Carcinogen Exposure Research Articles

Exposure assessment of polycyclic aromatic hydrocarbons from the consumption of processed cowhide (Wele), a West African delicacy

This study describes the occurrence and profile of eight polycyclic aromatic hydrocarbons (PAHs) in fresh and cooked processed cowhide (wele) singed with different fuels. It also assessed the health risks associated with the consumption of this popular delicacy. The 8PAHs were all detected in the wele samples singed with scrap tires, whereas 5 and 3 carcinogenic PAHs were detected in the firewood and liquefied petroleum gas (LPG) singed wele, respectively. For each of the specific PAH detected, the contents in the wele samples were generally ranked as scrap tires > firewood > LPG. The average concentrations of benzo[a]pyrene for cooked wele samples were 2.75 ng g−1(firewood) and 22.85 ng g−1(scrap tires); exceeding the 2.0 ng g−1 European Commission regulation maximum levels (MLs) for smoked products. For the carcinogenic risk exposure assessment, the dietary intake based on benzo[a]pyrene equivalents was estimated as 777.06 ng g−1 day (scrap tires), 101.52 ng g−1 day (firewood) and 9.45 ng g−1 day (LPG). The probable cancer risk estimated considering the consumption frequency and quantity of wele for an average adult consumer was highest in the population exposed to wele singed with scrap tires (3.11×10−5).

Benchmark dose estimation for benzene-exposed workers in China: Based on quantitative and multi-endpoint genotoxicity assessments

Based on previous exposure studies, benzene (BZ) has been classified as a human carcinogen and occupational exposure limit (OELs) for BZ has been set to be about 1 ppm around the world. However, health hazards have still been reported with exposure below the OEL. Thus, the OEL needs to be updated to reduce health risk. The overall aim of our study was therefore to generate new OEL for BZ via a benchmark dose (BMD) approach and based on quantitative and multi-endpoint genotoxicity assessments. Genotoxicities were determined using the novel human PIG-A gene mutation assay, the micronucleus (MN) test and the COMET assay in benzene-exposed workers. Among the 104 workers with below current OELs, they exhibited significantly higher PIG-A mutant frequencies (MFs) (15.96 ± 14.41 × 10−6) and MN frequencies (11.55 ± 6.83‰) than those among the controls (PIG-A MFs: 5.46 ± 4.56 × 10−6, MN frequencies: 4.51 ± 1.58 ‰), but no difference in the COMET assay. A significant association was also observed between BZ exposure doses and PIG-A MFs and MN frequencies (P < 0.001). Our results indicate that health hazards were induced among workers with below OEL exposures. Based on results from the PIG-A and MN assays, the lower confidence limit of the BMD (BMDL) were calculated to be 8.71 mg/m3-year and 0.44 mg/m3-year, respectively. Based on these calculations, the OEL for BZ was determined to be lower than 0.07 ppm. This value can be considered by regulatory agencies to set new exposure limits and to better protect workers.

Abstract 4247: Impact of 70% ethanol intraductal injections in MNU rat models for breast cancer prevention

Abstract Breast cancer (BC) is the leading cancer diagnosis in women. While many BC treatment options exist, only two methods are approved for prevention. Prophylactic mastectomy is an invasive surgery that removes the breast, thereby removing the targeted epithelial ductal tree cells, where most BC arises. Despite a 90% risk reduction, recovery time, risk of infection, pain management, and mental health toll on women deter them from this surgery. Hormonal preventatives, tamoxifen and raloxifene, reduce BC risk by up to 50%. However, increased risk of uterine cancer and intolerable sides effect deter women from this option. Therefore, new preventative methods are needed to maintain BC risk reduction while minimizing current BC prevention deterrents. Intraductal (ID) injection is a technique that can circumvent systemic toxicity by inserting a needle directly into the ductal tree opening. We study BC prevention using 70% ethanol (EtOH) as a cell killing, ablative solution for ID injections and have shown its effectiveness of ablation in an aggressive genetically engineered mouse model with minimum collateral tissue damage. EtOH is a safe, inexpensive reagent clinically used as a sclerosing and ablative agent. We introduced ethyl cellulose (EC), a gelling agent which further minimized damage outside the ductal tree. To confirm successful ductal tree filling without animal sacrifice, we introduced Tantalum Oxide (TaOx), a nanoparticle-based contrast agent for real time and long-term visualization of ductal tree filling. TaOx showed remarkable local retention, without impeding 70% EtOH ablative effects or EC compared to other contrast agents. Despite our refined ablative solution, ID injection is a difficult technique to perform with limited ability to confirm success of a fully filled ductal tree. To elucidate any impact of partial ductal tree filling, we utilized a Methyl-N-Nitrosourea (MNU) rat model. Rat models improve scalability toward clinical trials and increase ductal tree filling volume and control to study the impact of partial ductal tree filling. Our MNU rat model provides a time frame between carcinogen exposure and tumor formation optimal for prevention studies. Two weeks after intraperitoneal MNU injections, rats received full or half volume (partial) injections, fat pad (partial), or no injection into individual mammary glands. Rats were monitored for tumor formation from 2 weeks post injection until reaching euthanasia criteria. Fully injected glands had the highest tumor latency increase by 1 month (130 days, p &amp;lt; 0.0001) compared to non-injected controls (95 days). Partial and fat pad tumor latency also improved compared to control (122 days, p &amp;lt;0.01 and 110 days, p &amp;lt;0.05 respectively). No iatrogenic effects of EtOH were observed. Here, we show that ID injection of 70% EtOH is a safe, effective, and scalable technique for BC prevention, which can be enhanced with TaOx and EC for visualization and retention. Citation Format: Erin K. Zaluzec, Mohamed Ashry, Elizabeth Kenyon, Elizabeth G. Phelps, Legend Kenney, Katherine Powell, Maximilian Volk, Shatadru Chakravarty, Jeremy M.L. Hix, Matti Kiupel, Erik Shapiro, Lorenzo F. Sempere. Impact of 70% ethanol intraductal injections in MNU rat models for breast cancer prevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4247.

Abstract 1414: The role of chromosome arm 3p and human papillomavirus on proliferation, differentiation, and metastasis in squamous cancers

Abstract Squamous Cell Carcinoma (SCC) is an aggressive form of cancer that develops in the mucosal epithelium of the digestive and respiratory tracts as well as on the skin. Two major risk factors for development of SCC are carcinogen exposures, such as alcohol and tobacco, and Human Papillomavirus (HPV) infection. Viral- and carcinogen-driven SCCs have differential responses to radiation, chemotherapy, and immunotherapy, with HPV+ SCCs responding better to these treatments than HPV- carcinomas. Analysis of aneuploidy patterns of genomic samples from The Cancer Genome Atlas (TCGA) have shown that squamous cancers cluster together and are characterized by gain of chromosome arm 3q gain and loss of chromosome arm 3p. However, while HPV+ SCCs show similar rates of 3q gain, they have significantly lower rates of 3p loss, suggesting that 3p deletion and HPV infection might have overlapping roles in cancer initiation and/or progression. In addition, the degree to which these two paths of tumor development contribute to differences in disease progression and outcome has been largely unexplored. We have identified a strong correlation between 3p deletion and high epithelial-mesenchymal transition (EMT) gene signature across all cancer types. Interestingly, interferon signaling has been found to be upregulated in non-squamous cancers upon 3p deletion but downregulated in squamous cancers with 3p deletion. SCCs positive for HPV infection show decreased expression of EMT genes and increased expression of genes in interferon signaling and cell cycle checkpoint pathways. Together, the results of these TCGA analyses suggest mechanisms by which chromosome 3p deletion and HPV infection may affect cancer progression and are currently being validated in vitro in a panel of squamous cancer cell lines. Additionally, we will use a targeted CRISPR-Cas9 system developed in our lab to delete chromosome 3p, as well as transfect HPV oncoproteins, in normal keratinocytes to create isogenic models. With these models, we will study the role of individual aneuploidy events in tumorigenesis, tumor development, and metastasis in the context of HPV positive and negative SCC. Citation Format: Samyukta Mallick, Alison M. Taylor. The role of chromosome arm 3p and human papillomavirus on proliferation, differentiation, and metastasis in squamous cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1414.

Abstract 6463: Persistence of smoking mutational signatures in the non-small cell lung cancer genome

Abstract Mutational signatures offer insights into cancer etiology. Smoking tobacco is associated with three signatures involving single base substitutions (SBS4), double base substitutions (DBS2) and insertions/deletions (ID3). Combining mutational signatures with clinical data allows examination of temporal and quantitative aspects of carcinogenic exposures. We analyzed 132 non-small cell lung carcinoma (NSCLC) whole genomes, sequenced through the 100,000 Genomes Project (Genomics England), with paired clinical data available for 130/132 (98.5%). Clinical data included smoking status, duration, pack-years (py), and duration of smoking cessation. The majority were “ever-smokers” (ex-smokers: 90/130, 69.2%; current smokers: 32/130, 24.6%) and 120/122 (98.4%) had at least one smoking signature. DBS2 was the most sensitive signature for ever-smokers (118/122, 96.7%), although SBS4 was the optimal signature for diagnosing smoking-related NSCLCs (SBS4 positive likelihood ratio 7.15). An absence of ID3 best identified true never smoker NSCLCs (ID3 negative likelihood ratio 0.08). Ever-smokers had a higher tumor mutational burden (TMB) than never smokers (median 8.25 mutations/Mb vs 1.18 mutations/Mb, p = &amp;lt;0.0001), while TMB positively correlated with smoking pack-years (p = 0.044). Following smoking cessation, the median length of discontinuation was 11 years before a smoking-related NSCLC was diagnosed and, in some cases, smoking signatures persisted for up to 50 years prior to NSCLC diagnosis. To complement existing epidemiological data, 40 pack years was estimated as a critical cut-off for minimizing ongoing NSCLC risk. Prolonged smoking cessation did not reduce TMB (p = 0.055) or SBS4 mutations (p = 0.11), although this did produce lower DBS2 counts (p = 0.0067). Further signatures observed included SBS92 (previously seen in the bladder urothelium of ever-smokers) and a novel signature hypothesized to be linked to DNA mismatch repair deficiencies. NSCLCs from two patients with prior platinum chemo-radiotherapy harbored signatures of both chemotherapy- and radiotherapy-induced damage in their recurrent biopsy sample. These results highlight the importance of paired sequencing and clinical data, revealing that smoking-induced DNA damage can have long-lived effects, and strengthening health guidance of abstinence from smoking at the earliest possibility. Citation Format: Colin R. Lindsay, Pantelis Nicola, Andreas Gruber, Kate Brown, Mathew Carter, Helen Adderley, Shereen Rafee, Anna Moss, Andrew Wallace, George Burghel, Helene Schlecht, Katie Baker, Sharzad Moghadam, Jane Rogan, Jamie Weaver, Angeliki Malliri, William Newman, Fiona Blackhall, David Wedge, Genomics England. Persistence of smoking mutational signatures in the non-small cell lung cancer genome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6463.

Risks of toxic elements and endocrine disruptors in some soils in Ghana

ABSTRACT Endocrine disrupting chemicals (EDCs) and potentially toxic elements (PTEs) pose risks to human health, here assessed in soils from a municipal dump, an industrial site, agricultural use and a forest reserve. Across the spectrum, there are significant variations in PTEs and EDCs, and arsenic had minimum and maximum values of 2.58 and 2455.75 mg/kg, respectively. Carcinogenic exposure risks, ingestion cancer risks and toxic elements are also assessed.

Epidemiologic roadblocks in studying elongated mineral particles and mesothelioma risk

Elongated mineral particles (EMPs) are a type of both occupational and environmental exposures that have generated interest in the scientific community due to their potential health effects. Their possible association with mesothelioma represents an area of concern. We provide an overview of the current challenges around epidemiological assessments of EMP exposure and mesothelioma risk, including methodological aspects that need to be addressed when designing and analyzing a study on EMP exposure and mesothelioma. Future work is needed to investigate the relationship between EMPs and mesothelioma, focused on an improved definition of EMP exposure and accounting for other concomitant sources of carcinogen exposure.

Occupational asbestos exposure and survival among lung cancer patients

ObjectiveThis study investigated the association between occupational asbestos exposure (OAE) and survival in patients with histologically confirmed lung cancer (LC). MethodsThis monocentric study was conducted in the Comprehensive Cancer Centre Léon Bérard, Lyon, France. A systematic screening has been in place since 2014 for occupational exposure to carcinogens using a self-assessment questionnaire sent to all patients newly diagnosed with histologically confirmed LC identified through the multidisciplinary LC board from 2014 to 2019. When the physician suspected a work-related exposure from the questionnaire including job history, an occupational cancer consultation was carried out to detail carcinogen exposures and assess if the LC was work-related. Demographics, clinical characteristics and survival data were extracted from medical records. The association between asbestos exposure and overall survival (hazard ratio and 95% confidence intervals) was estimated by Cox proportional hazards regression. ResultsOverall, 702 patients were eligible to the present study, including 180 patients with OAE. In the crude analysis, LCs assessed as moderately or highly attributable to OAE were associated with decreased overall survival (HR = 1.32, 95 %CI 1.04–1.67) compared to LC without OAE or with a low degree of imputability to OAE (median follow-up 28.8 months). After adjustment for confounding (age at diagnosis, smoking status, stage, brain metastasis at diagnosis, and histology), the association of OAE with overall survival was no longer statistically significant (HR = 1.21, 95 %CI 0.94–1.56). ConclusionOverall survival in occupationally asbestos exposed LC patients may be decreased in comparison with non-exposed LC patients, warranting further investigations in larger studies.

Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation.

Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice. OH-BBN-induced bladder tumors exhibit significantly increased expression of lysine-specific demethylase 1 (LSD1), accompanied by decreased levels of H3K4 mono-methylation compared to normal bladder epithelium, whereas dietary kawain reverses the effects of OH-BBN on H3K4 mono-methylation. Human bladder cancer tumor tissues at different pathological grades also show significantly increased expression of LSD1 and decreased levels of H3K4 mono-methylation compared to normal urothelium. In addition, kava root extracts and the kavalactones kawain and methysticin all increase the levels of H3K4 mono- and di-methylation, leading to inhibitory effects on cell migration. Taken together, our results suggest that modification of histone lysine methylation may represent a new approach to bladder cancer prevention and treatment and that kavalactones may be promising agents for bladder cancer interception in both current and former smokers.

Risk of cutaneous squamous cell carcinoma due to occupational exposure to solar ultraviolet radiation: Protocol for a systematic review and meta-analysis.

Solar ultraviolet radiation (UVR) is the most significant occupational carcinogenic exposure in terms of the number of workers exposed (i.e., outdoor workers). Consequently, solar UVR-induced skin cancers are among the most common forms of occupational malignancies that are potentially expected globally. This systematic review is registered in PROSPERO (CRD42021295221) and aims to assess the risk of cutaneous squamous cell carcinoma (cSCC) associated to occupational solar UVR exposure. Systematic searches will be performed in three electronic literature databases (PubMed/Medline, EMBASE, and Scopus). Further references will be retrieved by a manual search (e.g., in grey literature databases, internet search engines, and organizational websites). We will include cohort studies and case-control studies. Risk of Bias assessment will be conducted separately for case-control and cohort studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be used for the certainty of assessment. In case quantitative pooling is not feasible, a narrative synthesis of results will be performed.

Metabolomic differences in young-onset versus average-onset colorectal adenocarcinoma.

174 Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC and healthy controls were identified from prospective biobanks and categorized based on age&lt;50 years (yoCRC or young controls) or age&gt;60 years (aoCRC or older controls). Serum metabolites were profiled using GC-TOF mass spectrometry. Differential abundance of metabolites was investigated using unadjusted logistic regression. Metabolic pathway analysis was performed using Metaboanalyst 5.0. All p-values were adjusted for multiple testing (false-discovery rate, FDR p&lt;0.20 considered significant). Results: The study population comprised 170 CRC patients (66 yoCRC and 104 aoCRC) and 49 healthy controls (34 young and 15 old). Association analyses revealed four differentially abundant metabolites: citrate (FDR p=0.04), cholesterol (0.14), and two unidentified metabolites (UM). Metabolic pathways significantly altered in yoCRC vs. aoCRC included: carbohydrate metabolism (citrate cycle, FDR p=0.11), carbohydrate biosynthesis (glyoxylate and dicarboxylate metabolism, FDR p=0.03), amino-acid metabolism (alanine, aspartate, and glutamate metabolism, FDR p=0.04, arginine biosynthesis, FDR p=0.04, and amino-acid t-RNA biosynthesis, FDR p=0.04). There were no significant metabolomic differences between young and older controls. Conclusions: We identified significant differences in the citrate cycle - a core pathway of cellular metabolism and associated with colorectal cancer. Metabolomic differences in pathways of carcinogenic significance (aspartate) and environmental exposures (arginine and dietary red meat) were also noted, suggesting potential relationships with younger age of CRC onset. The study provides future directions for more precise analyses with a larger sample size for healthy controls and adjusting for confounders. [Table: see text]

Traffic-Related Air Pollution and Ground-Level Ozone Associated Global DNA Hypomethylation and Bulky DNA Adduct Formation.

Studies have indicated that air pollution, including surface-level ozone (O3), can significantly influence the risk of chronic diseases. To better understand the carcinogenic mechanisms of air pollutants and identify predictive disease biomarkers, we examined the association between traffic-related pollutants with DNA methylation alterations and bulky DNA adducts, two biomarkers of carcinogen exposure and cancer risk, in the peripheral blood of 140 volunteers-95 traffic police officers, and 45 unexposed subjects. The DNA methylation and adduct measurements were performed by bisulfite-PCR and pyrosequencing and 32P-postlabeling assay. Airborne levels of benzo(a)pyrene [B(a)P], carbon monoxide, and tropospheric O3 were determined by personal exposure biomonitoring or by fixed monitoring stations. Overall, air pollution exposure was associated with a significant reduction (1.41 units) in global DNA methylation (95% C.I. -2.65-0.04, p = 0.026). The decrement in ALU repetitive elements was greatest in the policemen working downtown (95% C.I. -3.23--0.49, p = 0.008). The DNA adducts were found to be significantly increased (0.45 units) in the municipal officers with respect to unexposed subjects (95% C.I. 0.02-0.88, p = 0.039), mainly in those who were controlling traffic in downtown areas (95% C.I. 0.39-1.29, p < 0.001). Regression models indicated an increment of ALU methylation at higher B(a)P concentrations (95% C.I. 0.03-0.60, p = 0.032). Moreover, statistical models showed a decrement in ALU methylation and an increment of DNA damage only above the cut-off value of 30 µg/m3 O3. A significant increment of 0.73 units of IL-6 gene methylation was also found in smokers with respect to non-smokers. Our results highlighted the role of air pollution on epigenetic alterations and genotoxic effects, especially above the target value of 30 µg/m3 surface-level O3, supporting the necessity for developing public health strategies aimed to reduce traffic-related air pollution molecular alterations.

Prevalência de possíveis exposições cancerígenas ocupacionais em trabalhadores brasileiros: o que mostra a Pesquisa Nacional de Saúde?

Abstract Objective: to estimate the prevalence of possible carcinogenic exposures in Brazilian workers. Methods: cross-sectional study, with data from the 2019 National Health Survey. We calculated the prevalences and respective 95% confidence intervals (95%CI) for possible exposure to six occupational carcinogens: solar radiation, chemical substances, mineral dust, radioactive material, night work, and passive smoking at work, according to occupation and sex, considering the complex sample design. Results: 44,822 workers were included, 56.33% were male. Reported exposure to at least one carcinogenic agent from group 1, according to the classification of the International Agency for Research on Cancer, 49.0% (95%CI 47.8;50.2) of male workers and 16.9% (95%CI 16.0;17.9) of female workers. Male workers, compared with female workers, had a higher prevalence of exposure to solar radiation (38.1% [95%CI 37.0;39.3] vs 6.6% [95%CI 6.0;7.2]), chemical agents (19.4% [95%CI 18.5;20.5] vs 8.3% [95%CI 7.6;9.1]), mineral dust (18.9% [95%CI 17.9;20.0] vs 3.3% [95%CI 2.9;3.8]), night work (15.5% [95%CI 14.7;16.5] vs 9.4% [95%CI 8.6;10.2]), and passive smoking (14.3% [95%CI 13.3;15.4] vs 8.2% [95%CI 7.6;9.0]). Conclusion: the prevalence of exposure to possible occupational carcinogens is high and unequally distributed by sex and occupation. Actions to reduce, replace, and eliminate these carcinogens should be prioritized.

Abstract PR004: The role of NOTCH1 in bronchial pre-malignant lesions

Abstract Continuous carcinogen exposure through smoking creates a field of injury along the airway and resulting in mutations which promote remodeling of the bronchial epithelium. Over time lesions can form and exhibit increasing abnormalities progressing from goblet cell hyperplasia (GCH) which is the earliest detectable premalignant state through hyperplasia and squamous metaplasia to incremental stages of dysplasia, carcinoma in situ (CIS) and eventually to frank carcinoma. Unfortunately, more than half of all lung cancer patients are diagnosed with metastatic disease with a dismal 5-year survival rate of only 5.2%. However, when diagnosed at an early stage, the 5-year survival rate is more than 10 times as high. Our group has identified NOTCH1 as the most frequently mutated gene in progressive lung premalignant lesions (PMLs). However, these mutations are significantly less common in advanced lung squamous cell carcinoma (LUSC), indicating a role for NOTCH1 in the pre-tumorigenic environment rather than contributing to the actual tumor mass. Transcriptomic profiling of NOTCH1 mutated lesions identified up regulation of peri-goblet cells (PGC), a newly identified bronchial epithelial cell type that is associated with smoking, and a down regulation of immune components. Using highly multiplex Imaging Mass Cytometry (IMC) to analyze the epithelium of NOTCH1 mutated PMLs and its interplay with the immune system in situ. We identified a shift in epithelial composition with an increase in un- and de-differentiated cells. Interestingly, PGC appear to be an intermediate cell type on a previously undescribed path to goblet cell differentiation. In a parallel approach we are modeling NOTCH1 driven dysplasia in vitro to gain insight into the molecular mechanisms of lesion progression. Primary human bronchial epithelial cells (hBECs) grown at the air-liquid interface (ALI) into mature epithelia are exposed to cigarette smoke condensate (CSC) or IL-13 to model the early stages of bronchial airway dysplasia. Continuous exposure of these differentiating cultures to either stimulus increases the abundance of goblet cells and PGCs in a dose dependent manner with IL-13 additionally leading to the loss of baso-apical organization of the epithelium. After successfully modeling the first stage of bronchial epithelial dysplasia we are now advancing our model by co-culturing primary hBECs with NOTCH1 mutated cells and to disentangle the pathway of basal-PGC-goblet cell differentiation. Understanding driving forces in early lesion progression will further our ability to discern progressive lesions from those that regress naturally and facilitate interventions that force lesions into regression. Citation Format: Roxana Michaela Pfefferkorn, Darren Jianjhih Chiu, Divya Lakshmi Venkatraman, Jennifer Ellen Beane, Sarah Anne Mazzilli, Joshua David Campbell. The role of NOTCH1 in bronchial pre-malignant lesions. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR004.

Prevalence of possible occupational carcinogenic exposures in Brazilian workers: what does the National Health Survey say?

Resumo Objetivo: estimar a prevalência de possíveis exposições cancerígenas em trabalhadores brasileiros. Métodos: estudo transversal, com dados da Pesquisa Nacional de Saúde de 2019. Calcularam-se prevalências e respectivos intervalos de confiança de 95% (IC95%) para possível exposição a seis carcinógenos ocupacionais: radiação solar, substâncias químicas, poeiras minerais, material radioativo, trabalho noturno e tabagismo passivo no trabalho, segundo ocupação e sexo, considerando o desenho complexo da amostra. Resultados: foram incluídos 44.822 trabalhadores, 56,33% do sexo masculino. Referiram exposição a pelo menos um agente cancerígeno do grupo 1, segundo classificação da International Agency for Research on Cancer, 49,0% (IC95% 47,8;50,2) dos trabalhadores do sexo masculino e 16,9% (IC95% 16,0;17,9) do feminino. Trabalhadores do sexo masculino, em comparação ao feminino, apresentaram maiores prevalências de exposição à radiação solar (38,1% [IC95% 37,0;39,3] vs 6,6% [IC95% 6,0;7,2]), agentes químicos (19,4% [IC95% 18,5;20,5] vs 8,3% [IC95% 7,6;9,1]), poeiras minerais (18,9% [IC95% 17,9;20,0] vs 3,3% [IC95% 2,9;3,8]), trabalho noturno (15,5% [IC95% 14,7;16,5] vs 9,4% [IC95% 8,6;10,2) e tabagismo passivo (14,3% [IC95% 13,3;15,4] vs 8,2% [IC95% 7,6;9,0]). Conclusão: a prevalência da exposição a possíveis carcinógenos ocupacionais é elevada e desigualmente distribuída por sexo e ocupação. Ações de redução, substituição e eliminação desses carcinógenos devem ser priorizadas.

Environmental Health Risk Analysis of Copper Exposure to Catfish Commonly Consumed By People in Ulak Jermun Village, Ogan Komering Ilir

Catfish cultivated in rivers can be contaminated by heavy metals such as copper (Cu) which come from activities around the river. Copper exposure through the consumption of catfish will be harmful to health. This research aim to analyze the public health risks due to catfish consumption in Ulak Jermun Village, Ogan Komering Ilir. The design of study was cross sectional using the Environmental Health Risk Analysis method. The research respondents were 113 people with 5 samples of catfish taken from the river where the fish were cultivated. The analysis of heavy metal copper using the Atomic Absorption Spectrophotometer (AAS) method. The results showed copper contamination in catfish with an average concentration of 1.67 mg/kg. There were no respondents with RQ value &gt; 1 for realtime non-carcinogenic health risks, but 11 people (9.7%) of respondents with RQ value &gt; 1 for non-carcinogenic health risks in a lifetime. Meanwhile, for realtime carcinogenic exposure 34.5% had ECR values &gt; 10-4 and 100% of respondents had ECR values &gt; 10-4 for carcinogenic effects in lifetime. The conclusion was the people of Ulak Jermun are at risk of experiencing carcinogenic diseases due to copper exposure with the largest percentage of people aged&gt; 32 years, female, and weighing ≤ 57 kg.

Platycodon grandiflorus Polysaccharides Alleviate Cr(VI)-Induced Apoptosis in DF-1 Cells via ROS-Drp1 Signal Pathway.

Hexavalent chromium (Cr(VI)) is a widespread heavy metal that has been identified as a human carcinogen, and acute or chronic exposure to Cr(VI) can cause organ damage. Platycodon grandiflorus polysaccharide (PGPS) is a constituent extracted from the Chinese herb Platycodon grandiflorus, which has various pharmacological effects. Therefore, the author investigated the role of PGPSt in Cr(VI)-induced apoptosis in chicken embryo fibroblast cell lines (DF-1 cells). Firstly, this study infected DF-1 cells using Cr(VI) to set up a model for cytotoxicity and then added PGPSt. Then, the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis rate were evaluated. The results showed that PGPSt could inhibit Cr(VI)-induced mitochondrial damage and increase the apoptosis rate. For further exploration of the mechanism of regulation of PGPSt, the ROS-Drp1 pathway was investigated. The antioxidant N-acetyl-L-cysteine (NAC) and mitochondrial division inhibitor 1(Mdivi-1) were added, respectively. The results showed that the NAC and Mdivi-1 restored abnormal mitochondrial fission and cell apoptosis. Thus, PGPSt can alleviate Cr(VI)-induced apoptosis of DF-1 cells through the ROS-Drp1 signaling pathway, which may suggest new research ideas for developing new drugs to alleviate Cr(VI) toxicity.

The effect of Alloxan induced diabetes on baseline comet test in male laboratory mice fed on different feeding systems

Background: The comet analysis (electromagnetic relay analysis of a single cell) is ahighly sensitive method for determining DNA damage because to exposure tocarcinogens and other substances that consequently affect fertility.Objective: the aim of this study is to Evaluation the broken DNA in male diabeticmice. Created by alloxan and knowledge of the effect of some nutritional systems onthe treatment and repair of genetic material due to diabetes.Materials and methods: In this study were used, 42 male Albino mice labs at the ageof 2-3 months and weight (25-30) g then 6 animals were isolated to represent thecontrol group, The remaining animals were injected between the thighs by alloxan 150mg / kg and left the next day to make sure hit by diabetes and randomly distributed tosix groups in addition to a set of Not affected control transactions.Results and conclusion: It was found from the results of the statistical analysis shownin figure(1) showed the presence of the highest percentage of injuries in the geneticmaterial that was in the group of animals with diabetes and untreated for the durationof the experiment, as it was clear from the photos of this group that the tail lengthresulting from the migration of the genetic material DNA to outside the nucleusbecause to its damage, as well as the results showed that the group of animals affectedby diabetes and the treatment by adding the Salvia officinalis plant to both plant andanimal nutrition had a significant decrease (&amp;lt;0.05&amp;gt; P) in the proportion of geneticmaterial injuries where the proportion of high (long guilt) infections was low in thesetwo The two groups compared to the group of animals with diabetes and untreated forthe duration of the experiment.

FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias

BackgroundBladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. ObjectiveTo determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. Design, setting, and participantsWe developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. InterventionMutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Outcome measurements and statistical analysisImpact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. Results and limitationsFGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3–driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. ConclusionsMutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. Patient summaryBy developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

Cell Adhesion Molecules Affected by Ionizing Radiation and Estrogen in an Experimental Breast Cancer Model.

Cancer develops in a multi-step process where environmental carcinogenic exposure is a primary etiological component, and where cell–cell communication governs the biological activities of tissues. Identifying the molecular genes that regulate this process is essential to targeting metastatic breast cancer. Ionizing radiation can modify and damage DNA, RNA, and cell membrane components such as lipids and proteins by direct ionization. Comparing differential gene expression can help to determine the effect of radiation and estrogens on cell adhesion. An in vitro experimental breast cancer model was developed by exposure of the immortalized human breast epithelial cell line MCF-10F to low doses of high linear energy transfer α particle radiation and subsequent growth in the presence of 17β-estradiol. The MCF-10F cell line was analyzed in different stages of transformation that showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth, and invasive capability before becoming tumorigenic in nude mice. This model was used to determine genes associated with cell adhesion and communication such as E-cadherin, the desmocollin 3, the gap junction protein alpha 1, the Integrin alpha 6, the Integrin beta 6, the Keratin 14, Keratin 16, Keratin 17, Keratin 6B, and the laminin beta 3. Results indicated that most genes had greater expression in the tumorigenic cell line Tumor2 derived from the athymic animal than the Alpha3, a non-tumorigenic cell line exposed only to radiation, indicating that altered expression levels of adhesion molecules depended on estrogen. There is a significant need for experimental model systems that facilitate the study of cell plasticity to assess the importance of estrogens in modulating the biology of cancer cells.