A Genomic Approach to Identify the Different between Acute and Chronic UVB Exposures in the Causation of Inflammation and Cancer

As a principal component of solar radiation, ultraviolet B (UVB) exposure can be harmful depending on the duration and intensity because the human body can easily be exposed to it. Many studies have demonstrated that UVB causes a series of inflammatory and other skin disorders. UVB has been classified as the Group 1 carcinogen by the International Agency for Research on Cancer. Diverse studies have focused on UVB exposure but the complex perspective of acute and chronic UVB exposure is still lacking. This review presents the differences between acute and chronic exposure to UVB and summarizes public information in terms of toxicogenomic characteristics. We also demonstrated the differences between adverse effects of acute and chronic UVB exposure on the skin system. From the published literatures, we compared the biological pathways predict of the adverse effects caused by each UVB exposure type. Furthermore, our review not only clarifies the differences in each UVB exposure network but also suggests major hub genes related to cellular mechanisms and diseases that are thought to be affected by acute and chronic UVB exposure.

Genomic Approach to the Assessment of Adverse Effects of Particulate Matters on Skin Cancer and Other Disorders and Underlying Molecular Mechanisms

Air pollutants are in the spotlight because the human body can easily be exposed to them. Among air pollutants, the particulate matter (PM) represents one of the most serious toxicants that can enter the human body through various exposure routes. PMs have various adverse effects and classified as severe carcinogen by International Agency for Research on Cancer. Their physical and chemical characteristics are distinguished by their size. In this review, we summarized the published information on the physicochemical characteristics and adverse effects of PMs on the skin, including carcinogenicity. Through comparisons of biological networks constructed from relationships discussed in the previous scientific publications, we show it is possible to predict skin cancers and other disorders from particle-size-specific signaling alterations of PM-responsive genes. Our review not only helps to grasp the biological association between ambient PMs and skin diseases including cancer, but also provides new approaches to interpret chemical-gene-disease associations regarding the adverse effects of these heterogeneous particles.

Nanoparticles: Weighing the Pros and Cons from an Eco-genotoxicological Perspective

The exponential growth of nanotechnology and the industrial production have raised concerns over its impact on human and environmental health and safety (EHS). Although there has been substantial progress in the assessment of pristine nanoparticle toxicities, their EHS impacts require greater clarification. In this review, we discuss studies that have assessed nanoparticle eco-genotoxicity in different test systems and their fate in the environment as well as the considerable confounding factors that may complicate the results. We highlight key mechanisms of nanoparticle-mediated genotoxicity. Then we discuss the reliability of endpoint assays, such as the comet assay, the most favored assessment technique because of its versatility to measure low levels of DNA strand breakage, and the micronucleus assay, which is complementary to the former because of its greater ability to detect chromosomal DNA fragmentation. We also address the current recommendations on experimental design, including environmentally relevant concentrations and suitable exposure duration to avoid false-positive or -negative results. The genotoxicity of nanoparticles depends on their physicochemical features and the presence of co-pollutants. Thus, the effect of environmental processes (e.g., aggregation and agglomeration, adsorption, and transformation of nanoparticles) would account for when determining the actual genotoxicity relevant to environmental systems, and assay procedures must be standardized. Indeed, the engineered nanoparticles offer potential applications in different fields including biomedicine, environment, agriculture, and industry. Toxicological pathways and the potential risk factors related to genotoxic responses in biological organisms and environments need to be clarified before appropriate and sustainable applications of nanoparticles can be established.

Genomic Approach to the Assessment of Adverse Effects of Particulate Matters on Skin Cancer and Other Disorders and Underlying Molecular Mechanisms

Air pollutants are in the spotlight because the human body can easily be exposed to them. Among air pollutants, the particulate matter (PM) represents one of the most serious toxicants that can enter the human body through various exposure routes. PMs have various adverse effects and classified as severe carcinogen by International Agency for Research on Cancer. Their physical and chemical characteristics are distinguished by their size. In this review, we summarized the published information on the physicochemical characteristics and adverse effects of PMs on the skin, including carcinogenicity. Through comparisons of biological networks constructed from relationships discussed in the previous scientific publications, we show it is possible to predict skin cancers and other disorders from particle-size-specific signaling alterations of PM-responsive genes. Our review not only helps to grasp the biological association between ambient PMs and skin diseases including cancer, but also provides new approaches to interpret chemical-gene-disease associations regarding the adverse effects of these heterogeneous particles.

Nanoparticles: Weighing the Pros and Cons from an Eco-genotoxicological Perspective

The exponential growth of nanotechnology and the industrial production have raised concerns over its impact on human and environmental health and safety (EHS). Although there has been substantial progress in the assessment of pristine nanoparticle toxicities, their EHS impacts require greater clarification. In this review, we discuss studies that have assessed nanoparticle eco-genotoxicity in different test systems and their fate in the environment as well as the considerable confounding factors that may complicate the results. We highlight key mechanisms of nanoparticle-mediated genotoxicity. Then we discuss the reliability of endpoint assays, such as the comet assay, the most favored assessment technique because of its versatility to measure low levels of DNA strand breakage, and the micronucleus assay, which is complementary to the former because of its greater ability to detect chromosomal DNA fragmentation. We also address the current recommendations on experimental design, including environmentally relevant concentrations and suitable exposure duration to avoid false-positive or -negative results. The genotoxicity of nanoparticles depends on their physicochemical features and the presence of co-pollutants. Thus, the effect of environmental processes (e.g., aggregation and agglomeration, adsorption, and transformation of nanoparticles) would account for when determining the actual genotoxicity relevant to environmental systems, and assay procedures must be standardized. Indeed, the engineered nanoparticles offer potential applications in different fields including biomedicine, environment, agriculture, and industry. Toxicological pathways and the potential risk factors related to genotoxic responses in biological organisms and environments need to be clarified before appropriate and sustainable applications of nanoparticles can be established.

A Putative Adverse Outcome Pathway Relevant to Carcinogenicity Induced by Sulfuric Acid in Strong Inorganic Acid Mists

Based on epidemiological studies, an International Agency for Research on Cancer Working Group determined that strong inorganic acid mists containing sulfuric acid are carcinogenic to human even though, sulfuric acid, per se, is not. Accumulative studies indicate that there is a link between chronic occupational exposure to sulfuric acid mists and an increased risk of laryngeal cancer. Unintended, acute exposure to sulfuric acid mists can cause corrosive damage to target tissues depending on the route of exposure. This review compares the toxicity and carcinogenicity of sulfuric acid mists compared to other strong inorganic acid mists. It also examines the routes and duration of exposure (short-term, prolonged, and long-term). In vivo evidence does not support or refute the carcinogenicity of sulfuric inorganic mists even though its co-carcinogenic or promoting potential has been considered. On the basis of existing evidence on sulfuric acid mist toxicity, we suggested a putative adverse outcome pathway (AOP) relevant to carcinogenicity caused by mists containing sulfuric acid. A possible key factor involved in sulfuric acid mist carcinogenesis is the genotoxic effects of low pH since it can increase instability in chromosomes and DNA. A putative AOP for sulfuric acid mist carcinogenicity would help generate better risk assessments and more accurate predictions regarding the risk of developing cancer due to prolonged exposure. Establishing an AOP would also be useful for future studies examining the carcinogenicity of other strong inorganic mists.

Application of the Adverse Outcome Pathway Framework to Risk Assessment for Predicting Carcinogenicity of Chemicals

As industry develops in modern society, many chemicals are being used. The safety of chemicals is an important issue because humans are constantly exposed to chemicals throughout their daily life. Through a risk assessment, the hazardous human effects of chemicals can be identified. Recently, the adverse outcome pathway (AOP) framework has been used to predict the adverse effects of chemicals. As a conceptual framework for organizing existing biological knowledge, the AOP consists of a molecular initiating event, key events, and an adverse outcome. These independent elements represent biological responses and are connected by key event relationships. This AOP framework provides intuitive hazard identification that can be helpful for carcinogenic risk assessment of chemicals. In this review, we introduce the application of the AOP framework to risk assessment for predicting carcinogenicity of chemicals and illustrate the utility of this approach for cancer prevention.

Predictive and Prognostic Biomarkers of Respiratory Diseases due to Particulate Matter Exposure

Air pollution is getting severe and concerns about its toxicity effects on airway and lung disease are also increasing. Particulate matter (PM) is major component of air pollutant. It causes respiratory diseases, such as asthma, chronic obstructive pulmonary disease, lung cancer, and so on. PM particles enter the airway and lung by inhalation, causing damages to them. Especially, PM2.5 can penetrate into the alveolus and pass to the systemic circulation. It can affect the cardiopulmonary system and cause cardiopulmonary disorders. In this review, we focused on PM-inducing toxicity mechanisms in the framework of oxidative stress, inflammation, and epigenetic changes. We also reviewed its correlation with respiratory diseases. In addition, we reviewed biomarkers related to PM-induced respiratory diseases. These biomarkers might be used for disease prediction and early diagnosis. With recent trend of using genomic analysis tools in the field of toxicogenomics, respiratory disease biomarkers associated with PM will be continuously investigated. Effective biomarkers derived from earlier studies and further studies might be utilized to reduce respiratory diseases.

High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity

BACKGROUND: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in ApcMin/+ mice. METHODS: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. RESULTS: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2'-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). CONCLUSIONS: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis.

High-fat Diet Accelerates Intestinal Tumorigenesis Through Disruption Intestinal Cell Membrane Integrity

There is an error in a grant number in Acknowledgements.

Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust

OBJECTIVES: The primary aim of this study is to evaluate the gene expression profile of Asian sand dust (ASD)-treated human middle ear epithelial cell (HMEEC) using microarray analysis. METHODS: The HMEEC was treated with ASD (400 microg/mL) and total RNA was extracted for microarray analysis. Molecular pathways among differentially expressed genes were further analyzed. For selected genes, the changes in gene expression were confirmed by real-time polymerase chain reaction. RESULTS: A total of 1,274 genes were differentially expressed by ASD. Among them, 1,138 genes were 2 folds up-regulated, whereas 136 genes were 2 folds down-regulated. Up-regulated genes were mainly involved in cellular processes, including apoptosis, cell differentiation, and cell proliferation. Down-regulated genes affected cellular processes, including apoptosis, cell cycle, cell differentiation, and cell proliferation. The 10 genes including ADM, CCL5, EDN1, EGR1, FOS, GHRL, JUN, SOCS3, TNF, and TNFSF10 were identified as main modulators in up-regulated genes. A total of 11 genes including CSF3, DKK1, FOSL1, FST, TERT, MMP13, PTHLH, SPRY2, TGFBR2, THBS1, and TIMP1 acted as main components of pathway associated with 2-fold down regulated genes. CONCLUSION: We identified the differentially expressed genes in ASD-treated HMEEC. Our work indicates that air pollutant like ASD, may play an important role in the pathogenesis of otitis media.

An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention

Almost all heavy metals are serious toxicants as carcinogens. However, due to their chemical and physiological properties, heavy metals are useful in industrial areas including alloy, smelting and production of commercial products. Such applications increase the opportunity for heavy metal exposure. Waste from industrial processes is also a major source of environmental contamination and accumulation in the human body. Arsenic, cadmium, chromium, and nickel are classified as group 1 carcinogens by the International Agency for Research on Cancer, and are utilized commercially. In this review, we used molecular pathway analysis to understand the toxicity and carcinogenic mechanisms of these metals. Our analyzed data showed that above-mentioned metallic substances induce oxidative stress, DNA damage, and cell death processes, resulting in increase the risk of cancer and cancer-related diseases. Thus, we might think phytochelatin molecules and antioxidative phytochemical substances are helpful for prevention of heavy metal-induced cancer.

Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors.

Significance of p27(kip1) as potential biomarker for intracellular oxidative status

Our previous proteomic study demonstrated that oxidative stress and antioxidant delphinidin regulated the cellular level of p27(kip1) (referred to as p27) as well as some heat shock proteins in human colon cancer HT 29 cells. Current study was conducted to validate and confirm the regulation of these proteins using both in vitro and in vivo systems. The level of p27 was decreased by hydrogen peroxide in a dose-dependent manner in human colon carcinoma HCT 116 (p53-positive) cells while it was increased upon exposure to hydrogen peroxide in HT 29 (p53-negative) cells. However, high concentration of hydrogen peroxide (100 micrometer) downregulated p27 in both cell lines, but delphindin, one of antioxidative anthocyanins, enhanced the level of p27 suppressed by 100 micrometer hydrogen peroxide. ICR mice were injected with varying concentrations of hydrogen peroxide, delphinidin and both. Western blot analysis for the mouse large intestinal tissue showed that the expression of p27 was upregulated by 25 mg/kg BW hydrogen peroxide. To investigate the association of p27 regulation with hypoxia-inducible factor 1-beta (HIF-1beta), the level of p27 was analyzed in wild-type mouse hepatoma hepa1c1c7 and Aryl Hydrocarbon Nuclear Translocator (arnt, HIF-1beta)-defective mutant BPRc1 cells in the absence and presence of hydrogen peroxide and delphinidin. While the level of p27 was responsive to hydrogen peroxide and delphinidin, it remained unchanged in BPRc1, suggesting that the regulation of p27 requires functional HIF-1beta. We also found that hydrogen peroxide and delphinidin affected PI3K/Akt/mTOR signaling pathway which is one of upstream regulators of HIFs. In conclusion, hydrogen peroxide and antioxidant delphinidin seem to regulate intracellular level of p27 through regulating HIF-1 level which is, in turn, governed by its upstream regulators comprising of PI3K/Akt/mTOR signaling pathway. The results should also encourage further study for the potential of p27 as a biomarker for intracellular oxidative or antioxidant status.

Hyperthermia-induced Apoptosis is Independent upon DNA Strand Breaks in Human Lymphoid Cells

Heat shock (43oC for 60 minutes) is sufficient to induce apoptosis in a wide number of cell lines. In this study, we asked whether DNA strand breaks are responsible for this phenomenon. Using the highly sensitive comet assay for DNA damage detection, we were unable to demonstrate DNA breaks immediately after heat shock in Raji human lymphoid cells. It showed that DNA breaks were not necessary for hyperthermic apoptosis, since its activity is indicative of DNA lesions. Here, we present a suggestion that a protein (s) is the major target for heat shock apoptosis. We firstly found glycerol, which reportedly stabilizes protein structure, showed a protective effect in Raji cells against hyperthermic apoptosis. In addition, quercetin, which modulates transcription of the heat shock protein family members, enhanced apoptotic death induced by hyperthermia. Furthermore, Raji cells are protected by a pre-mild heat treatment prior to the killing dose of heat shock.

Cytotoxicological Effect of Tebufenozide, an Insect Growth Regulator (IGR) : Stimulation of Filamentous Actin Reorganization and Enhancement of Hsp27 Expression in Drosophila Kc Cells

The cytotoxicological responses to insect growth regulator (IGR), using tebufenozide as ecdysteroid mimic, were investigated in Drosophila Kc cells. Treatment of Kc cells with tebufenozide showed significant growth inhibition and striking morphological changes including aggregation and elongation of the cells. In order to understand the cellular mechanism underlying the response of Drosophila cells to tebufenozide, immunofluorescence microscopy was performed. We found that treatment of Kc cells with tebufenozide enhanced the reorganization of f-actin and stimulated the expression of hsp27. These data suggest a possible association of filamentous actin (f-actin) and hsp27 in the cytotoxicological mechanisms of growth regulators in Drosophila cells.

The potential roles of p53 tumor suppressor in nucleotide excision repair (NER) and base excision repair (BER)

The p53 tumor suppressor has long been envisaged to preserve genetic stability by the induction of cell cycle checkpoints and apoptosis. More recently, p53 has been implicated to play roles in DNA repair responses to genotoxic stresses. UV-damage and the damage caused by certain chemotherapeutics including cisplatin and nitrogen mustards are known to be repaired by the nucleotide excision repair (NER) pathway which is reportedly regulated by p53 and its downstream genes. There are evidences to suggest that the base excision repair (BER) induced by the base-damaging agent methyl methanesulfonate (MMS) is partially deficient in cells lacking functional p53. This result suggests that the activity of BER might be also dependent on the p53 status. In this review, we discuss the possibilities that p53 regulates BER as well as NER; these are one of the most significant potentials of p53 tumor suppressor for repairing the vast majority of DNA damages that is incurred from various environmental stresses.

Relationship Between Chronic Prostatitis and Psychological Problem / 대한비뇨기과학회지

PURPOSE: We investigated whether psychological factors could influence on the symptoms of chronic prostatitis based on general population that have not previously been examined or treated. MATERIALS AND METHODS: Between August and November 2000, we randomly selected 100 male residents in the area of Chung-nam including Daejoen city. The participants completed self- administered questionnaires. Based on our inclusion criteria, 87 participants were included in this study. RESULTS: Scores of Beck Depression Inventory of participants with higher pain and urinary symptoms domain scores were significantly higher than those with lower pain and urinary symptoms domain scores of the National Institutes of Health-chronic prostatitis symptom index (p=0.001 and p=0.028, respectively). However, anxiety did not influence on the symptoms of chronic prostatitis based on the results of State-Trait Anxiety Inventory. Based on the results of Bem Sex Role Inventory, masculinity score of participants with higher urinary symptoms domain scores were significantly lower than those with lower urinary symptoms domain scores (p=0.042). CONCLUSIONS: Our results suggest that psychological problems may involve in an early stage of chronic prostatitis and have a causative role in chronic prostatitis.

Nickel (II)-induced apoptosis and G2/M enrichment

Treatment with certain DNA-damaging agents induce a complex cellular response comprising pertubation of cell cycle progression and/or apoptosis on proliferating mammalian cells. Our studies were focused on the cellular effects of nickel (II) acetate, DNA-damaging agent, on Chinese hamster ovary (CHO) cells. Fragmented DNAs were examined by agarose gel electrophoresis and cell cycle was determined by DNA flow cytometry using propidium iodide fluorescence. Apparent DNA laddering was observed in cells treated with 240 microM nickel (II) and increased with a concentration-dependent manner. Treatment of nickel (II) acetate resulted in apoptosis which was accompanied by G2/M cell accumulation. Proportion of CHO cells in G2/M phase was also significantly increased in cells exposed to at least 480 microM nickel (II) from 57.7% of cells in the G0/G1 phase, 34.7% in the S phase, and 7.6% in the G2/M1 phase for 0 microM nickel (II), to 58.6%, 14.5%, and 26.9% for 640 microM nickel (II). These findings suggest that nickel (II) can modulate cellular response through some common effectors involving in both apoptotic and cell cycle regulatory pathways.