Carcinogenic Potential Research Articles

Longitudinal biomonitoring of mycotoxin exposure during pregnancy in the Yale pregnancy Outcome Prediction study

Mycotoxins are fungal toxins that may trigger adverse health effects in pregnant women and their unborn children. Yet, data is scarce on the dynamic exposure patterns of mycotoxins in pregnant women, especially in the United States. This study assessed mycotoxin exposure profiles (n = 50) from the Yale Pregnancy Outcome Prediction Study (YPOPS) cohort at four distinct time points. Multi-analyte human biomonitoring (HBM) assays based on liquid chromatography tandem mass spectrometry (LC-MS/MS), were developed for human serum and plasma matrices. The serum method was applied, together with an established urine method, to quantify mycotoxin levels in longitudinally collected matched serum (n = 200) and spot urine (n = 200) samples throughout pregnancy. The serum samples were mostly contaminated by the potential carcinogen ochratoxin A (detection rate: 49 %; median: 0.09 ng/mL), the hepato- and nephrotoxic citrinin (detection rate: 32 %; median: 0.02 ng/mL) and two enniatins (EnnB; detection rate: 97 %; median: 0.01 ng/mL and EnnB1; detection rate: 12 %; median: 0.003 ng/mL) which may act as immunotoxins. The most prevalent mycotoxins quantified in urine included deoxynivalenol (detection rate: 99 %; median: 23 ng/mL), alternariol monomethyl ether (detection rate: 69 %; median: 0.04 ng/mL), and zearalenone (detection rate: 63 %; median: 0.16 ng/mL). Seven other biomarkers of exposure including the highly estrogenic α-zearalenol and genotoxic Alternaria toxins, were also determined. Carcinogenic aflatoxins were not detected in any of the samples. Exposure assessment was based on the urinary data and performed by calculating the probable daily intakes (PDIs) and comparing the human biomonitoring guidance value (HBM-GV) for deoxynivalenol. The results showed that the individuals exceeded the tolerable daily intake (TDI) for deoxynivalenol and zearalenone on average at 28 % and 2 % over the different time points. Using the HBM-GV approach, the average exceedances for deoxynivalenol increased to 48 % indicating high exposure. For all the samples in which ochratoxin A was quantified, the estimated margin of exposure for neoplastic effects was below 10,000, indicating possible health concerns. Overall, this study showed that pregnant women were exposed to several regulated and emerging mycotoxins and that exposome-scale assessment should be a future priority in susceptible populations to better characterize xenobiotic exposure.

Colorimetric Detection of Aqueous N-Nitrosodimethylamine via Photonitrosation of a Naphtholsulfonate Indicator.

N-Nitrosamines are contaminants found throughout the environment, including in drinking water, and many nitrosamines are likely potent carcinogens. Correspondingly, there is a need for rapid and cost-effective in-field detection methods that can provide timely information about their contamination levels in water. This study details a colorimetric assay for detecting aqueous N-nitrosodimethylamine (NDMA) by photochemical nitrosation of a commercial naphtholsulfonate, to offer an attractive alternative to traditional laboratory-based analysis. The resulting naphthoquinone-oxime coordinates to aqueous iron(II) ions to form a green complex, allowing for direct visual detection. Characterization via Mössbauer and electron paramagnetic resonance (EPR) spectroscopy, alongside single-crystal structure determination, provides comprehensive structure information on the iron indicator complex. Optimization of detection conditions, including UV irradiation and response times, led to an improved colorimetric detection method with a limit of detection of 0.66 ppm for NDMA. The practical applicability and selectivity of this colorimetric detection scheme make it a promising candidate for the development of field-deployable sensors for NDMA in environmental water samples.

TERT upregulation promotes cell proliferation via degradation of p21 and increases carcinogenic potential.

Telomerase reverse transcriptase (TERT) gene aberration is detectable in >80% of cases with hepatocellular carcinoma (HCC). TERT reactivation is essential for cellular immortalization because it stabilizes telomere length, although the role of TERT in hepatocarcinogenesis remains unelucidated. To elucidate the significance of aberrant TERT expression in hepatocytes in inflammation-associated hepatocarcinogenesis, we generated Alb-Cre;TertTg mice, which overexpress TERT in the liver and examined their phenotype during chronic inflammation. Based on transcriptome data from the liver tissue of Alb-Cre;TertTg mice, we examined the role of TERT in hepatocarcinogenesis in vitro. We also evaluated the relationship between TERT and cell-cycle-related molecules, including p21, in HCC samples. The liver tumor development rate was increased by TERT overexpression during chronic inflammation, especially in the absence of p53 function. Gene set enrichment analysis of liver tissues revealed that gene sets related to TNF-NFκB signaling, cell cycle, and apoptosis were upregulated in Alb-Cre;TertTg liver. A luciferase reporter assay and immunoprecipitation revealed that TERT interacted with NFκB p65 and enhanced NFκB promoter activity. On the other hand, TERT formed protein complexes with p21, cyclin A2, and cyclin E and promoted ubiquitin-mediated degradation of p21, specifically in the G1 phase. In the clinical HCC samples, TERT was highly expressed but p21 was conversely downregulated, and TERT expression was associated with the upregulation of molecules related to the cell cycle. Taken together, the aberrant upregulation of TERT increased NFκB promoter activity and promoted cell cycle progression via p21 ubiquitination, leading to hepatocarcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Hydrogeochemical evolution and heavy metal characterization of groundwater from southwestern, Nigeria: An integrated assessment using spatial, indexical, irrigation, chemometric, and health risk models

This study examines the hydrogeochemical and heavy metal parameters of groundwater in Ojo District to determine its suitability for use, potential sources, and human health implications. Ten groundwater samples were assessed, and hydrogeochemical modelling was performed via the Aquachem software. The chemical ions were in the following order: EC > (107.78–448.65 μS/cm) > TDS (182.02–320.77 mg/l) > TH (46.22–182.45 mg/l) > pH (5.55–6.35); HCO3− (64.13–125.82 mg/l) > Na+ (36.87–96.49 mg/l) > Ca2+ (47.65–58.88 mg/l) > SO42− (19.94–53.67) > NO3− (15.55–44.25 mg/l) > Cl− (20.43–27.16 mg/l) > Mg2+ (11.09–16.87 mg/l) and K+ (2.55–7.86 mg/l). The concentrations of heavy metals in groundwater were in the range of: Fe (0.11–0.27 mg/l) > Mn (0.003–0.16 mg/l) > Ni (0.05–0.12 mg/l) > Zn (0.003–0.05 mg/l) > Pb (0.001–0.03 mg/l) > As (0.001–0.005 mg/l) > Cr (0.002–0.005 mg/l) > Cd (0.001–0.003 mg/l) and Cu (0.001–0.0002 mg/l), with Pb, Mn, and Ni exceeding their allowable limits. The Schoeller and Gibbs plots revealed that the major mechanisms controlling the aquifer groundwater in Ojo region are geological rock weathering and mineralization, with a minimal influence of saltwater intrusion. The piper trilinear diagram also revealed that none of the cation was dominant while the anions were strongly dominated by HCO3− (weak acids). The hydrogeochemical facies which describes the geochemical characteristics of the groundwater were classified into 3 types; “Ca2+–Mg+–HCO3– (65 %)”, “mixing zones (30 %)”, and “Na+–K+–Cl––HCO3– (5 %)”. The hydrogeochemical modelling revealed that the groundwater is characterized by forward cation exchange, while rock–water interactions (silicate dissolution) were heavily involved in the geochemical processes. The single pollution index showed that Pb, Ni, and Mn contributed significantly to contamination, and the multi–pollution indices showed that the groundwater was slightly-moderately polluted. The integrated groundwater quality index revealed that only 10 % were clean, 50 % were poor or moderately unclean, 30 % were highly unclean, and only 10 % were extremely unclean (unfit for utilization). The water pollution index showed that 70 % of the groundwater was good. The irrigation indices suggest that the groundwater would enhance soil quality and support plant growth. Multivariate analysis revealed that the groundwater is being influenced by geogenic factors and anthropogenic activities. The health risk assessment (Hazard Quotient and Hazard Index) showed that exposure of adults to the investigated groundwaters could result in noncarcinogenic adverse effects. The cancer risk values also exceeded the minimum limit (1.0 x 10−6) and thresholds (1.0 x 10−4) for adults, indicating the carcinogenic potential of the groundwater.

Thymoquinone Abrogates Acrylamide-Induced Cerebellar Toxicity via Modulation of Nuclear Factor Erythroid 2-Related Factor 2/Nuclear Factor Kappa B Signaling, Oxidative Neuroinflammation, and Neuroapoptosis in Rats.

Acrylamide (ACR) is an obligate human neurotoxicant ubiquitously produced and found in foods processed at high temperature. There is an increasing public health concern regarding its probable carcinogenic potential. Its prevailing toxicity mechanism is oxidative inflammation and apoptosis. Herein, we explored whether thymoquinone (TQ), a bioactive quinone in Nigella sativa seed, could mitigate ACR-induced cerebellar toxicity in rats. Our study design featured four rat groups: control, TQ (5 mg/kg bw), ACR (50 mg/kg bw), and TQ + ACR (5 mg/kg + 50 mg/kg). After 14 days of respective treatments, cerebellar homogenate was used to estimate acetylcholinesterase activity (AchE) activity, antioxidant enzymes (catalase [CAT], superoxide dismutase [SOD], and glutathione peroxidase [GPx]), malondialdehyde (MDA), inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, IL-4, and IL-10), nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), caspase-3, and caspase-9. The level of DNA damage by fragmentation and histopathological lesions was also determined in the cerebellum. The rat exposure to ACR caused significant decreases in the cerebellar activities of AchE, CAT, SOD, and GPx, IL-4, IL-10, and expression of Nrf2, whereas the levels of MDA, IL-6, TNF-α, caspase-3, and caspase-9 were prominently increased compared with the control. ACR induced significant DNA fragments and cerebellar lesions when compared with the control. Contrarily, TQ treatment inhibited the depression of CAT, SOD, and GPx activities and reversed the MDA level and expression of Nrf2/NF-κB, cytokines, and caspases. These effects were confirmed by reduced DNA damage and cerebellar histopathological lesions in comparison with the ACR. TQ afforded neuroprotection via its antioxidant, anti-inflammatory, and antiapoptotic mechanisms in rats.

Potential mammary carcinogens used in food contact articles: implications for policy, enforcement, and prevention.

Many nations have food contact material (FCM) legislation purporting to protect citizens from hazardous chemicals, often specifically by regulating genotoxic carcinogens. Despite such regulations, cancers that are associated with harmful chemical exposures are highly prevalent, especially breast cancer. Using the novel Key Characteristics of Toxicants framework, Kay et al. found 921 substances that are potential mammary carcinogens. By comparing Kay et al.'s chemicals list with our own Database on migrating and extractable food contact chemicals (FCCmigex), we found that 189 (21%) of the potential mammary carcinogens have been measured in FCMs. When limiting these results to migration studies published in 2020-2022, 76 potential mammary carcinogens have been detected to migrate from FCMs sold in markets across the globe, under realistic conditions of use. This implies that chronic exposure of the entire population to potential mammary carcinogens from FCMs is the norm and highlights an important, but currently underappreciated opportunity for prevention. Reducing population-wide exposure to potential mammary carcinogens can be achieved by science-based policy amendments addressing the assessment and management of food contact chemicals.

N-Nitrosamine drug substance related impurities (NDSRIs) – A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da

The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200–600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000.

Geological and mineralogical characterization of fibrous tremolite from Iacolinei quarry (Basilicata, Italy).

Naturally Occurring Asbestos (NOA) has drawn the attention worldwide when investigation revealed an increased incidence of malignant mesothelioma in population living near NOA sites. In Basilicata region (South Italy), population living in the villages of Castelluccio Superiore and Inferiore, Lauria, Latronico, Episcopia, San Severino Lucano, and Francavilla in Sinni may be considered at high risk of asbestos exposure because these villages are either surrounded by or built on NOA-rich ophiolitic outcrops. In this work we investigated an asbestos tremolite sample coming from the ophiolitic rocks outcropping in the quarry of Iacolinei, widely used in the past to extract aggregates for various applications. A detailed mineralogical characterization has been attained by using a multi-analytical approach (EMPA, SEM-EDS, TEM-EDS, Mössbauer, µ-Raman, X-ray powder diffraction, and thermal analysis). Morphological investigation highlighted that the sample is composed of long fibers (> 5 µm) with a significant fraction (ca. 55%) having width below 0.25 µm, considered the most biologically active fibers. Moreover, the crystal chemical characterization showed that Fe occurs at the octahedral sites of the tremolite structure. It should be noted that Fe plays a primary role in the toxicity of asbestos. Based on these results, the investigated asbestos tremolite may be considered a potent mesothelial carcinogen, requiring therefore special attention for public health protection purposes. Investigations using sentinel animals to assess the diffusion of the tremolite fibers into the environment from the serpentinite rocks and soils of Iacolinei quarry are in progress.

Overview of human health effects related to glyphosate exposure.

Glyphosate is a chemical compound derived from glycine, marketed as a broad-spectrum herbicide, and represents one of the most widely used pesticides in the world. For a long time, it was assumed that glyphosate was harmless, either due to its selective enzymatic acting method on plants, and because commercial formulations were believed to contain only inert chemicals. Glyphosate is widely spread in the environment, the general population is daily exposed to it via different routes, including the consumption of both plant, and non-plant based foods. Glyphosate has been detected in high amounts in workers' urine, but has been detected likewise in bodily fluids, such as blood and maternal milk, and also in 60%-80% of general population, including children. Considering its massive presence, daily exposure to glyphosate could be considered a health risk for humans. Indeed, in 2015, the IARC (International Agency for Research on Cancer) classified glyphosate and its derivatives in Group 2A, as probable human carcinogens. In 2022, nevertheless, EFSA (European Food Safety Authority) stated that the available data did not provide sufficient evidence to prove the mutagenic/carcinogenic effects of glyphosate. Therefore, the European Commission (EC) decided to renew the approval of glyphosate for another 10years. The purpose of this review is to examine the scientific literature, focusing on potential risks to human health arising from exposure to glyphosate, its metabolites and its commercial products (e.g., Roundup®), with particular regard to its mutagenic and carcinogenic potential and its effects as endocrine disrupter (ED) especially in the human reproductive system.

One-Week Kava Dietary Supplementation Increases Both Urinary N- and O-Glucuronides of NNAL, a Lung Carcinogen Major Metabolite, among Smokers.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.

Urinary bladder carcinogenic potential of 4,4'-methylenebis(2-chloroaniline) in humanized-liver mice.

Occupational exposure to 4,4'-methylenebis(2-chloroaniline) (MOCA) has been linked to an increased risk of bladder cancer among employees in Japanese plants, indicating its significance as a risk factor for urinary bladder cancer. To investigate the role of MOCA metabolism in bladder carcinogenesis, we administered MOCA to non-humanized (F1-TKm30 mice) and humanized-liver mice for 4 and 28 weeks. We compared MOCA-induced changes in metabolic enzyme expression, metabolite formation, and effects on the urinary bladder epithelium in the two models. At week 4, MOCA exposure induced simple hyperplasia, cell proliferation, and DNA damage in the urothelium of the humanized-liver mice, while in the non-humanized mice these effects were not observed. Notably, the concentration of 4-amino-4'-hydroxylamino-3,3'-dichlorodiphenylmethane (N-OH-MOCA) in the urine of humanized-liver mice was more than 10 times higher than that in non-humanized mice at the 4-week mark. Additionally, we observed distinct differences in the expression of cytochrome P450 isoforms between the two models. Although no bladder tumors were detected after 28 weeks of treatment in either group, these findings suggest that N-OH-MOCA significantly contributes to the carcinogenic potential of MOCA in humans.

Reducing the acrylamide concentration in homemade bread processed with L-asparaginase

Acrylamide is the main contaminant for starchy foods cooked at temperatures above 120 °C. It represents a potential carcinogen, and consequently, its reduction is important for safeguarding global health. The L-asparaginase enzyme catalyses the hydrolytic cleavage of L-asparagine, a precursor of acrylamide, into L-aspartic acid and ammonia, thus reducing the formation of acrylamide. The objective of this work was to test the enzyme L-asparaginase at two concentrations (150 and 300 U/kg flour) under normal baking conditions to reduce acrylamide. The results showed that the use of 300 U/g of the enzyme led to a reduction of 78% in acrylamide, meeting the reference level reported by Reg. (EU) 2017/2158 (50 μg/kg) without influencing parameters such as colour that impact the final characteristics of the product.

Mitigating CYP3A4-mediated aflatoxin toxicity with algal-derived Sodium Copper Chlorophyllin: Production and In-silico insights

The present research explores the cytotoxic mechanism of protein Cytochrome P450 (CYP3A4) with aflatoxin (AFB1), a potent carcinogen. Cytochrome P450 is an essential enzyme involved in drug metabolism, however epoxide formation due to the binding event of AFB1 leads to cell cytotoxicity. In this direction, our study elucidates the scavenging effect of algal-derived Sodium Copper Chlorophyllin (SCC) over AFB1 cytotoxicity. Cyanobacteria/ microalgae-derived SCC have garnered attention due to its diverse applications in pharmacological and food industries. This work began with the production of SCC from Spirulina and Chlorella sp. over a stipulated period of growth. Subsequently, the study delved into the interplay between SCC and the carcinogenic impact of AFB1 on the CYP3A4 enzyme. Computational studies demonstrated SCC binding and blocking mechanisms against AFB1. Our research intended to determine whether CYP3A4 can bind to SCC that, in turn, act as an interceptor for AFB1 or influence the metabolism of bound AFB1. Current results support that SCC is an effective AFB1 trap as it shows interactions with AFB1. These findings would open up new avenues in clinical biology/pharmacology to further explore the mechanisms of action of CYP3A4 with AFB1 and SCC, offering promising prospects for abating cell cytotoxicity.

Development and validation of a DLLME-HPLC-FLD method for determination of aflatoxins in Chrysanthemum morifolium based on quality by design principles.

Aflatoxins, potent carcinogens produced by Aspergillus species, present significant health risks and commonly contaminate herbal products such as Chrysanthemum morifolium. Detecting these toxins in C. morifolium proves challenging due to the complex nature of the herbal matrix and the fluctuating levels of toxins found in different samples. This study aimed to develop and optimize a novel method for the detection of aflatoxins in C. morifolium using dispersive liquid-liquid microextraction combined with high-performance liquid chromatography-fluorescence detection based on quality by design principles. The method involved determining critical method attributes and parameters through the Plackett-Burman design, followed by optimization using the Box-Behnken design. Monte Carlo simulation was employed to establish a design space, which was experimentally verified. Method validation was performed to confirm accuracy, precision, and stability. The developed method exhibited excellent linearity (R2 > 0.9991) for aflatoxins B1, B2, G1, and G2 across a range of concentrations, with recovery rates between 85.52% and 102.01%. The validated method effectively quantified aflatoxins in C. morifolium under different storage conditions, highlighting the impact of temperature and storage time on aflatoxin production. This study successfully established a reliable and effective method for the detection of aflatoxins in C. morifolium, highlighting the importance of strict storage conditions to reduce aflatoxin contamination. Using a quality by design framework, the method demonstrated robustness and high analytical performance, making it suitable for routine quality control of herbal products.

Development of a bioluminescent immunoassay based on Fc-specific conjugated antibody–nanoluciferase immunoreagents for determining aflatoxin B1

Aflatoxin B1 (AFB1) is a potent carcinogen, and is among the most hazardous mycotoxins in agricultural products. Therefore, the development of sensitive and convenient detection methods for AFB1 is significant for food safety against mycotoxins. Herein, a bioluminescent enzyme immunoassay (BLEIA) was developed for ultrasensitive detection of AFB1, based on the novel Fc-specific antibody–nanoluciferase (Ab–Nluc) conjugates which were fabricated using an IgG-binding protein-assisted photo-conjugation strategy. In indirect competitive immunoassay format, the proposed BLEIA exhibited the detection limit of 0.0232 ng mL−1, which was 37.4-fold lower than that obtained using the classical enzyme-linked immunosorbent assay (ELISA) based on Ab–horseradish peroxidase (Ab–HRP) chemical conjugates (0.868 ng mL−1). Meanwhile, the BLEIA exhibited high accuracy and precision. Thus, the proposed Fc-specific Ab–Nluc conjugates-based BLEIA provides an ultrasensitive and reliable method for detecting toxins and has potential for use in food safety monitoring.

Key characteristics of carcinogens meet hallmarks for prevention-cutting the Gordian knot.

The complexity of cancer requires a comprehensive approach to understand its diverse manifestations and underlying mechanisms. Initially outlined by Hanahan and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a conceptual basis for understanding inherent variability in cancer biology. Recent expansions have further elucidated additional hallmarks, including phenotypic plasticity and senescent cells. The International Agency for Research on Cancer (IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate their carcinogenic potential. We analyzed chemicals of concern for environmental exposure that interact with specific receptors to induce genomic instability, epigenetic alterations, immune suppression, and receptor-mediated effects, thereby contributing to chronic inflammation. Despite their varying degrees of carcinogenicity, these chemicals have similar KCC profiles. Our analysis highlights the pivotal role of receptor binding in activating most other KCCs, underscoring their significance in cancer initiation. Although KCCs are associated with early molecular or cellular events, they do not encompass processes directly linked to full cellular malignancy. Thus, there is a need to integrate clear endpoints that anchor KCCs to the acquisition of a complete malignant phenotype into chemical testing. From the perspective of toxicology and cancer research, an all-encompassing strategy that incorporates both existing and novel KCCs and cancer hallmarks is essential to enable the targeted identification of prevalent carcinogens and facilitate zone-specific prevention strategies. To achieve this goal, collaboration between the KCC and cancer hallmarks communities becomes essential.

The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans.

The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10μM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10μM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.

Chromosome aberrations cause tumorigenesis through chromosomal rearrangements in a hepatocarcinogenesis rat model.

Chromosome aberrations (CAs), a genotoxic potential of carcinogens, are believed to contribute to tumorigenesis by chromosomal rearrangements through micronucleus formation. However, there is no direct evidence that proves the involvement of CAs in tumorigenesis invivo. In the current study, we sought to clarify the involvement of CAs in chemical carcinogenesis using a rat model with a pure CA-inducer hepatocarcinogen, acetamide. Whole-genome analysis indicated that hepatic tumors induced by acetamide treatment for 26-30 weeks showed a broad range of copy number alterations in various chromosomes. In contrast, hepatic tumors induced by a typical mutagen (diethylnitrosamine) followed by a nonmutagen (phenobarbital) did not show such mutational patterns. Additionally, structural alterations such as translocations were observed more frequently in the acetamide-induced tumors. Moreover, most of the acetamide-induced tumors expressed c-Myc and/or MDM2 protein due to the copy number gain of each oncogene. These results suggest the occurrence of chromosomal rearrangements and subsequent oncogene amplification in the acetamide-induced tumors. Taken together, the results indicate that CAs are directly involved in tumorigenesis through chromosomal rearrangements in an acetamide-induced hepatocarcinogenesis rat model.

Polycyclic Aromatic Hydrocarbons (PAHs) Contamination Levels in Some Commercial Olive Oils Sold on the Markets in Giresun, Türkiye

Olive oil is widely consumed worldwide and well-known for its health beneficial effects. However, polycyclic aromatic hydrocarbons (PAHs) contamination in olive oils has been a serious concern and knowledge regarding PAH concentrations in olive oils is scarce. The aim of this study was the determination and evaluation of PAH contamination levels in olive oils in the market. In this study, commercial olive oils (n=14) available in the markets of Giresun (Türkiye), including extra virgin and riviera olive oil samples, were investigated. Samples were analyzed by a gas chromatography unit coupled with a mass spectrometer. Significant amounts of PAHs were determined in all olive oil samples. The PAH contents of the samples varied between 0.04 µg kg-1 and 4637.13 µg kg-1 with the mean content of 264.61 µg kg-1. Regarding benzo[a]pyrene, 64.28% of the samples was incompatible with the EU requirements. None of the samples were compatible with the EU requirements in terms of PAH4 components (benzo[a]pyrene, benzo(a)anthracene, chrysene, and benzo[b]fluoranthene). Results showed that commercial olive oils studied in this research might contain PAHs categorized under potential carcinogens.

Transcriptomic analysis reveals transcription factors implicated in radon-induced lung carcinogenesis.

Radon, a potent carcinogen, is a significant catalyst for lung cancer development. However, the molecular mechanisms triggering radon-induced lung cancer remain elusive. Utilizing a radon exposure concentration of 20,000Bq/m3 for 20min/session, malignant transformation was induced in human bronchial epithelial cells (BEAS-2B). Radon-exposed cells derived from passage 25 (BEAS-2B-Rn) exhibited enhanced proliferation and increased colony formation. Analysis of differential gene expression (DEG) through transcription factors revealed 663 up-regulated and 894 down-regulated genes in radon-exposed cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant alterations in the malignant transformation pathway of cells, including those related to cancer and the PI3K/AKT signaling pathway. A PPI network analysis indicated a significant association of oncogenes, such as CCND1, KIT, and GATA3, with lung cancer among differentially expressed genes. In addition, the stability of the housekeeping gene was determined through RT-qPCR analysis, which also confirmed the results of transcriptome analysis. The results suggest that transcription factors may play a pivotal role in conferring a survival advantage to radon-exposed cells. This is achieved by malignant transformation of human bronchial epithelial cells into lung carcinogenesis cell phenotypes.