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Ochratoxin A (OTA) is a rat renal carcinogen that induces karyomegaly and micronuclei in proximal tubular epithelial cells (PTECs). We previously performed comprehensive gene profiling of alterations in promoter-region methylation and gene expression in PTECs of rats treated with OTA for 13 weeks. The OTA-specific gene profile was obtained by excluding genes showing expression changes similar to those upon treatment with 3-chloro-1,2-propanediol, a renal carcinogen not inducing karyomegaly. In this study, we validated the candidate genes using methylated DNA enrichment PCR and real-time RT-PCR, and identified Gen1, Anxa3, Cdkn1a, and Osm as genes showing OTA-specific epigenetic changes. These genes and related molecules were subjected to gene expression and immunohistochemical analyses in the PTECs of rats treated with OTA, other renal carcinogens, or non-carcinogenic renal toxicants for 4 or 13 weeks. Cdkn1a upregulation and increase of p21 WAF1/CIP1+ karyomegalic PTECs were observed with OTA, matching the findings associated with micronucleus-inducing carcinogens. This suggested that the increase of p21 WAF1/CIP1+ karyomegalic PTECs is linked to micronucleus formation, which in turn accelerates chromosomal instability. The upregulation of Cdkn1a-related genes with OTA suggests the acquisition of a senescence-associated secretory phenotype, which promotes the establishment of a carcinogenic environment. Meanwhile, OTA specifically caused a decrease of GEN1 + PTECs reflecting Gen1 downregulation and an increase of ANXA3 + PTECs reflecting Anxa3 upregulation, as well as Osm upregulation. OTA may efficiently disrupt pathways for repairing the DNA double-strand breaks that it itself causes, via Gen1 downregulation, and enhance cell proliferation through the upregulation of Anxa3 and Osm. This may exacerbate the chromosomal instability from the early stage of OTA-induced renal carcinogenesis before proliferative lesions form. OTA may cause renal carcinogenesis involving multiple epigenetic mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Acute Lymphoblastic Leukemia (ALL) is the most prevalent neoplasia in children and teenagers in Mexico. Although epidemiological data supports that children's residence close to emissions from vehicular traffic or industrial processes increases the risk of ALL; and the IARC states that benzene, PAHs, and PM 2.5 are well-known environmental carcinogens, there is a gap in linking these carcinogenic hazards with the sources and their distribution from scenario perspective., Aim: To identify ALL clusters in the population under 19 years of age and characterize the environment at the neighborhood level by integrating information on sources of carcinogenic exposure using spatial analysis techniques in the Metropolitan Area of San Luis Potosi, Mexico., Methods: Using the Kernel Density test, we designed an ecological study to identify ALL clusters from incident cases in the population under 19 years of age. A multicriteria analysis was conducted to characterize the risk at the community level from carcinogenic sources. A hierarchical cluster analysis was performed to characterize risk at the individual level based on carcinogenic source count within 1 km for each ALL case., Results: Eight clusters of carcinogenic sources were located within the five identified ALL clusters. The multicriteria analysis showed high-risk areas (by density of carcinogenic source) within ALL clusters., Conclusions: This study has a limited source and amount of available data on ALL cases, so selection bias is present as well as the inability to rule out residual confounding factors, since covariates were not included. However, in this study, children living in environments with high vehicular density, gas stations, brick kilns, incinerators, commercial establishments burning biomass, or near industrial zones may be at higher risk for ALL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

In this study, we aimed to use the loss of happy life expectancy (LHpLE), an indicator that enables risk assessment considering wellbeing, to compare the risks of environmental carcinogenic chemicals in Japan. First, we surveyed Japanese people to determine their emotional happiness by age and sex and evaluated whether cancer incidence reduced emotional happiness. Questionnaires were administered to a general population panel and a panel of patients with cancer in 2022, recruiting a predetermined number of responses of 5000 and 850, respectively. Second, using the survey data, LHpLE was calculated for radon, arsenic, and fine particulate matter (aerodynamic diameter <2.5 μm; PM 2.5 ) and compared to psychological distress, considering increased mortality and decreased emotional happiness due to these risks. We discovered no significant decrease in emotional happiness due to cancer incidence and no significant associations between emotional happiness and cancer type, history, or stage. LHpLE was calculated to be 6.4 × 10 -3 years for radon, 2.6 × 10 -3 years for arsenic, 1.1 × 10 -2 years (2012 exposure) and 8.6 × 10 -4 years (2020 exposure) for PM 2.5 , and 9.7 × 10 -1 years for psychological distress. The fraction of losses caused by these carcinogenic chemicals to HpLE exceeded 10 -5 , suggesting that risk reduction for these chemicals is important in environmental policies. The LHpLE indicator allows for comparing different types of risks, such as environmental chemicals and psychological distress. This is the first study to compare chemical risks using the LHpLE indicator., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Understanding interactions between legacy and emerging environmental contaminants has important implications for risk assessment, especially when mutagens and carcinogens are involved, whose critical effects are chronic and therefore difficult to predict. The current work aimed to investigate potential interactions between benzo[a]pyrene (B[a]P), a carcinogenic polycyclic aromatic hydrocarbon and legacy pollutant, and diclofenac (DFC), a non-steroidal anti-inflammatory drug and pollutant of emerging concern, and how DFC affects B[a]P toxicity. Exposure to binary mixtures of these chemicals resulted in substantially reduced cytotoxicity in human HepG2 cells compared to single-chemical exposures. Significant antagonistic effects were observed in response to high concentrations of B[a]P in combination with DFC at IC 50 and ⅕ IC 50 . While additive effects were found for levels of intracellular reactive oxygen species, antagonistic mixture effects were observed for genotoxicity. B[a]P induced DNA strand breaks, γH2AX activation, and micronuclei formation at ½ IC 50 concentrations or lower, whereas DFC induced only low levels of DNA strand breaks. Their mixture caused significantly lower levels of genotoxicity by all three endpoints compared to those expected based on concentration additivity. In addition, antagonistic mixture effects on CYP1 enzyme activity suggested that the observed reduced genotoxicity of B[a]P was due to its reduced metabolic activation as a result of enzymatic inhibition by DFC. Overall, the findings further support the growing concern that co-exposure to environmental toxicants and their non-additive interactions may be a confounding factor that should not be neglected in environmental and human health risk assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Environmental carcinogens exert their carcinogenic effects by forming DNA adducts. This type of DNA damage can also be formed endogenously as a result of, e.g., oxidative damage. Unrepaired  DNA adducts may induce mutations in critical genes, leading to the initiation of chemical carcinogenesis. Therefore,  detection, identification, and quantification of DNA adducts is essential for cancer risk assessment. Over the last 50 years, the major DNA adducts formed by different classes of environmental carcinogens were characterized. With the development of techniques such as 32P-postlabeling, their measurement was implemented into molecular epidemiology. Advances in liquid chromatography-tandem mass spectrometry (LC-MS ) made the measurement of adducts more precise  and allowed to gain knowledge about their identity and structures. Therefore,  opened the way to  DNA adductomics, the  "omics" approach investigating DNA adducts comprehensively, similarly to proteomics. This review presents the historical perspective of DNA adducts research and the emerging field of adductomics.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Hexavalent chromium (Cr(VI)) is a well-known occupational and environmental human carcinogen. The cellular effect of Cr(VI) is complex and often nonspecific due to its ability to modulate multiple cellular targets. The toxicity of Cr(VI) is strongly linked to the generation of reactive oxygen species (ROS) during its reduction process. ROS can cause oxidation of cellular macromolecules, such as proteins, lipids, and DNA, thereby altering their functions. A major genotoxic effect of Cr(VI) that contributes to carcinogenesis is the formation of DNA adducts, which can lead to DNA damage. Modulations of cellular signaling pathways and epigenetics may also contribute to the carcinogenic effects of Cr(VI). Cr(VI) has a major impact on many aspects of mitochondrial biology, including oxidative phosphorylation, mitophagy, and mitochondrial biogenesis. These effects have the potential to alter the trajectory of Cr(VI)-induced carcinogenic process. This perspective article summarizes current understandings of the effect of Cr(VI) on mitochondria and discusses the future directions of research in this area, particularly with regard to carcinogenesis.

Alterations in complex cellular phenotype each typically involve multistep activation of an ultrasensitive molecular switch (e.g., to adaptively initiate an apoptosis, inflammasome, Nrf2-ARE anti-oxidant, or heat-shock activation pathway) that triggers expression of a suite of target genes while efficiently limiting false-positive switching from a baseline state. Such switches exhibit nonlinear signal-activation relationships. In contrast, a linear no-threshold (LNT) dose-response relationship is expected for damage that accumulates in proportion to dose, as hypothesized for increased risk of cancer in relation to genotoxic dose according to the multistage somatic mutation/clonal-expansion theory of cancer, e.g., as represented in the Moolgavkar-Venzon-Knudsen (MVK) cancer model by a doubly stochastic nonhomogeneous Poisson process. Mesothelioma and lung cancer induced by exposure to carcinogenic (e.g., certain asbestos) fibers in humans and experimental animals are thought to involve modes of action driven by mutations, cytotoxicity-associated inflammation, or both, rendering ambiguous expectations concerning the nature of model-implied shape of the low-dose response for above-background increase in risk of incurring these endpoints. A recent Inflammation Somatic Mutation (ISM) theory of cancer posits instead that tissue-damage-associated inflammation that epigenetically recruits, activates and orchestrates stem cells to engage in tissue repair does not merely promote cancer, but rather is a requisite co-initiator (acting together with as few as two somatic mutations) of the most efficient pathway to any type of cancer in any reparable tissue (Dose-Response 2019; 17(2):1-12). This theory is reviewed, implications of this theory are discussed in relation to mesothelioma and lung cancer associated with chronic asbestos inhalation, one of the two types of ISM-required mutations is here hypothesized to block or impede inflammation resolution (e.g., by doing so for GPCR-mediated signal transduction by one or more endogenous autacoid specialized pro-resolving mediators or SPMs), and supporting evidence for this hypothesis is discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The current paradigm of carcinogenesis as a cellular evolutionary process driven by mutations of a few critical driver genes has immediate logical implications for the epidemiology of cancer. These include the impact of age on cancer risk, the role played by inherited tumor predisposition syndromes, and the interaction of genetics and environmental exposures on cancer risk. In this paper, we explore the following logical epidemiological consequences of carcinogenesis as a clonal process of mutation accumulation, with special emphasis on asbestos-related cancers, specifically malignant mesothelioma:1 All cancers, including mesothelioma, can and do occur spontaneously, i.e., in the absence of exposure to any environmental carcinogens. 2. Age is an important determinant of cancer risk, with or without exposure to environmental carcinogens. 3. Genetic tumor predisposition syndromes, such as the BAP1 syndrome, increase enormously the risk of cancer even in the absence of exposure to environmental carcinogens. We illustrate these concepts by applying a multistage clonal expansion model to U.S. Surveillance, Epidemiology, and End Results cancer registry data for pleural and peritoneal malignant mesotheliomas in 1975-2018., Competing Interests: Declaration of competing interest Exponent is an international consulting company. SM has served as a consulting and testifying expert in asbestos and talc litigation. EC has served as a consulting and testifying expert in talc litigation. EGL has no competing interests. This work received no funding and the authors received no compensation for this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer is one of the longest-known human diseases, yet only in recent times have we begun to perceive that the percentage of neoplasms caused by environmental factors, lifestyle and chemicals, is likely underestimated. The first medical reports associating cancer with pollutants like tars appeared by the early 20th century, but despite initial evidence relating oncogenesis and chromosomal alterations, only after the structure of DNA had been elucidated in the 1950s have genetic disorders been fully perceived as cause. This led to a growing interest in genotoxic and mutagenic pollutants. Even though we are now familiar with a range of environmental carcinogens spanning between aromatic hydrocarbons and asbestos to radionuclides and forms of carbon nanomaterials, establishing causal networks between pollutants and cancer remains cumbersome. In most part, this is due to the complexity of toxicant matrices, unknown modes-of-action of chemicals or their mixtures, the widening array of novel pollutants plus difficulties in subtracting background effects from true aetiology of disease. Recent advances in analytical chemistry, high-throughput toxicology, next-generation sequencing, computational biology and databases that allocate whole normal and cancer genomes, all indicate that we are on the verge of a new age of research into mechanistic 'oncotoxicology', but how can it impact risk assessment and prevention?

Hexavalent chromium [Cr(VI)], one common environmental contaminant, has long been recognized as a carcinogen associated with several malignancies, such as lung cancer, but little information was available about the effects of its low-dose environmental exposure in prostate cancer. Our previous study has shown that low-dose Cr(VI) exposure could promote prostate cancer(PCa) cell growth in vitro and in vivo. In the present study, we furthermore found that low-dose Cr(VI) exposure could induce DNA demethylation in PCa cells. Based on our transcriptome sequencing data and DNA methylation database, we further identified MAGEB2 as a potential effector target that contributed to tumor-promoting effect of low-dose Cr(VI) exposure in PCa. In addition, we demonstrated that MAGEB2 was upregulated in PCa and its knockdown restrained PCa cell proliferation and tumor growth in vitro and in vivo. Moreover, Co-IP and point mutation experiments confirmed that MAGEB2 could bind to the NH 2 -terminal NTD domain of AR through the F-box in the MAGE homology domain, and then activated AR through up-regulating its downstream targets PSA and NX3.1. Together, low-dose Cr(VI) exposure can induce DNA demethylation in prostate cancer cells, and promote cell proliferation via activating MAGEB2-AR signaling pathway. Thus, inhibition of MAGEB2-AR signaling is a novel and promising strategy to reverse low-dose Cr(VI) exposure-induced prostate tumor progression, also as effective adjuvant therapy for AR signaling-dependent PCa., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β -galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca 2+ ) and activity of nuclear factor kappa B (NF- κ B). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca 2+ , activated NF- κ B, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca 2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF- κ B inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF- κ B mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca 2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca 2+ -NF- κ B signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yujing Zhang et al.)

Accumulating evidence indicates a carcinogenic role of environmental arsenic exposure, but mechanisms on how arsenic fosters malignant transformation of the normal cells are not fully established. By applying untargeted global metabolomics approach, we now show that arsenic is highly capable of perturbing the intracellular metabolic programs of the human bronchial epithelial cells, some of which are prominent hallmarks of cancer cell metabolism. To understand the spatiotemporal patterns of arsenic regulation on multiple metabolic pathways, we treated the cells with environmentally relevant concentration of arsenic, 0.25 μM, consecutively for 6 weeks to 24 weeks, and found that arsenic prompted heme metabolism, glycolysis, sphingolipid metabolism, phospholipid catabolism, protein degradation, and cholesterol breakdown constitutively, but inhibited metabolism of uracil-containing pyrimidine, carnitine, serotonin, polyamines, and fatty acid β-oxidation. A strong inhibition of all metabolites in mitochondrial tricarboxylic acid (TCA) cycle was noted in the cells treated with As 3+ for 6 to 13 weeks. However, the metabolites in the earlier, but not the later steps of TCA cycle, including citrate, aconitate and isocitrate, were induced at 16 weeks through 24 weeks of arsenic treatment. This comprehensive metabolomics analysis provides new insights into metabolic perturbation by arsenic and may lead to more precise indications of arsenic in molecular carcinogenesis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Fumonisins are a kind of mycotoxin that has harmful influence on the health of humans and animals. Although some research studies associated with fumonisins have been reported, the regulatory limits of fumonisins are imperfect, and the effects of fumonisins on fecal bacterial flora of mice have not been suggested. In this study, in order to investigate the effects of fumonisin B1 (FB1) on fecal bacterial flora, BALB/c mice were randomly divided into seven groups, which were fed intragastrically with 0 mg/kg, 0.018 mg/kg, 0.054 mg/kg, 0.162 mg/kg, 0.486 mg/kg, 1.458 mg/kg and 4.374 mg/kg of FB1 solutions, once a day for 8 weeks. Subsequently, feces were collected for analysis of microflora. The V3-V4 16S rRNA of fecal bacterial flora was sequenced using the Illumina MiSeq platform. The results revealed that fecal bacterial flora of mice treated with FB1 presented high diversity. Additionally, the composition of fecal bacterial flora of FB1 exposure groups showed marked differences from that of the control group, especially for the genus types including Alloprevotella, Prevotellaceae&#95;NK3B31&#95;group, Rikenellaceae&#95;RC9&#95;gut&#95;group, Parabacteroides and phylum types including Cyanobacteria. In conclusion, our data indicate that FB1 alters the diversity and composition of fecal microbiota in mice. Moreover, the minimum dose of FB1 exposure also causes changes in fecal microbiota to some extent. This study is the first to focus on the dose-related effect of FB1 exposure on fecal microbiota in rodent animals and gives references to the regulatory doses of fumonisins for better protection of human and animal health.

Hexavalent chromium [Cr(VI)] exists in the ambient air at low concentrations (average upperbound ~0.1 ng/m 3 ) yet airborne concentrations typically exceed EPA's Regional Screening Level for residential exposure (0.012 ng/m 3 ) and other similar benchmarks, which assume a mutagenic mode of action (MOA) and use low-dose linear risk assessment models. We reviewed Cr(VI) inhalation unit risk estimates developed by researchers and regulatory agencies for environmental and occupational exposures and the underlying epidemiologic data, updated a previously published MOA analysis, and conducted dose-response modeling of rodent carcinogenicity data to evaluate the need for alternative exposure-response data and risk assessment approaches. Current research supports the role of non-mutagenic key events in the MOA, with growing evidence for epigenetic modifiers. Animal data show a weak carcinogenic response, even at cytotoxic exposures, and highlight the uncertainties associated with the current epidemiological data used in risk assessment. Points of departure from occupational and animal studies were used to determine margins of exposure (MOEs). MOEs range from 1.5 E+3 to 3.3 E+6 with a median of 5 E+5, indicating that current environmental exposures to Cr(VI) in ambient air should be considered of low concern. In this comprehensive review, the divergent results from default linear and MOE assessments support the need for more relevant and robust epidemiologic data, additional mechanistic studies, and refined risk assessment strategies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The environmental pollutant benzo[ a ]pyrene (BaP) is a human carcinogen that reacts with DNA after metabolic activation catalysed by cytochromes P450 (CYP) 1A1 and 1B1 together with microsomal epoxide hydrolase. The azo dye Sudan I is a potent inducer of CYP1A1/2. Here, Wistar rats were either treated with single doses of BaP (150 mg/kg bw) or Sudan I (50 mg/kg bw) alone or with both compounds in combination to explore BaP-derived DNA adduct formation in vivo . Using 32 P-postlabelling, DNA adducts generated by BaP-7,8-dihydrodiol-9,10-epoxide were found in livers of rats treated with BaP alone or co-exposed to Sudan I. During co-exposure to Sudan I prior to BaP treatment, BaP-DNA adduct levels increased 2.1-fold in comparison to BaP treatment alone. Similarly, hepatic microsomes isolated from rats exposed to Sudan I prior to BaP treatment were also the most effective in generating DNA adducts in vitro with the activated metabolites BaP-7,8-dihydrodiol or BaP-9-ol as intermediates. DNA adduct formation correlated with changes in the expression and/or enzyme activities of CYP1A1, 1A2 and 1B1 in hepatic microsomes. Thus, BaP genotoxicity in rats in vivo appears to be related to the enhanced expression and/or activity of hepatic CYP1A1/2 and 1B1 caused by exposure of rats to the studied compounds. Our results indicate that the industrially employed azo dye Sudan I potentiates the genotoxicity of the human carcinogen BaP, and exposure to both substances at the same time seems to be hazardous to humans.

Purpose: The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack., Experimental Design: We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster., Results: No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort ( n = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure., Conclusions: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy., (©2021 American Association for Cancer Research.)

We have reported sub-fertility in F 1 progeny rats with gestational exposure to hexavalent chromium [Cr(VI)], which had disrupted Sertoli cell (SC) structure and function, and decreased testosterone (T). However, the underlying mechanism for reduced T remains to be understood. We tested the hypothesis "transient prenatal exposure to Cr(VI) affects testicular steroidogenesis by altering hormone receptors and steroidogenic enzyme proteins in Leydig cells (LCs)." Pregnant Wistar rats were given drinking water containing 50, 100, and 200 mg/L potassium dichromate during gestational days 9-14, encompassing fetal differentiation window of the testis from the bipotential gonad. F 1 male rats were euthanized on postnatal day 60 (peripubertal rats with adult-type LCs alone). Results showed that prenatal exposure to Cr(VI): (i) increased accumulation of Cr(III) in the testis of F 1 rats; (ii) increased serum levels of luteinizing and follicle stimulating hormones (LH and FSH), and 17β estradiol, and decreased prolactin and T; (iii) decreased steroidogenic acute regulatory protein, cytochrome P450 11A1, cytochrome P450 17A1, 3β- and 17β-hydroxysteroid dehydrogenases, cytochrome P450 aromatase and 5α reductase proteins, (iv) decreased specific activities of 3β and 17β hydroxysteroid dehydrogenases; (v) decreased receptors of LH, androgen and estrogen in LCs; (vi) decreased 5α reductase and receptor proteins of FSH, androgen, and estrogen in SCs. The current study concludes that prenatal exposure to Cr(VI) disrupts testicular steroidogenesis in F 1 progeny by repressing hormone receptors and key proteins of the steroidogenic pathway in LCs and SCs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Genotoxicity of chemical compounds is primarily associated with the interaction with DNA, formation of mutations, damage to chromosomes and initiating carcinogenesis processes. Currently, many compounds found in the environment are considered to be genotoxic agents, among them chromium: trivalent (III) and hexavalent (VI). The genotoxicity of hexavalent (VI) chromium has been proven in numerous epidemiological, in vitro and in vivo studies. The main source of Cr (VI) is environmental pollution associated with its use in various industries. On the other hand, the role of chromium (III) as a microelement is widely discussed. Due to its beneficial properties, associated with maintaining adequate blood glucose levels and supporting weight loss, it is widely used in the form of dietary supplements, often in doses exceeding the daily requirement. However, the safety of chromium compounds is disputable. Data about the mechanism of genotoxic effects are still incomplete., Objective: The aim of this review is to present the current knowledge about the induction of genotoxicity from two forms of chromium: trivalent (III) and hexavalent (VI)., State of Knowledge: Chromium (VI) is a carcinogen with proven mutagenic and genotoxic effects, but this issue is still being investigated by scientists. In recent years, numerous studies have also been conducted on the genotoxic effect of chromium (III)., Conclusions: Due to the still unexplained mechanism of the genotoxic action and incomplete knowledge about the transformation of chromium in the body, further research is needed, especially due to the growing popularity of Cr (III) compounds and their consumption in the form of dietary supplements and doubts as to the safety of its use, as well as environmental exposure to Cr (VI).

Intervening on risk factors for noncommunicable diseases (including cancer) in industrialized countries could achieve a reduction of between 30% and 40% of premature deaths. In the meantime, the need to intervene against the threat of climate change has become obvious. CO 2 emissions must be reduced by 45% by the year 2030 and to zero by 2050 according to recent agreements. We propose an approach in which interventions are designed to prevent diseases and jointly mitigate climate change, the so-called cobenefits. The present article describes some examples of how climate change mitigation and cancer prevention could go hand in hand: tobacco control, food production, and transportation (air pollution). Many others can be identified. The advantage of the proposed approach is that both long-term (climate) and short-term (health) benefits can be accrued with appropriate intersectoral policies., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Polychlorinated biphenyls (PCBs) are human carcinogens, based on sufficient evidence for melanoma and limited evidence for non-Hodgkin lymphoma and breast cancer. Few data are available for liver cancer, although PCBs cause it in rats and determined liver damage in poisoned people. We investigated the association between PCB serum levels and hepatocellular carcinoma (HCC) with a case-control study in a PCB-polluted area in North Italy. We enrolled prospectively 102 HCC incident cases and 102 age and gender-matched hospital controls. Serum concentrations of 33 PCB congeners were determined by a gas chromatograph coupled to mass spectrometry. Of 102 HCC cases, 62 who had lost < 3 kg of body weight in past 3 years were included in the analysis (67.7% males, mean age 68 years). The odds ratio (OR) for HCC for 3rd compared to 1st tertile of PCB distribution was 1.76 (95% confidence interval 0.62-5.03) for total PCB, adjusting for socio-demographic variables and risk factors for HCC by logistic regression. For most PCB congeners, ORs > 1.5 or 2 were found, although the 95% CIs included the null value for almost all of them. This preliminary study suggests that PCBs might play a role in HCC development.

Due to their unique chemical properties, per- and polyfluoroalkyl substances (PFAS) have been used extensively as industrial surfactants and processing aids. While several types of PFAS have been voluntarily phased out by their manufacturers, these chemicals continue to be of ecological and public health concern due to their persistence in the environment and their presence in living organisms. Moreover, while the compounds referred to as "legacy" PFAS remain in the environment, alternative compounds have emerged as replacements for their legacy predecessors and are now detected in numerous matrices. In this review, we discuss the historical uses of PFAS, recent advances in analytical techniques for analysis of these compounds, and the fate of PFAS in the environment. In addition, we evaluate current biomonitoring studies of human exposure to legacy and emerging PFAS and examine the associations of PFAS exposure with human health impacts, including cancer- and non-cancer-related outcomes. Special focus is given to short-chain perfluoroalkyl acids (PFAAs) and ether-substituted, polyfluoroalkyl alternatives including hexafluoropropylene oxide dimer acid (HFPO-DA; tradename GenX), 4,8-dioxa-3H-perfluorononanoic acid (DONA), and 6:2 chlorinated polyfluoroethersulfonic acid (6:2 Cl-PFESA; tradename F-53B).

Fumonisin B 1 (FB 1 ) is a natural contaminant of agricultural commodities that has displayed a myriad of toxicities in animals. Moreover, it is known to be a hepatorenal carcinogen in rodents and may be associated with oesophageal and hepatocellular carcinomas in humans. The most well elucidated mode of FB 1 -mediated toxicity is its disruption of sphingolipid metabolism; however, enhanced oxidative stress, endoplasmic reticulum stress, autophagy, and alterations in immune response may also play a role in its toxicity and carcinogenicity. Alterations to the host epigenome may impact on the toxic and carcinogenic response to FB 1 . Seeing that the contamination of FB 1 in food poses a considerable risk to human and animal health, a great deal of research has focused on new methods to prevent and attenuate FB 1 -induced toxic consequences. The focus of the present review is on the molecular and epigenetic interactions of FB 1 as well as recent research involving FB 1 detoxification.

Chemicals in commerce or under development must be assessed for genotoxicity; assessment is generally conducted using validated assays (e.g. Tk mouse lymphoma assay) as part of a regulatory process. Currently, the MutaMouse FE1 cell mutagenicity assay is undergoing validation for eventual use as a standard in vitro mammalian mutagenicity assay. FE1 cells have been shown to be metabolically competent with respect to some cytochrome P450 (CYP) isozymes; for instance, they can convert the human carcinogen benzo[a]pyrene into its proximate mutagenic metabolite. However, some contradictory results have been noted for other genotoxic carcinogens that require two-step metabolic activation (e.g. 2-acetylaminofluorene and 2-amino-3-methylimidazo[4,5-f]quinoxaline). Here, we examined three known or suspected human carcinogens, namely acrylamide, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4-aminobiphenyl (4-ABP), together with their proximate metabolites (i.e. glycidamide, N-OH-PhIP and N-OH-4-ABP), to aid in the validation of the FE1 cell mutagenicity assay. Assessments of the parent compounds were conducted both in the presence and absence of an exogenous metabolic activation mixture S9; assessments of the metabolites were in the absence of S9. The most potent compound was N-OH-PhIP -S9, which elicited a mutant frequency (MF) level 5.3-fold over background at 5 µM. There was a 4.3-fold increase for PhIP +S9 at 5 µM, a 1.7-fold increase for glycidamide -S9 at 3.5 mM and a 1.5-fold increase for acrylamide +S9 at 4 mM. Acrylamide -S9 elicited a marginal 1.4-fold MF increase at 8 mM. Treatment with PhIP -S9, 4-ABP ±S9 and N-OH-4-ABP -S9 failed to elicit significant increases in lacZ MF with any of the treatment conditions tested. Gene expression of key CYP isozymes was quantified by RT-qPCR. Cyp1a1, 1a2 and 1b1 are required to metabolise PhIP and 4-ABP. Results showed that treatment with both compounds induced expression of Cyp1a1 and Cyp1b1 but not Cyp1a2. Cyp2e1, which catalyses the bioactivation of acrylamide to glycidamide, was not induced after acrylamide treatment. Overall, our results confirm that the FE1 cell mutagenicity assay has the potential for use alongside other, more traditional in vitro mutagenicity assays., (© The Author(s) 2021. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genomic instability is generally considered as a hallmark of tumorigenesis and a prerequisite condition for malignant transformation. Aluminium salts are suspected environmental carcinogens that transform mammary epithelial cells in vitro through unknown mechanisms. We report here that long-term culture in the presence of aluminium chloride (AlCl 3 ) enables HC11 normal mouse mammary epithelial cells to form tumours and metastases when injected into the syngeneic and immunocompetent BALB/cByJ strain. We demonstrate that AlCl 3 rapidly increases chromosomal structural abnormalities in mammary epithelial cells, while we failed to detect direct modulation of specific mRNA pathways. Our observations provide evidence that clastogenic activity-a well-recognized inducer of genomic instability-might account in part for the transforming abilities of aluminium in mammary epithelial cells.

This study outlines a methodological approach to evaluate the environmental risk from integrating data of Aniline in groundwater near to coal-based industries using fuzzy logic, and a comprehensive artificial intelligence approach and the results were validated using conventional risk assessment approach. The Aniline is well-known carcinogenic pollutant released from coal-based industries, so to understand the associated cancer and non-cancer risks (CR and NCR), 15 groundwater samples were analyzed for Aniline, whose concentration was found within the range 0.10-0.34 mg/L, which is up to 68 times higher than the permissible limit. The alkaline pH of water samples resulted in reduced attractive forces between the soil particles with Aniline, and thereby increased percolation of Aniline into the groundwater. Women were at least risk in terms of Mamdani cancer risk (MCR) and Mamdani hazard index (MHI) which was observed up to 1.04E-04 and 3.04, respectively, while maximum MCR and MHI were observed in case of children, i.e., 1.21-E04 and 3.26, respectively. The newly proposed fuzzy inference rule-based Mamdani combined index (MCI) depicts the combined effect of both CR and NCR and was found to be highly correlated with each other. The detailed comparison analysis exhibited that the fuzzy inference rule-based MCI has better resolving ability to find out priority risk prediction over conventional methods under efficient parameter uncertainty control. Hence, it can be concluded that the fuzzy analyses can reflect human considerations and expertise in indices, empowering them to manage nonlinear, questionable, uncertain and subjective data. Therefore, this tool can predict the more meaningful risk estimation of any pollutants on human health.

Geophagy is a cultural behavior, based on the recurrent intentional eating of clay soil, that is raising increasing concern as it implies multidimensional (space, time) potential risk of serious adverse health effects. This study investigated the level of toxic metals (Cd and Pb) in 20 Nigerian geophagic clays intended for both local consumption and distribution to the West Africa market. After sampling in 4 open markets in southern Nigeria (Akwa Ibom, Abia, Rivers, Imo), samples were subjected to digestion, ashing and analysis. The Pb levels in all samples exceeded the WHO/FAO maximum permissible limit of 0.1 mg kg -1 whereas 16% exceeded the Cd limit of 0.3 mg kg -1 . The estimated daily intake of Pb for all samples ranged from 0.0032-0.0286 mg kg bw -1  day -1 to 0.0024-0.0215 mg kg bw -1  day -1 for children and adults, respectively. The estimated daily intakes for Cd ranged from bdl (below detection limit)-0.0010 mg kg bw -1  day -1 to bdl-0.0028 mg kg bw -1  day -1 for children and adults, respectively. In both cases, the WHO/FAO provisional Tolerable Weekly Intake is exceeded through the ingestion of these soils. Our results confirm health risks related to the geophagic practices, its role in exceeding health guidelines when considering aggregate exposure in the Nigerian scenario and body burden in developing organisms, young women, women at fertile age, and pregnant women. We discuss how geophagists consider clays as traditional nutraceuticals and how clarifying the nutraceutical role of geophagy could facilitate risk communication. Geophagic products are implicitly or explicitly marketed as dietary supplements, and as such they should be regulated (1) by labeling, and prohibition of scientifically unfounded health claims and (2) by safety standards before marketing. This is particularly critical when clays originate from countries living rapid, unplanned and uncontrolled development and dumped, like Nigeria.

Volatile organic compounds (VOCs) typically exist in the aqueous environment due to global anthropogenic activities. The distribution and contaminated profile (or characteristics) of VOCs in the groundwater of Lanzhou, China, were investigated in this study. Groundwater samples were collected from 30 sampling points in December 2015, and a total of 17 VOCs were analyzed by purge and trap gas chromatography-mass spectrometry. Thirteen types of VOCs were detected at 29 sampling points in the study area. Of these, dichloromethane and toluene, which were found at 22 sampling points, had the highest detection frequency (73.3%), followed by benzene (66.7%), 1,2-dichloroethane (50%), and xylenes (50%). The highest average concentration among the detected VOCs was found for chloroform (5151.5 μg/L). The spatial distribution of VOC contamination in four major urban areas of Lanzhou and the variation in VOC concentration caused by land use transitions were also analyzed. The results showed that Xigu district was the most polluted area in Lanzhou, mainly due to land use for industrial proposes. On the contrary, the samples for Anning district showed lower VOC concentrations because of better groundwater quality, which is associated with the absence of manufacturing industries in this region. The health risk assessment model developed by the United States Environmental Protection Agency was employed in this study to evaluate safety for drinking water use. This study found that despite considering the volatilization of VOCs from water due to heating, six sampling points (G05 in Qilihe district; G07 and G09 in Xigu district; G16, G17, and G15 in Chengguan district) showed non-carcinogenic risks, ranging from 1.63 to 14.2, while three points (G16 in Chengguan district, and G10 and G07 in Xigu district) exhibited high carcinogenic risks for human health, ranging from 2.94 × 10 -4 to 6.85 × 10 -4 . Trichloroethylene, tetrachloroethylene, and 1,2-dichloroethylene were identified as the dominant VOCs, presenting high non-carcinogenic risk. 1,2-dichloroethane and vinyl chloride were the primary factors for high carcinogenic risk. The high-risk areas were concentrated in Xigu and Chengguan districts, suggesting the need to alert the relevant local government departments.

Following earlier reports of water contamination and arsenic (As) toxicity symptoms in residents of Kurdistan Province, As was determined in rock, soil and plant samples to investigate its fate from rock to crops and its potential effects on human health. Total As content ranged from 4.9 to 10,000 mg/kg, 7.7-430 mg/kg and < 0.05-25,079 µg/kg (dry weight) in rock, soil and plant samples, respectively. The Qorveh-Bijar region data indicated that magmatic differentiation has enriched late magmatic fluids in As. High rare earth elements concentration, dissociation coefficient, and positive Eu anomaly in volcanic rocks, indicated the prevalence of intermediate to felsic composition. The highest As concentration was measured in travertine. In soil, As average level in Qorveh and Bijar was 48.5 and 107 mg/kg, respectively. Higher pollution index and geoaccumulation index (I geo ) were also calculated for Bijar County. The As concentration in crop samples was greater than the recommended maximum permissible concentration for foodstuff. Mann-Whitney U test revealed significant differences between As concentration in different plant species and no difference between plants in Bijar and Qorveh. Also, alfalfa displayed the highest biological accumulation coefficient among the investigated plants. The calculated chronic daily intake of As in Bijar County was higher than the recommended levels for wheat and barley grains. Moreover, the hazard quotient (HQ) and incremental lifetime cancer risk assessments revealed high non-cancer (HQ > 1 for both adults and children) and cancer (particularly for barley in Bijar) risks for inhabitants via consumption of As contaminated crops cultivated in the study area.

Benzo[a]pyrene (BaP) is one of the most well studied carcinogenic polycyclic aromatic hydrocarbons (PAHs) that has been associated with a wide range of toxic effects in aquatic organisms. In the present study, the mosquitofish and zebrafish were exposed to BaP (100 μg/L) for 15 days. We analyzed the intestinal microbial community of mosquitofish and zebrafish using 16S rRNA gene amplicon sequencing and also performed transcriptional profiling of the inflammation pathway related genes in the intestinal tissues. Our results showed that BaP exposure induced similar changes to the composition of microbial community in mosquitofish and zebrafish. At the phylum level, the abundance of Proteobacteria decreased while the abundance of Firmicutes increased following BaP exposure. At the genus level, a common pathogenic genus staphylococcus significantly increased in the BaP treatment groups, compared to the control (DMSO, ~0.001% v/v). In addition, it was observed that BaP significantly increased the mRNA level of il1β in both mosquitofish and zebrafish. The transcript levels of il6, il8, il10 and ifnphi1 were significantly increased in zebrafish, however not in mosquitofish, following Bap exposure. Our findings suggest that BaP could induce microbiota dysbiosis and inflammation in the intestine of mosquitofish and zebrafish., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

1,2-Dichloropropane (1,2-DCP) is recognized as the causative agent for cholangiocarcinoma among offset color proof-printing workers in Japan. The aim of the present study was to characterize the molecular mechanisms of 1,2-DCP-induced hepatotoxic effects by proteomic analysis. We analyzed quantitatively the differential expression of proteins in the mouse liver and investigated the role of P450 in mediating the effects of 1,2-DCP. Male C57BL/6JJcl mice were exposed to 0, 50, 250, or 1250 ppm 1,2-DCP and treated with either 1-aminobenzotriazole (1-ABT), a nonselective P450 inhibitor, or saline, for 8 h/day for 4 weeks. Two-dimensional difference in gel electrophoresis (2D-DIGE) combined with matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF/MS) was used to detect and identify proteins affected by the treatment. PANTHER overrepresentation test on the identified proteins was conducted. 2D-DIGE detected 61 spots with significantly different intensity between 0 and 250 ppm 1,2-DCP groups. Among them, 25 spots were identified by MALDI-TOF/TOF/MS. Linear regression analysis showed significant trend with 1,2-DCP level in 17 proteins in mice co-treated with 1-ABT. 1-ABT mitigated the differential expression of these proteins. The gene ontology enrichment analysis showed overrepresentation of proteins functionally related to nickel cation binding, carboxylic ester hydrolase activity, and catalytic activity. The results demonstrated that exposure to 1,2-DCP altered the expression of proteins related with catalytic and carboxylic ester hydrolase activities, and that such effect was mediated by P450 enzymatic activity.

Fumonisin B 1 is a mycotoxin produced by Fusarium verticillioides and Fusarium proliferatum found in various crops, particularly maize. Besides carcinogenicity, other manifestations have been registered in different animals and in humans. In the case of humans, epidemiological studies have reported high prevalence of esophageal cancer in populations exposed to fumonisins. This study aimed to evaluate the minimum concentration of FB 1 capable of inducing cytotoxicity (cell viability test), genotoxicity (comet assay) and mutagenicity (micronucleus) in cultured human leukocytes and to evaluate the effectiveness of in silico tests to predict FB 1 toxicity. All concentrations analyzed (200; 100; 50; 5; 0.5; 0.05; 0.005 μg/mL and 300; 30; 3; 1; 0.1; 0.01 fg/mL) except the lowest demonstrated dose-dependent toxicity in all parameters analyzed (p < 0.05 to p < 0.0001). As for predictions, only the Lazar software showed carcinogenicity of FB 1 for rats. Thus, it is evident that FB 1 is able to induce dose-dependent damage at low concentrations, and that computational tests, although desirable for prediction, are not effective as biological tests to determine toxicity, at least of FB 1 and within the experimental conditions tested., Competing Interests: Declaration of competing interest No conflict of interest declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The International Agency for Research on Cancer classified radon and its decay-products as Group-1-human-carcinogens, and with the current knowledge they are linked specifically to lung cancer. Biokinetic models predict that radon could deliver a carcinogenic dose to breast tissue. Our previous work suggested that low-dose radon was associated with estrogen-receptor (ER)-negative breast cancer risk. However, there is limited research to examine the role of radon in breast cancer biology at the tissue level. We aim to understand molecular pathways linking radon exposure with breast cancer biology using transcriptome-wide-gene-expression from breast tumor and normal-adjacent tissues., Methods: Our study included 943 women diagnosed with breast cancer from the Nurses' Health Study (NHS) and NHSII. We estimated cumulative radon concentration for each participant up-to the year of breast cancer diagnosis by linking residential addresses with a radon exposure model. Transcriptome-wide-gene-expression was measured with the Affymetrix-Glue-Human-Transcriptome-Array-3.0 and Human-Transcriptome-Array-2.0. We performed covariate-adjusted linear-regression for individual genes and further employed pathway-analysis. All analyses were conducted separately for tumor and normal-adjacent samples and by ER-status., Results: No individual gene was associated with cumulative radon exposure in ER-positive tumor, ER-negative tumor, or ER-negative normal-adjacent tissues at FDR < 5%. In ER-positive normal-adjacent samples, PLCH2-reached transcriptome-wide-significance (FDR < 5%). Gene-set-enrichment-analyses identified 2-upregulated pathways (MAPK signaling and phosphocholine biosynthesis) enriched at FDR < 25% in ER-negative tumors and normal-adjacent tissues, and both pathways have been previously reported to play key roles in ionizing radiation induced tumorigenesis in experimental settings., Conclusion: Our findings provide insights into the molecular pathways of radon exposure that may influence breast cancer etiology.

Fumonisin B1 (FB1) is a mycotoxin frequently found in agricultural commodities, and poses a considerable risk for human and animal health. The aim of this study was to investigate the toxic effect of FB1 in mice intestine. Male Kunming mice (n = 40) were treated with FB1 diet for 42 days. Histopathological and biochemical analyses, including ion concentrations, transcription of ATPase subunits and mRNA expression of cytochrome P450s (CYP450s) analyses were performed on duodenum, cecum and colon of mice. The results revealed that FB1 caused histological alterations, including partial shedding of villous epithelial cells and inflammatory cell infiltration. Furthermore, a significant change in Na + , K + and Ca 2+ in serum, and the mRNA expression of ATPase subunits and CYP450s in intestinal tracts were observed in FB1-exposed mice. Our results suggested that FB1 exposure induce histopathological injury via disrupting CYP isoforms transcription and triggering ion homeostasis imbalance in mice intestinal tracts., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of this manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The aim of the study is to analyze the potential occupational hazards of fluorouracil (FU) and doxorubicin (DOX). The literature review was based on factual and bibliographic scientific databases of the available peer-reviewed journals and the so-called gray literature. In Poland, the process of determining the acceptable levels of occupational exposure for selected anticancer drugs has been underway since 2014, and the basis for determining the maximum allowable concentration values is usually the concentration equivalent to 0.1% of the lowest therapeutic dose found in the literature. In addition, uncertainty coefficients are used, which take into account the mechanism of action of the cytostatics, the dynamics of metabolism, the assessment of classification and labeling for carcinogenic, mutagenic, genotoxic, reproductive toxicity, organ toxicity, the ability to accumulate cytostatics, the assessment of cumulative effects with other cytostatics, the physicochemical form and data completeness. Where possible, the risk of additional cancer is estimated. Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens at work (the carcinogens and mutagens directive ‒ CMD) is a key legal solution in the field of public health in the European Union, focused on the issue of occupational cancer. These cytostatics, FU and DOX, are genotoxic and are classified as hazardous. Life-threatening heart damage is a serious side effect of both FU and DOX. The analysis has shown that the inclusion of dangerous drugs in the list of substances subject to the requirements of the CMD is completely justified. The cytostatics classification and labeling procedure should be harmonized throughout the European Union, which will ensure a reliable and credible risk management in this area. Med Pr. 2020;71(3):363-73., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

The heavy metal contamination like Cr(VI) has been increased by human activities and that threats the ecosystem health of mangrove areas. Bioindicator is an emerging tool in the environmental contamination assessment. The objective of this study was to investigate the Geloina erosa response mechanisms and sensitivities of several biomarkers in the Cr(VI) exposure and identify the G. erosa capability of being used as heavy metals bioindicator. In this study, G. erosa was exposed to 100 μmol·L - 1 Cr(VI) for 48 h. After transcriptome sequencing, a total of 134,817 unigenes were obtained, including 12,555 up-regulated and 18,829 down-regulated differentially expressed genes and were validated through quantitative real-time PCR. In addition, a total of 12,185 SSRs and 1,428,214 candidate SNPs were identified from all the G. erosa transcriptome libraries. Histopathology of the gill indicated the Cr(VI) exposure induced damage of the organ leading to its immunization, detoxification or apoptosis reactions. Among eight genes of the selected biomarkers, Calm, HSP70, CYP450, ATG5, TLR2, MYD88 and CASP8 were up-regulated, while TLR4 was down-regulated in response to the Cr(VI) exposure., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Arsenic and benzo[a]pyrene (BaP) are among the most common environmental carcinogens causing lung cancer. Millions of people are exposed to arsenic through consuming arsenic-contaminated drinking water. High levels of BaP are found in well-done barbecued meat and other food in addition to cigarette smoke. Hence, arsenic and BaP co-exposure in humans is common. However, the combined health effect and the underlying mechanism of arsenic and BaP co-exposure have not been well-understood. In this study we investigate the combined tumorigenic effect of arsenic and BaP co-exposure and the mechanism using both cell culture and mouse models. It was found that arsenic (sodium arsenite, 1.0 µM) and BaP (2.5 µM) co-exposure for 30 weeks synergizes in inducing malignant transformation of immortalized non-tumorigenic human bronchial epithelial cells and cancer stem cell (CSC)-like property to enhance their tumorigenicity. In animal studies, A/J mice were exposed to arsenic in drinking water (sodium arsenite, 20 ppm) starting from gestation day 18. After birth, the dams continuously received arsenic water throughout lactation. At weaning (3 weeks of age), male offspring were exposed to either arsenic alone via drinking the same arsenic water or exposed to arsenic plus BaP. BaP was administered via oral gavage (3 µmol per mouse per week) once a week starting from 3 weeks of age for 8 weeks. All mice were euthanized 34-weeks after the first BaP exposure. It was found that mice in control and arsenic exposure alone group did not develop lung tumors. All mice in BaP exposure alone group developed lung adenomas. However, arsenic and BaP co-exposure synergized in increasing lung tumor multiplicity and tumor burden. Furthermore, 30% of mice in arsenic and BaP co-exposure group also developed lung adenocarcinomas. Mechanistic studies revealed that arsenic and BaP co-exposure does not produce more BPDE-DNA adducts than BaP exposure alone; but acts synergistically in activating aryl hydrocarbon receptor (AhR) to up-regulate the expression of a histone H3 lysine 9 methyltransferase SUV39H1 and increase the level of suppressive H3 lysine 9 dimethylation (H3K9me2), which down-regulates the expression of tumor suppressive SOCS3 leading to enhanced activation of Akt and Erk1/2 to promote cell transformation, CSC-like property and tumorigenesis. Together, these findings suggest that arsenic and BaP co-exposure synergizes in causing epigenetic dysregulation to enhance cell transformation, CSC-like property and tumorigenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This investigation was arranged to elucidate whether single nucleotide polymorphisms (SNPs) of lncRNA UCA1 was implicated in elevating colorectal cancer (CRC) risk by interacting with environmental exposures., Methods: LncRNASNP database was firstly adopted to predict SNPs that possibly affected binding of UCA1 with miRNAs and then the interactive effect of SNPs and environmental exposure on CRC risk was evaluated by recurring to type 2 gene-environment interactions (GEI) model. Besides, MTT assay, colony formation assay, transwell assay and wound healing assay were performed to assess the activity of CRC cell lines which carried distinct genotypes of specific SNPs. The impact of nicotine on activity of CRC cells was also appraised., Results: SNP rs12982687 of UCA1 intervened in the binding capacity of UCA1 with several miRNAs, especially miR-873-5p. MiRNAs regulated by UCA1, as predicted by mirPath software, shared genes that were enriched in HIF1 signaling pathway. Moreover, homozygote TT of rs12982687 reduced CRC risk among smokers, and CRC cells that carried rs12982687 (CC) displayed strong migration and invasion. By contrast, miR-873-5p mimic, which reduced UCA1 expression, delayed metastasis of CRC cells (all P < 0.05). Additionally, nicotine not merely elevated UCA1 and HIF-1α expressions in CRC cells, but also facilitated proliferation and metastasis of CRC cells (P < 0.05)., Conclusions: SNP rs12982687 was involved in smoking-triggered CRC progression, given its influence on UCA1's binding with miR-873-5p and HIF-1 signaling.

Although health hazards of 4-nitrophenol (PNP) exposure have been reported, the adverse effects of PNP exposure on cancer biological features are still unknown. We investigated the effects of administration of PNP in T24 human bladder cancer cells. The results showed that PNP exposure promoted cellular proliferation, migration and invasion, inhibited adhesion and apoptosis in vitro. Using quantitative real-time PCR, we found that (1) the mRNA expression levels of cell-cycle regulators PCNA, cyclin D1 and COX-2 were increased in PNP-treated cells compared to controls, however, that of pro-apoptotic gene Bax was decreased; (2) the expression level of EMT-associated gene E-cadherin was decreased in PNP-treated cells, whereas those of N-cadherin, vimentin, snail, and slug were increased; (3) the expression levels of cancer-promoting genes HIF-1, IL-1β, VEGFα and K-Ras were enhanced, but those of tumor suppressors p53, PTEN and BRCA were decreased. There was a positive association between PNP exposure times and the promotion effects. Finally, we found that the expression level of PPARγ (γ1 isoform) was increased in PNP-treated T24 cells. GW9662, a specific PPARγ antagonist, attenuated PNP-induced cell migration and invasion. These findings indicate that PNP exposure may promote bladder cancer growth and progression involving PPARγ signaling. PPARγ is a potential target for development of novel intervention study on environment pollution. Environ. Mol. Mutagen. 61:316-328, 2020. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

The focus of this research on children's playgrounds with artificial surfaces aimed to establish levels of potentially toxic elements (PTEs) in dust, their origin, and impact on children at 15 playgrounds: 9 on school grounds and 6 on day nurseries in Belgrade (Serbia). Soil samples were taken from the immediate vicinity of the playgrounds to establish the origin of PTEs in the dust samples. Soil analyses revealed the lithogenic origin of Co, Cr, Ni, Fe, Mn, As, Cd, Cu, Pb, and Zn and the anthropogenic origin of As, Cd, Cu, Pb, and Zn. However, in the dust samples, the origin of the elements was different with As, Co, Fe, and Mn originating from the surrounding soil; Cr and Ni levels affected by both atmospheric deposition and the surrounding soil; Cd, Pb, and Zn concentrations impacted by atmospheric deposition; and Cu levels affected by factors of a local character. No noncancer risk was found for any of the individual elements investigated, nor for any of the playgrounds being studied, while a minimal cancer risk was found from As with values greater than 1E-6 at almost all the sites. Based on the results obtained for the spatial distribution of individual PTE levels, it was determined that the surrounding soil and atmospheric deposition have an almost equal impact on noncancer risk values.

Benzene homologues often used as organic raw materials or as detergents in chemical industry are prone to accidental release into the environment which can cause serious long-term soil pollutions. In a large former herbicide factory site, we investigated 43 locations for benzene homologues contaminations in soil, soil gas, and groundwater and studied the hydrogeological conditions. An inverse distance weighted interpolation method was employed to determine the pollutants three-dimensional spatial distribution in the soils. Results showed that benzene homologues residues were mainly originated from the herbicide production workshop and that the pollution had horizontally expanded at the deeper soil layer. Contaminants had already migrated 15 m downward from ground surface. Contaminant phase distribution study showed that NAPL was the primary phase (> 99%) for the pollutants accumulated in the unsaturated zone, while it had not migrated to groundwater. The primary mechanism for contaminant transport and attenuation included dissolution of "occluded" NAPL into pore water and pollutant volatilization into soil pore space. Risk assessment revealed that the pollutants brought unacceptable high carcinogenic and non-carcinogenic risks to public health. In order to convert this former chemical processing factory site into a residential area, a remediation to the polluted production workshop sites is urgently required.

Hexavalent chromium [Cr(VI)] is one of the most common environmental carcinogen causing lung cancer in humans; however, the mechanism of Cr(VI) carcinogenesis remains elusive. Cancer stem cells (CSCs) are considered as cancer initiating and maintaining cells. Ours and other recent studies showed that chronic Cr(VI) exposure induces CSC-like property representing an important mechanism of Cr(VI) carcinogenesis. However, how Cr(VI) exposure induces CSC-like property remains largely unknown. In this study, we found that stably knocking down the expression of c-Myc, a proto-oncogene and one of key stemness factors playing critical roles in cancer initiation and progression, in Cr(VI)-transformed human bronchial epithelial cells [BEAS-2B-Cr(VI)] significantly decreased their CSC-like property and tumorigenicity in mice. Moreover, stably knocking down c-Myc expression in parental nontransformed BEAS-2B cells significantly impaired the capability of chronic Cr(VI) exposure to induce CSC-like property and cell transformation. It was also found that stably overexpressing c-Myc alone in parental nontransformed BEAS-2B cells is capable of causing CSC-like property and cell transformation. Mechanistic studies showed that chronic Cr(VI) exposure increases c-Myc expression by down-regulating the level of microRNA-494 (miR-494). It was further determined that overexpressing miR-494 significantly reduces Cr(VI)-induced CSC-like property, cell transformation, and tumorigenesis mainly through down-regulating c-Myc expression. Together, these findings indicate that chronic low dose Cr(VI) exposure induces CSC-like property and tumorigenesis by increasing c-Myc expression through down-regulating the level of miR-494, revealing an important role of the proto-oncogene c-Myc in Cr(VI) carcinogenesis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Analysis of soil samples around pristine and major gold-mining areas in Ghana was carried out for heavy metals as part of a larger soil contamination and metal background study. The surface soil samples were digested using microwave digester (aqua regia) and analyzed with ICP-MS for As, Cd, Hg, Zn, Co, Cu, Mn, Fe, Al, V, Cr, and Pb. The average concentrations (mg/L) for the metals ranged from 0.01 ± 0.01 (Cd) to 86,859.36 ± 47.07 (Fe) for the pristine sites, and 0.01 ± 0.01 (Cd) to 59,006.95 ± 79.06 (Fe) for the mining sites. Mercury was below the detection limit of the analytical instrument (0.029). The concentrations of heavy metals from this study were used to assess their contamination levels, and health risks. The results showed that, the metals ranked by severity of health risks as As > Pb > Cr > Cd. Principal component analysis (PCA) and cluster analysis showed two groupings with the PCA showing metals variability explained by 79.02%. Results from the PCA and Cluster analysis indicate anthropogenic sources of the metals which may be emanating from gold-mining activities. Results from multi-criteria ranking and pattern recognition employing PROMETHEE and GAIA revealed major contribution of the metals from the mining sites with metal variability explained by 72.83%. This is the first time a multi-criteria approach is employed to characterize heavy metal contamination in Ghana, and the study nevertheless brought to light the impact of mining on human health and the environment with implications for other mineral areas around the globe.

A total of 39 lower brominated PBDE congeners in surface soils from the Yellow River Delta Natural Reserve (YRDNR) were analyzed in the present study. The total concentrations of PBDEs (ΣPBDEs) ranged from "not detected" to 0.732 ng g -1 , with a mean concentration of 0.142 ng g -1 . The concentrations of the ΣPBDEs displayed no correlation with the content of the total organic carbon in the YRDNR. The ΣPBDEs concentrations in the Experimental Area were significantly higher than that of the Buffer Area and Core Area, and ΣPBDEs in soils in the North were lower than that of the South. PentaBDEs and HexaBDEs were the most abundant homologues, and the occurrence of PBDEs in the YRDNR may be attributed to the debromination and long range transport of DecaBDEs. Even though the cancer risk and mass inventory of PBDEs in the present study area were estimated to be very low, due to the widespread presence of PBDEs and the particularity of the natural reserve, vigilance should not be let up on the issue of environmental contamination caused by these compounds despite the gradual phase out of their commercial products in the world.

While improvements in the environment and living conditions have contributed to a significant increase in human longevity for over a century, the role of environmental factors in the occurrence of cancer has become a public health concern. It is recognized that a number of environmental factors such as environmental quality (air, water, soil), or environmental changes contribute to the occurrence of certain cancers. Despite this awareness, their potential impacts on health raise many scientific questions. The development of new methodological tools for the characterization of exposure, the study of the association between environmental agents and cancer through an exposure-cancer approach and the health impacts associated, have led to changes in scientific paradigms including the concept of exposome. This concept, at the heart of health and environmental issues, takes into account the determinants of health related to the quality of populations' living environments and provides assistance in public policy decision-making. Ultimately, the aim is to develop measures likely to reduce exposure and prevent health risks and damage to the most vulnerable populations, both in their physical environment and in their living environment, including the economic and social determinants., (Copyright © 2019. Published by Elsevier Masson SAS.)

Hexavalent chromium (Cr(VI)) compounds are classified as carcinogenic to humans. Whereas chromium measurements in urine and plasma attest to the last few hours of total chromium exposure (all oxidation states of chromium), chromium in red blood cells (RBC) is attributable specifically to Cr(VI) exposure over the last few days. Before recommending Cr in RBC (CrIE) as a biological indicator of Cr(VI) exposure, in vivo studies must be undertaken to assess its reliability. The present study examines the kinetics of Cr(VI) in rat after a single intravenous dose of ammonium dichromate. Chromium levels were measured in plasma, red blood cells and urine. The decay of the chromium concentration in plasma is one-phase-like (with half-life time of 0.55 day) but still measurable two days post injection. The excretion of urinary chromium peaks between five and six hours after injection and shows large variations. Intra-erythrocyte chromium (CrIE) was very constant up to a minimum of 2 days and half-life time was estimated to 13.3 days. Finally, Cr(III) does not interfere with Cr(VI) incorporation in RBC. On the basis of our results, we conclude that, unlike urinary chromium, chromium levels in RBC are indicative of the amount of dichromate (Cr(VI)) in blood., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response-an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.