Of the 10 studies, 7 were published after 2000, and 6 assessed products. Of the studies, 7 examined spirits; 3, beer; and 4, wines. Benzo[a]pyrene was most prevalent among spirit products, particularly whisky, with values generally exceeding acceptable levels for drinking water. Some beer and wine products also contained PAHs, albeit at lower levels and less frequently than spirit products.
DISCUSSION
PAHs are found in some alcohol products and appear to vary by beverage type. However, there is an incomplete understanding of their presence and levels among large, representative samples from the range of currently available alcohol products. Addressing this gap could improve understanding of alcohol-cancer relationships and may have important implications for public health and the regulation of alcohol products. In addition, novel methods, such as direct mass spectroscopy, may facilitate more thorough testing of samples to further investigate this relationship. https://doi.org/10.1289/EHP13506.
Topics: Polycyclic Aromatic Hydrocarbons; Benzo(a)pyrene; Alcoholic Beverages; Beer; Wine; Ethanol; Carcinogens
PubMed: 38241192
DOI: 10.1289/EHP13506 -
ACS Omega Jan 2024Supercritical cyclohexane (SC-cyclohexane) shows significant advantages in mild operating conditions and the modulation of product distribution. To gain insights into...
Supercritical cyclohexane (SC-cyclohexane) shows significant advantages in mild operating conditions and the modulation of product distribution. To gain insights into the upgrading process of heavy oil in SC-cyclohexane, the dissolution process of polycyclic aromatic hydrocarbons (PAHs) contained in heavy oil was simulated based on molecular dynamics with the use of naphthalene, benzopyrene, and mixtures of naphthalene and benzopyrene as the model compounds. As indicated by the radial distribution function results, in SC-cyclohexane exhibiting low density, cyclohexane formed a solvent shell around PAHs such that the local concentration was reduced and the aggregation of PAHs was inhibited. The results of the solvation free energy suggested that van der Waals forces between PAHs and cyclohexane were mainly dominant. As revealed by the dissolution process of the model compounds in SC-cyclohexane, a low density and a suitable temperature contributed to the solubilization of PAHs. An appropriate temperature and a low density can be selected for the upgrading reaction to limit coke formation.
PubMed: 38222523
DOI: 10.1021/acsomega.3c04101 -
Scientific Reports Jan 2024Steroidogenesis of gonadal cells is tightly regulated by gonadotropins. However, certain polycyclic aromatic hydrocarbons, including Benzo[a]pyrene (BaP), induce...
Steroidogenesis of gonadal cells is tightly regulated by gonadotropins. However, certain polycyclic aromatic hydrocarbons, including Benzo[a]pyrene (BaP), induce reproductive toxicity. Several existing studies have considered higher than environmentally relevant concentrations of BaP on male and female steroidogenesis following long-term exposure. Also, the impact of short-term exposure to BaP on gonadotropin-stimulated cells is understudied. Therefore, we evaluated the effect of 1 nM and 1 µM BaP on luteinizing hormone/choriogonadotropin (LH/hCG)-mediated signalling in two steroidogenic cell models, i.e. the mouse tumor Leydig cell line mLTC1, and the human primary granulosa lutein cells (hGLC) post 8- and 24-h exposure. Cell signalling studies were performed by homogeneous time-resolved fluorescence (HTRF) assay, bioluminescence energy transfer (BRET) and Western blotting, while immunostainings and immunoassays were used for intracellular protein expression and steroidogenesis analyses, respectively. BaP decreased cAMP production in gonadotropin-stimulated mLTC1 interfering with Gαs activation. Therefore, decrease in gonadotropin-mediated CREB phosphorylation in mLTC1 treated with 1 μM BaP was observed, while StAR protein levels in gonadotropin-stimulated mLTC1 cells were unaffected by BaP. Further, BaP decreased LH- and hCG-mediated progesterone production in mLTC1. Contrastingly, BaP failed to mediate any change in cAMP, genes and proteins of steroidogenic machinery and steroidogenesis of gonadotropin-treated hGLC. Our results indicate that short-term exposure to BaP significantly impairs steroidogenic signalling in mLTC1 interfering with Gαs. These findings could have a significant impact on our understanding of the mechanism of reproductive toxicity by endocrine disruptors.
Topics: Humans; Animals; Mice; Female; Male; Benzo(a)pyrene; Leydig Cells; Chorionic Gonadotropin; Biological Assay; Blotting, Western
PubMed: 38191651
DOI: 10.1038/s41598-024-51516-7