Search Results (316)

1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mutagenic monoadducts and DNA–DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in mutagenicity is a well-established mode of action for 1,3-butadiene, characterization of the extent of inter-individual variability in response to BD exposure is a gap in our knowledge. Previous studies showed that population-wide mouse models can be used to evaluate variability in 1,3-butadiene DNA adducts; therefore, we hypothesized that this approach can be used to also study variability in the formation and loss of BD DNA adducts across tissues and between sexes. To test this hypothesis, female and male mice from five genetically diverse Collaborative Cross (CC) strains were exposed to filtered air or 1,3-butadiene (600 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Some animals were kept for two additional weeks after exposure to study DNA adduct persistence. EB-GII and bis-N7G-BD adducts were quantified in liver, lungs and kidney using established isotope dilution ESI-MS/MS methods. We observed strain- and sex-specific effects on both the accumulation and loss of both DNA adducts, indicating that both factors play important roles in the mutagenicity of 1,3-butadiene. In addition, we quantified the intra-species variability for each adduct and found that for most tissues/adducts, variability values across strains were modest compared to default uncertainty factors. Full article

The mudflat crab (H. tientsinensis) is a dominant species in coastal tidal flat areas, primarily inhabiting the high tide region of the intertidal zone, and possesses significant ecological and economic value. Vibrio species are one of the main bacterial pathogens responsible for diseases in marine organisms, and they are widely distributed in seawater and estuarine environments. However, the immune mechanisms employed by H. tientsinensis in response to Vibrio infections remain unclear. This study aims to investigate the physiological and immune mechanisms by analyzing the structural changes and differential gene expression in the gill and hepatopancreas following Vibrio parahaemolyticus infection. The results indicate that V. parahaemolyticus infection causes cellular damage, with structural alterations observed in the gills (epithelial cell edema in the gill filaments, and aneurysm formation) and the hepatopancreas (changes in lumen size, nuclear condensation, and modifications in connective tissue morphology). Transcriptome analysis revealed 9766 differentially expressed genes (DEGs) in the gills of the experimental group, with 4687 upregulated and 5079 downregulated genes. These DEGs are primarily involved in different ribosomal subunits. In the hepatopancreas, 1594 DEGs were identified, with 834 upregulated and 760 downregulated. These DEGs are predominantly associated with energy-coupled proton transmembrane transport, electron transport-coupled proton transport, and lipid transporter activity. H. tientsinensis gene annotation and KEGG enrichment analysis revealed that chemical carcinogens DNA adducts, amino acid metabolism, and some immune pathways play key roles in the ability of H. tientsinensis to defend against V. parahaemolyticus infection. The findings of this study contribute to a deeper understanding of the immune mechanisms of H. tientsinensis against V. parahaemolyticus infection and provide new insights for aquaculture management. Full article

Interactions between protamines and DNA are essential for the correct structure of human sperm chromatin. Reproductive health can be adversely affected by environmental pollutants like per- and polyfluoroalkyl substances (PFAS). We previously reported that exposure to PFAS in the Veneto region causes alterations in sperm nuclear basic proteins (SNBP), along with reduced seminal antioxidant activity and increased lipoperoxides. This study analysed the protamine-to-histone ratio in SNBP and quantified the extent of DNA damage induced by SNBP in subjects in Veneto with serum perfluorooctanoic acid (PFOA) levels above the reference threshold. We found that all individuals with serum PFOA above the threshold exhibited grade three DNA damage, regardless of the protamine–histone ratio, which was generally altered but consistently shifted toward protamines. This indicate that exposure to PFAS can alter the protamine–histone ratio in these subjects. Moreover, SNBPs from these individuals showed reduced DNA-protective capacity under pro-oxidant conditions, suggesting a role in oxidative damage. To rationalize these effects, in this cross sectional study, we investigated the potential interactions between PFAS and human protamines by molecular docking analyses which showed that PFAS can form stable complexes with DNA through hydrophobic and polar interactions, especially with thymine pyrimidine rings. Further, docking analyses revealed that fluorine atoms in PFAS may interact with guanidinium groups in protamine P1 via electrostatic and van der Waals forces, competing with DNA for binding sites and potentially disrupting chromatin organisation. A ternary PFAS–DNA–protamine adduct may underpin the observed DNA damage. These results suggest that PFAS induce oxidative stress, which could affect male fertility. Full article

While the cause of preterm birth (PTB) (i.e., delivery before 37 weeks of gestation) is likely multifactorial, ambient exposure to environmental chemicals has been postulated to play a role in its etiology. Our prior studies of exposure to polycyclic aromatic hydrocarbons (PAHs) in pregnancy have shown an increased level of placental PAH-induced bulky DNA adducts with increasing levels of PAH exposures. In this investigation, we hypothesized that higher levels of placental PAHs would be associated with an increased risk of PTB. Using gas chromatography and mass spectrometry (GC-MS/MS), we measured levels of benzo(a)pyrene (BaP), benzo(b)fluoranthene (BbF) and dibenz(a,h)anthracene (DBA) from n = 323 subjects. We found higher levels of BbF in placentae collected from preterm compared with term deliveries (mean 100.3 vs. 84.14 ng/mL, p = 0.038). Placental BbF levels negatively correlated with gestational age at delivery (r_s = −0.171, p = 0.002) and placental DBA levels were higher in placentae from spontaneous PTBs compared to those that were medically indicated (mean 743.7 vs. 599.9 ng/mL, p = 0.049), suggesting a potentially causal role in spontaneous preterm birth. Lastly, we analyzed placental levels of each PAH in male (n = 164) and female (n = 159) gestations and found that levels of BaP are significantly higher in males (mean 204.4 vs. 169.9 ng/mL, p = 0.049). These studies show a potential causal role of PAH exposure in the etiology of spontaneous preterm birth. Full article

Aflatoxins (AFs), harmful secondary metabolites produced by the genus Aspergillus, particularly Aspergillus flavus and Aspergillus parasiticus, are one of the best-known potent mycotoxins, posing a significant risk to public health. The primary type, especially aflatoxin B₁ (AFB₁), is a potent carcinogen associated with liver cancer, immunosuppression, and other health problems. Environmental factors such as high temperatures, humidity, and inadequate storage conditions promote the formation of aflatoxin in staple foods such as maize, peanuts, and rice. Immunocompromised individuals, including those with HIV/AIDS, hepatitis, cancer, or diabetes, are at increased risk due to their reduced detoxification capacity and weakened immune defenses. Chronic exposure to AF in these populations exacerbates liver damage, infection rates, and disease progression, particularly in developing countries and moderate-income populations where food safety regulations are inadequate and reliance on contaminated staple foods is widespread. Biomarkers such as aflatoxin-albumin complexes, urinary aflatoxin M₁, and aflatoxin (AF) DNA adducts provide valuable insights but remain underutilized in resource-limited settings. Despite the globally recognized health risk posed by AF, research focused on monitoring human exposure remains limited, particularly among immunocompromised individuals. This dynamic emphasizes the need for targeted studies and interventions to address the particular risks faced by immunocompromised individuals. This review provides an up-to-date overview of AF exposure in immunocompromised populations, including individuals with cancer, hepatitis, diabetes, malnutrition, pregnant women, and the elderly. It also highlights exposure pathways, biomarkers, and biomonitoring strategies, while emphasizing the need for targeted interventions, advanced diagnostics, and policy frameworks to mitigate health risks in these vulnerable groups. Addressing these gaps is crucial to reducing the health burden and developing public health strategies in high-risk regions. Full article

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive intake has been shown to lead to chronic inflammation, which is related to increased production of reactive oxygen species (ROS). This conditioncan initiate lipid peroxidation in cell membranes, leading to the degradation of their fatty acids. One of the main products of omega-6 peroxidation is the α,β-unsaturated aldehyde, i.e., 4-hydroxynonenal (4-HNE), which is able to form four diastereoisomeric adducts with guanine. These 4-HNE adducts have been identified in the DNA of humans and rodents. Depending on their stereochemistry, they are able to influence double helix stability and cause DNA–DNA or DNA–Protein cross-links. Moreover, studies have shown that 4-HNE adducts formed in the human genome are considered mutation hotspots in hepatocellular carcinoma. Although the cell possesses defence mechanisms, without a well-balanced diet allowing correct cell function, they may not be sufficient to protect the genetic code. This review provides an overview of the molecular mechanisms underlying oxidative stress, lipid peroxidation, and the formation of DNA adducts. Particular emphasis is placed on the role of an omega-6-rich diet in inflammatory diseases, and on the formation of 4-HNE, which is a major product of lipid peroxidation, and its broader implications for genome stability, ageing, and disease progression. Full article

Solid fuels are still widely used in household heating in Europe and North America. Emissions from boilers are released in proximity to people. Therefore, there is a need to minimise the toxicity of emissions affecting human health to the greatest extent possible. This study compares the genotoxic potential of the emissions of four boilers of modern and old design (automatic, gasification, down-draft, over-fire) operating at reduced output to simulate the real-life combustion fed by various fossil and renewable solid fuels (hard coal, brown coal, brown coal briquettes, wood pellets, wet and dry spruce). Organic emissions were tested for genotoxic potential by analysing bulky DNA adducts and 8-oxo-dG adduct induction. There was no consistent genotoxic pattern among the fuels used within the boilers. Genotoxicity was strongly correlated with polycyclic aromatic hydrocarbon (PAH) content, and even stronger correlation was observed with particulate matter (PM). In all measured variables (PM, PAHs, genotoxicity), the technology of the boilers was a more important factor in determining the genotoxic potential than the fuels burned. The highest levels of both bulky and 8-oxo-dG DNA adducts were induced by organics originating from the over-fire boiler, while the automatic boiler exhibited genotoxic potential that was ~1000- and 100-fold lower, respectively. Full article

Estrogens are considered the most important risk factor for the development of breast cancer. Therefore, attempts are being made to reduce their level through diminished synthesis on one hand and to protect against the formation of DNA-damaging estrogen metabolites on the other. Cytochromes P450 (CYPs) play key roles in estrogen synthesis and catabolism, leading to potentially carcinogenic metabolites. CYP19 (aromatase) catalyzes the conversion of androgens to estrogens. The estrogen receptor-dependent pathway induces cell growth. CYP1 family enzymes, particularly CYP1B1, are involved in the redox cycling of estrogen metabolites and the subsequent estrogen–DNA adducts formation. Naturally occurring phytochemicals of different classes were shown to modulate the CYP expression and activity in cell-free systems or breast cancer cells. One of the most promising CYP19 inhibitors is chrysin (flavone), while stilbenes seem to be the most effective CYP1B1 inhibitors. In most cases, their effect is not specific. Therefore, different approaches are made to find the best candidate for the drug prototype of a new therapeutic or chemopreventive agent and to improve its pharmacokinetic parameters. This review presents and discusses the possible effects on major CYPs involved in estrogen metabolism by phytochemicals from the most investigated classes, namely flavonoids, stilbenes, and glucosinolates breakdown products. Full article

The efficient synthetic routes and evaluates cytotoxic profiles of denitroaristolochic acids II–V (DAA-II–V) were demonstrated in this study. Based on retrosynthetic analysis, a modular synthetic strategy was developed through Suzuki–Miyaura coupling, Wittig reaction, and bismuth triflate-catalyzed intramolecular Friedel–Crafts cyclization to efficiently construct the phenanthrene core. Process optimization significantly improved yields: aryl bromide intermediate A reached 50.8% yield via bromination refinement, while arylboronic ester intermediate B overcame selectivity limitations. Combining Darzens condensation with Wittig reaction enhanced throughput, achieving 88.4% yield in the key cyclization. Structures were confirmed by NMR and mass spectra. CCK-8 cytotoxicity assays in human renal proximal tubular epithelial cells revealed distinct toxicological profiles: DAA-III and DAA-IV exhibited IC₅₀ values of 371 μM and 515 μM, respectively, significantly higher than the nitro-containing prototype AA-I (270 μM), indicating that the absence of nitro group attenuates but does not eliminate toxicity, potentially via altered metabolic activation. DAA-II and DAA-V showed no detectable cytotoxicity within assay limits, suggesting reduced toxicological impact. Structure–activity analysis exhibited that the nitro group is not essential for cytotoxicity, with methoxy substituents exerting limited influence on potency. This challenges the conventional DNA adduct-dependent toxicity paradigm, implying alternative mechanisms like oxidative stress or mitochondrial dysfunction may mediate damage in denitro derivatives. These systematic findings provide new perspectives for AA analog research and a foundation for the rational use and safety assessment of Aristolochiaceae plants. Full article

Background: Nedaplatin is a platinum-based anticancer drug that combines the benefits of Cisplatin and Carboplatin, retaining Cisplatin’s anticancer activity while reducing toxicity similar to Carboplatin. After hydrolysis, Nedaplatin targets purines in DNA and forms cross-links that induce cell death via apoptosis. However, it is important to consider how the presence of other chemical compounds with structural similarities to Adenine or Guanine, such as aromatic, purine, or pyrimidine compounds containing a nitrogen atom with a free electron pair, might influence its activity at the cellular level. Alkaloids with structures similar to DNA nucleobases are common, and their influence on Nedaplatin’s activity requires investigation. Methods: In this study, the interactions between Nedaplatin (including its hydrolyzed forms, such as [Pt(NH₃)₂(H₂O)₂]²⁺ and [Pt(NH₃)₂(H₂O)(OH)]⁺) and nucleobases (Adenine and Guanine) and purine alkaloids (Caffeine, Theobromine and Theophylline) were thoroughly investigated using theoretical (density functional theory, DFT) and experimental (UV-Vis spectroscopy) methods. DFT calculations were performed at the B3LYP/6-31G(d,p)/LANL2DZ and MN15/def2-TZVP levels, with structure optimization and harmonic analysis in the gas phase and aqueous solution (modeled using IEF-PCM). UV-Vis spectroscopy was used to verify theoretical findings by examining changes in absorption spectra. Results: Both theoretical and experimental studies confirmed that Nedaplatin forms complexes with both nucleobases and purine alkaloids. Nedaplatin was found to exhibit a higher affinity for nucleobases than for purine alkaloids. Furthermore, this affinity was dependent on the computational method used and on the hydrolyzed form of Nedaplatin. Theoretical calculations showed the formation of stable complexes through bonding with nitrogen atoms in the ligand molecules, which was confirmed by changes in UV-Vis spectra, indicating adduct formation. Conclusions: The results indicate that Nedaplatin readily forms complexes with both nucleobases and purine alkaloids, showing a stronger affinity for nucleobases. This finding highlights the potential importance of Nedaplatin’s interactions with other compounds present in the body, which may influence its effectiveness and mechanism of action in cancer therapy. These studies provide new insights into the molecular mechanisms of Nedaplatin’s action and may contribute to a better understanding of its pharmacological interactions. However, research requires confirmation not only in in vivo studies but also in clinical trials. Full article

Hepatocellular carcinoma (HCC) imposes a significant burden on global public health. Exposure to aflatoxins, potent mycotoxins produced by Aspergillus fungi contaminating staple foods, and chronic hepatitis B virus (HBV) infection are major etiological factors, especially where they co-exist. This review examines the critical role of the p53 tumor suppressor pathway as a primary target and convergence point for the carcinogenic actions of aflatoxins and HBV. Aflatoxin B₁ (AFB₁), a Group 1 carcinogen, exerts significant genotoxicity, characteristically inducing a specific hotspot mutation (R249S) in the TP53 gene via DNA adduct formation, thereby compromising p53’s critical tumor suppressor functions. This R249S mutation is considered a molecular fingerprint of aflatoxin exposure. Concurrently, the HBV X protein (HBx) functionally inactivates wild-type p53 through direct binding and by promoting its degradation. The synergistic disruption of the p53 pathway, driven by AFB₁-induced mutation and amplified by HBV-mediated functional inhibition, significantly enhances the risk of HCC development. This review addresses how aflatoxin exposure alters key aspects of p53 and how this damage interacts with HBV-mediated p53 suppression, providing crucial insights into hepatocarcinogenesis. The knowledge synthesized here underscores the importance of mitigating aflatoxin exposure alongside HBV control for effective HCC prevention and treatment strategies. Full article

Alcohol consumption is a known risk factor for esophageal and liver cancers. Recently, it was reported that mutation signatures characterized by T:A to C:G mutations (SBS16), which are suggested to be associated with alcohol intake, are frequently detected in esophageal, liver, and stomach cancers among the Japanese population. However, the scientific evidence linking alcohol consumption to SBS16 remains lacking. Acetaldehyde (AA), a carcinogenic metabolite of alcohol, is considered a key contributor to alcohol-related cancer development. Although the guanine adducts associated with alcohol exposure have been reported as part of its carcinogenic mechanism, an adenine adduct, N⁶-ethyl-deoxyadenosine (N⁶-ethyl-dA), a potential contributor to the SBS16 mutation pattern, was recently identified using a mass spectrometry-based DNA adductome approach. However, the mutagenicity assessment of N⁶-ethyl-dA using primer extension assays and the supF gene mutation test showed that this adenine adduct is not mutagenic. To identify another candidate as a driver adduct for SBS16, a DNA adductome approach was conducted, leading to the identification of a novel adenine adduct, 3-(2′-deoxyribos-1′-yl)-7,9-dimethyl-3,9-dihydro-7H-[1,3,5]oxadiazino[4,3-i]purine (N¹-oxydiethylidene-dA), in which two AA molecules are bound to an adenine base. Moreover, N¹-oxydiethylidene-dA was detected in mouse livers, and its levels increased following ethanol administration, suggesting that alcohol may contribute to SBS16 induction via the formation of N¹-oxydiethylidene-dA. Full article

In this study, the chemopreventive effects of rosmarinic acid (RA), a major phenolic acid of the plant Rosmarinus officinalis L., against the carcinogenic naturally occurring mycotoxin aflatoxin B1 (AFB1) were investigated using both in silico and in vitro approaches. The in silico investigation of the chemical reactions between rosmarinic acid and the carcinogenic metabolite of AFB1, aflatoxin B1 exo-8,9-epoxide (AFBO), was conducted by activation free energies calculations with DFT functionals M11-L and MN12-L, in conjunction with the 6-311++G(d,p) flexible basis set and implicit solvation model density (SMD), according to a newly developed quantum mechanics-based protocol for the evaluation of carcinogen scavenging activity (QM-CSA). Following the computational analyses, the chemoprotective effects of RA were further studied in vitro in human hepatocellular carcinoma HepG2 cells by analyzing its influence on AFB1-induced genotoxicity using a comet assay, γH2AX, and p-H3, while its impact on cell proliferation and cell cycle modulation was assessed using flow cytometry. Our computational results revealed that the activation free energy required for the reaction of RA with AFBO (14.86 kcal/mol) is significantly lower than the activation free energy for the competing reaction of AFBO with guanine (16.88 kcal/mol), which indicates that RA acts as an efficient natural scavenger of AFBO, potentially preventing AFB1-specific DNA adduct formation. The chemoprotective activity of RA was confirmed through in vitro experiments, which demonstrated a statistically significant (p < 0.05) reduction in AFB1-induced single- and double-strand breaks in HepG2 cells exposed to a mixture of AFB1 and RA at non-cytotoxic concentrations. In addition, RA reversed the AFB1-induced reduction in cell proliferation. Full article

This research explored the role of aflatoxin oxidase CotA in mitigating aflatoxin B₁ (AFB₁)-induced hepatotoxicity in Japanese quails. A total of 225 female Japanese quails, aged two weeks, were randomly assigned to three dietary groups: a control diet, an AFB₁-contaminated diet, and an AFB₁-contaminated diet supplemented with aflatoxin oxidase CotA for three weeks. The results indicate that quails receiving the AFB₁-contaminated diet exhibited reduced body weight gain, pronounced vacuolar degeneration within hepatocytes, and inflammatory cell infiltration. Additionally, the AFB₁ group demonstrated an increased liver index and elevated serum liver enzyme activities (ALT, AST, and ALP). Supplementation with CotA improved body weight gain and conferred protection against AFB₁-induced liver injury. Furthermore, the addition of CotA significantly enhanced liver antioxidant enzyme activities (T-AOC, GST, GSH-Px, POD, and CAT), reduced hepatic H₂O₂ and MDA levels, and upregulated the mRNA expression levels of genes in the Nrf2 pathway in quails exposed to AFB₁. AFB₁ exposure led to lipid droplet accumulation in liver tissues and elevated serum TG and LDL-C levels. However, the introduction of CotA mitigated AFB₁-induced alterations in lipid metabolism. Furthermore, dietary supplementation with CotA inhibited AFB₁-induced hepatocyte apoptosis and decreased the mRNA expression of apoptosis-related genes, including Bax, caspase-9, and caspase-3. Notably, the AFB₁+CotA group exhibited a significant reduction in AFB₁ residues and AFB₁-DNA adducts in quail liver tissues compared to the AFB₁ group. These findings indicate that aflatoxin oxidase CotA holds promise as a feed additive to alleviate AFB₁-induced hepatotoxicity. Full article

The exposome represents the totality of endogenous and exogenous exposures across the lifespan. These exposures may result in DNA and RNA damage, in the form of adducts, which is a key factor in the etiology of a variety of human diseases, including cancer. It is understood that, following their repair, nucleic acid adducts are excreted into the urine, making urine an ideal, non-invasive matrix in which to study the whole-body nucleic acid adductome (the totality of nucleic acid adducts). However, the measurement of these adducts in urine presents challenges due to matrix interference and the variety of the chemical nature across the spectrum of nucleic adducts making their “one-size-fits-all” extraction by solid-phase extraction (SPE) challenging. Here, different types of SPE sorbents, and their combination, were evaluated for maximal recovery of nucleic acid adducts from urine. The SPE column combination of ENV+ coupled with PHE provided the best retention of a cocktail of 20 nucleic acid adduct standards. An untargeted high resolution mass spectrometry approach incorporating FeatureHunter 1.3 software was used to demonstrate the ability of this SPE method to successfully recover endogenous urinary nucleic acid adducts in addition to those represented by the cocktail of isotopically labeled standards. Using our approach, FeatureHunter 1.3 recognized approximately 500 adducts in both mouse and human urine samples. Isotopically labeled standards were used to identify a selection of the endogenous adducts and begin the characterization of the urinary nucleic acid adductome of mice and humans. Full article