Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.

The methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is an important regulator for the balance of DNA methylation and hydroxymethylation through various pathways. Increasing evidence has suggested that TET1 probably involved in DNA methylation and demethylation dysregulation during chemical carcinogenesis. However, the role and mechanism of TET1 during lung cancer remains unclear. In this study, we found that TET1 expression was significantly down-regulated and the methylation level was significantly up-regulated in 3-methylcholanthrene (3-MCA) induced cell malignant transformation model, rat chemical carcinogenesis model, and human lung cancer tissues. Demethylation experiment further confirmed that DNA methylation negatively regulated TET1 gene expression. TET1 overexpression inhibited cell proliferation, migration and invasion in vitro and in vivo, while knockdown of TET1 resulted in an opposite phenotype. DNA hydroxymethylation level in the promoter region of base excision repair (BER) pathway key genes XRCC1, OGG1, APEX1 significantly decreased and the degree of methylation gradually increased in malignant transformed cells. After differential expression of TET1, the level of hydroxymethylation, methylation and expression of these genes also changed significantly. Furthermore, TET1 binds to XRCC1, OGG1, and APEX1 to maintain them hydroxymethylated. Blockade of BER pathway key gene alone or in combination significantly diminished the effect of TET1. Our study demonstrated for the first time that TET1 expression is regulated by DNA methylation and TET1-mediated hydroxymethylation regulates BER pathway to inhibit the proliferation, migration and invasion during 3-MCA-induced lung carcinogenesis. These results suggested that TET1 gene can be a potential biomarker and therapy target for lung cancer.

Arsenic, a class I human carcinogen, is ubiquitously found throughout the environment and around the globe, posing a great public health concern. Notably, Bangladesh and regions of West Bengal have been found to have high levels (0.5–4600 μg/L) of arsenic drinking water contamination, and approximately 50 million of the world’s 200 million people chronically exposed to arsenic in Bangladesh alone. This study was carried out to examine genome-wide gene expression changes in individuals chronically exposed to arsenic-contaminated drinking water. Our study population includes twenty-nine Bangladeshi female participants with urinary arsenic levels ranging from 22.32 to 1828.12 μg/g creatinine. RNA extracted from peripheral blood mononuclear cells (PBMCs) were evaluated using RNA-Sequencing analysis. Our results indicate that a total of 1,054 genes were significantly associated with increasing urinary arsenic levels (FDR p < 0.05), which include 418 down-regulated and 636 up-regulated genes. Further Ingenuity Pathway Analysis revealed potential target genes (DAPK1, EGR2, APP), microRNAs (miR-155, -338, −210) and pathways (NOTCH signaling pathway) related to arsenic carcinogenesis. The selection of female-only participants provides a homogenous study population since arsenic has significant sex dependent effects, and the wide exposure range provides new insight for key gene expression changes that correlate with increasing urinary arsenic levels.

Arsenic (As) is a metalloid element that is ubiquitous in the marine environment and its contamination has received worldwide attention due to its potential toxicity. Arsenic can induce multiple adverse effects, such as lipid metabolism disorder, immune system dysfunction, oxidative stress and carcinogenesis, in animals. Inorganic arsenic includes two chemical forms, arsenite (As (III)) and arsenate (As (V)), in natural environment. As (V) is the dominant form in natural waters. In the present study, metabolomic and proteomic alterations were investigated in juvenile rockfish Sebastes schlegelii exposed to environmentally relevant concentrations of As (V) for 14 d. The analysis of iTRAQ-based proteomics combined with untargeted NMR-based metabolomics indicated apparent toxicological effects induced by As (V) in juvenile rockfish. In details, the metabolites, including lactate, alanine, ATP, inosine and phosphocholine were significantly altered in As-treated groups. Proteomic responses suggested that As (V) could not only affected energy and primary metabolisms and signal transduction, but also influenced cytoskeleton structure in juvenile rockfish. This work suggested that the combined proteomic and metabolomic approach could shed light on the toxicological effects of pollutants in rockfish S. schlegelii.

Both occupational and environmental exposure to asbestos-mineral fibres can be associated with lung diseases. The pathogenic effects are related to the dimension, biopersistence and chemical composition of the fibres. In addition to the major mineral elements, mineral fibres contain trace elements and their content may play a role in fibre toxicity. To shed light on the role of trace elements in asbestos carcinogenesis, knowledge on their concentration in asbestos-mineral fibres is mandatory. It is possible that trace elements play a synergetic factor in the pathogenesis of diseases caused by the inhalation of mineral fibres. In this paper, the concentration levels of trace elements from three chrysotile samples, four amphibole asbestos samples (UICC amosite, UICC anthophyllite, UICC crocidolite and tremolite) and fibrous erionite from Jersey, Nevada (USA) were determined using inductively coupled plasma mass spectrometry (ICP-MS). For all samples, the following trace elements were measured: Li, Be, Sc, V, Cr, Mn, Co, Ni, Cu, Zn, As, Rb, Sr, Y, Sb, Cs, Ba, La, Pb, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Th, U. Their distribution in the various mineral species is thoroughly discussed.The obtained results indicate that the amount of trace metals such as Mn, Cr, Co, Ni, Cu and Zn is higher in anthophyllite and chrysotile samples, whereas the amount of rare earth elements (REE) is higher in erionite and tremolite samples. The results of this work can be useful to the pathologists and biochemists who use asbestos minerals and fibrous erionite in-vitro studies as positive cyto- and geno-toxic standard references.

The carcinogenic potential of urban particulate matter (PM) has been partly attributed to polycyclic aromatic hydrocarbons (PAHs) content, which activates the aryl hydrocarbon receptor (AhR). Here we report the effect of PM with an aerodynamic size of 10 μm (PM10) on the induction of AhR pathway in A549 cells, evaluating its downstream targets CYP1B1, IL-6, IL-8 and c-Jun. Significant increases in CYP1B1 protein and enzyme activity; IL-6 and IL-8 secretion and c-Jun protein were found in response to PM10. The formation of PAH-DNA adducts was also detected. The involvement of AhR pathway was confirmed with Resveratrol as AhR antagonist, which reversed CYP1B1 and c-Jun induction. Nevertheless, in IL-6 and IL-8 secretion, the Resveratrol was ineffective, suggesting an effect independent of this pathway. Considering the role of c-Jun in oncogenesis, its induction by PM may be contributing to its carcinogenic potential through induction of AhR pathway by PAHs present in PM10.

Lung cancer is the most common cancer in China and second worldwide, of which the incidence of lung adenocarcinoma is rising. As an independent factor, air pollution has drawn the attention of the public. An increasing body of studies has focused on the effect of PM₂.₅ on lung adenocarcinoma; however, the mechanism remains unclear. We collected the PM₂.₅ in two megacities, Beijing (BPM) and Shijiazhuang (SPM), located in the capital of China, and compared the different components and sources of PM₂.₅ in the two cities. Vehicle emissions are the primary sources of BPM, whereas SPM is industrial emissions. We found that chronic exposure to PM₂.₅ promotes the tumorigenesis and metastasis of lung adenocarcinoma in patient-derived xenograft (PDX) models, as well as the migration and invasion of lung adenocarcinoma cell lines. SPM has more severe effects in vivo and in vitro. The underlying mechanisms are related to the stem cell properties of cancer cells, the epithelial-mesenchymal transition (EMT) process, and the corresponding miRNAs. It is hopeful to provide a theoretical basis for improving air pollution in China, especially in the capital area, and is of the significance of long-term survival of lung cancer patients.

As a widely used pure elemental carbon in colloidal particles, carbon black was listed as a group 2B carcinogen by IARC in 2010. The most available mechanism information about carbon black and carcinogenesis are from in vivo or in vitro studies. However, few studies concerned the nanoparticle's real-ambient exposure causing systemic change and further affecting the target organ. Herein, we used an ex vivo biosensor assay to investigate the transcriptome change of primary bronchial epithelial cells after treatment with the plasma from workers with long-term occupational carbon black exposure history. Based on ex vivo biosensor assay and transcriptome sequencing, we found the effect of internal systemic environment on epithelial cells after carbon black exposure was an inflammatory response, which mainly activates cell cycle-related pathways. After exposure to carbon black, the internal systemic environment could activate cancer-related pathways like epithelial-mesenchymal transition, hypoxia, TNF-α signaling via NF-κB. The hub genes in the carbon black group (CDC20 and PLK1) and their correlation with the systemic environment were uncovered by constructing the protein-protein interaction network. Inflammatory cytokines, especially CRP, were strongly correlated with the expression of CDC20 and PLK1. Besides, we also find a strong correlation between CDC20 and cytokinesis-block micronucleus endpoints in peripheral blood (rho = 0.591, P < 0.001). Our results show that long-term carbon black exposure might activate cell cycle-related pathways through circulating inflammation and increase the risk of cancer, while the oxidative stress caused by diesel exhaust particles are mainly related to PAHs exposure. After exposure to carbon black, the systemic environment could activate cancer-related pathways like diesel exhaust particles, increasing the risk of lung cancer. These attempts might provide a further understanding of the indirect effect of chronic occupational inhaled carbon black exposure on pulmonary carcinogenesis.

Bisphenol A (BPA) is a classical chemical contaminant in food, and the mode of action (MOA) of BPA remains unclear, constraining the progress of risk assessment. This study aims to assess the potential MOAs of BPA regarding reproductive/developmental toxicity, neurological toxicity, and proliferative effects on the mammary gland and the prostate potentially related to carcinogenesis by using the Comparative Toxicogenomics Database (CTD)-based bioinformatics analysis and the quantitative weight of evidence (QWOE) approach on the basis of the principles of Toxicity Testing in the 21st Century. The CTD-based bioinformatics analysis results showed that estrogen receptor 1, estrogen receptor 2, mitogen-activated protein kinase (MAPK) 1, MAPK3, BCL2 apoptosis regulator, caspase 3, BAX, androgen receptor, and AKT serine/threonine kinase 1 could be the common target genes, and the apoptotic process, cell proliferation, testosterone biosynthetic process, and estrogen biosynthetic process might be the shared phenotypes for different target organs. In addition, the KEGG pathways of the BPA-induced action might involve the estrogen signaling pathway and pathways in cancer. After the QWOE evaluation, two potential estrogen receptor-related MOAs of BPA-induced testis dysfunction and learning-memory deficit were proposed. However, the confidence and the human relevance of the two MOAs were moderate, prompting studies to improve the MOA-based risk assessment of BPA.

Hydroquinone (HQ), one of the main metabolites of benzene, is a well-known human leukemogen. However, the specific mechanism of how benzene or HQ contributes to the development of leukemia is unknown. In a previous study, we demonstrated the upregulation of DNA methyltransferase (DNMT) expression in HQ-induced malignant transformed TK6 (HQ-TK6) cells. Here, we investigated whether a regulatory loop between the long noncoding RNA FAS-AS1 and DNMT3b exists in HQ-TK6 cells and benzene-exposed workers. We found that the expression of FAS-AS1 was downregulated in HQ-TK6 cells and workers exposed to benzene longer than 1.5 years via histone acetylation, and FAS-AS1 expression was negatively correlated with the time of benzene exposure. Restoration of FAS-AS1 in HQ-TK6 cells promoted apoptosis and inhibited tumorigenicity in female nude mice. Interestingly, treatment with a DNMT inhibitor (5-aza-2-deoxycytidine), histone deacetylase inhibitor (trichostatin A), or DNMT3b knockout led to increased FAS-AS1 through increased H3K27ac protein expression in HQ-TK6 cells, and DNMT3b knockout decreased H3K27ac and DNMT3b enrichment to the FAS-AS1 promoter region, which suggested that DNMT3b and/or histone acetylation involve FAS-AS1 expression. Importantly, restoration of FAS-AS1 resulted in reduced expression of DNMT3b and SIRT1 and increased expression of FAS in both HQ-TK6 cells and xenograft tissues. Moreover, the average DNMT3b expression in 17 paired workers exposed to benzene within 1.5 years was decreased, but that of the remaining 103 paired workers with longer exposure times was increased. Conversely, DNMT3b was negatively correlated with FAS-AS1 expression. Both FAS-AS1 and DNMT3b influenced the enrichment of H3K27ac in the FAS promoter region by regulating the expression of SIRT1, consequently upregulating FAS expression. Taken together, these observations demonstrate crosstalk between FAS-AS1 and DNMT3b via a mutual inhibition loop and indicate a new mechanism by which FAS-AS1 regulates the expression of FAS in benzene-related carcinogenesis.