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The origin of 2D electron gas (2DEG) at LaAlO3/SrTiO3 (LAO/STO) interfaces has remained highly controversial since its discovery. Various models are proposed, which include electronic reconstruction via surface‐to‐interface charge transfer and defect‐mediated doping involving cation intermixing or oxygen vacancy (V O) formation. It is shown that the polar field‐assisted V O formation at the LAO/STO surface plays critical roles in the 2DEG formation and concurrent structural transition. Comprehensive scanning transmission electron microscopy analyses, in conjunction with density functional theory calculations, demonstrate that V O forming at the LAO/STO surface above the critical thickness (t c) cancels the polar field by doping the interface with 2DEG. The antiferrodistortive (AFD) octahedral rotations in LAO, which are suppressed below the t c, evolve with the formation of V O above the t c. The present study reveals that local symmetry breaking and shallow donor behavior of V O induce the AFD rotations and relieve the electrical field by electron doping the oxide heterointerface., Comprehensive scanning transmission electron microscopy analyses, in conjunction with density functional theory calculations, demonstrate that oxygen vacancy forming at LaAlO3/SrTiO3 (001) surface above the critical thickness (t c) cancels the polar electric field by doping the interface with two‐dimensional electron gas. The antiferrodistortive octahedral rotations in LaAlO3, which are suppressed below t c, evolve with the formation of oxygen vacancy above t c.

Dibutyl phthalates (DBP) are widely used as plasticizers to soften and increase the flexibility of polyvinyl chloride plastics, although they can leach into the surrounding environment. Many studies have reported that changes in thyroid function are linked to a variety of chemicals in the environment. Although the mechanism is not known, DBP decreases T3 and T4, and downregulates the sodium/iodide symporter promoter in the thyroid. We undertook a genome-wide analysis of transcriptional responses in human thyroid follicular carcinoma FTC-238 cells to non-toxic doses of DBP (100 μM). Whole human genome microarrays detected a total of 4,480 genes that exhibited altered expression after exposure to non-toxic doses of DBP compared with the vehicle control. We found that 2,218 and 2,262 genes showed different expression levels following treatment with non-toxic doses of DBP (1.5-fold (p

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) that is carcinogenic to humans. Although the environmental distribution and metabolism of BaP have been reported and many researchers are performing risk-assessment and toxicological studies of BaP by means of physical and chemical measurements, only a few studies have examined the expression of mRNAs and their functions in BaP-induced toxicity. Toxicogenomic technology, a new paradigm in toxicity screening, is a useful approach for evaluating the toxic properties of environmental pollutants. We analyzed gene expression profiles using human oligonucleotide chips and identified genes in human hepatocellular carcinoma (HepG2) cells whose expression changed > 1.5-fold after exposure to BaP. The expression of 4,048 and 3,926 genes was up-and down-regulated > 1.5-fold (P < 0.01), respectively, after exposure. Gene ontology (GO) analysis of these genes revealed significant enrichment in several key biological processes related to DNA damage, including DNA repair, cell cycle arrest, and apoptosis. We also performed a contrastive study of cellular effects in HepG2 cells exposed to BaP, and identified increased expression of related genes, cell cycle arrest, and apoptotic cells. These results suggest that genetic markers of BaP-induced toxicity may be molecular blueprints that can be more widely implemented in combination with more traditional techniques for assessment and prediction.

Genomic-wide mapping of epigenetic changes is essential for understanding the mechanisms involved in chemical-induced gene regulation. The identification of DNA methylation patterns is a common procedure in the study of epigenetics, as methylation is known to have significant effects on gene expression, and is involved with normal development as well as disease. Thus, the ability to discriminate between methylated DNA and non-methylated DNA is essential for generating methylation profiles for such studies. Methylated DNA immunoprecipitation (MeDIP) is a recently devised method for the extraction of methylated DNA from a sample of interest and used to determine the distribution of DNA-methylation within functional regions (e.g., promoters) or in the entire genome robustly and cost-efficiently. This approach is based on the enrichment of methylated DNA with an antibody that specifically binds to 5-methyl-cytosine (5mC) and can be combined with PCR and microarray. Here we summarize the experimental procedure of MeDIP followed by high throughput microarray and provides a comprehensive summary of quality control strategies.

Although polycyclic aromatic hydrocarbons (PAHs) are carcinogenic and have been extensively studied with regard to tumor formation, few studies have investigated the involvement of these environmental chemicals in tumor migration and invasion. Polycyclic aromatic hydrocarbons induce reactive oxygen species (ROS) and activate MAPK signal transduction. The p38 signaling transduction pathway, one of the most typical MAPK pathways, plays an essential role in regulating cell migration. Therefore, we investigated whether three PAHs, benzo[a]anthracene (B[a]A), benzo[k]fluoranthene (B[k]F), and indeno[1,2,3-c,d]pyrene (IND), induce migration in human hepatocellular carcinoma cell line HepG2 through ROS-mediated p38 MAPK signal transduction. Reactive oxygen species generation and p38 MAPK activity both increased in a dose-dependent manner and were prevented by SB203580, an inhibitor of p38 MAPK, and N-acetylcysteine (NAC), a ROS scavenger. Expression of migration-related genes was also increased by B[a]A, B[k]F, and IND in a dose-dependent manner and was inhibited by SB203580 and NAC. The migration of HepG2 cells, observed using the Transwell migration assay, also increased in a dose-dependent manner and was prevented by SB203580 and NAC. Our results indicate that the ROS-mediated p38 MAPK signaling pathway plays an essential role in the PAH-induced migration of HepG2 cells. (Cancer Sci 2011; 102: 1636–1644)

Toxaphene is a bioaccumulative, persistent, and toxic pollutant. Toxaphene is one of the 12 priority of Persistent Organic Pollutants (POPs) intended for global action by the United Nations Environment Program (UNEP) Governing Council. POPs are manmade synthetic chemicals highly resistant to biodegradation, with a high affinity for bioaccumulation (due to their hydrophobic and/or lipophilic nature) and biomagnification in the environment and living organisms, including humans. Once deposited in humans (mainly in adipose tissue), they form stable compounds that result in a lasting toxic body burden. Most human populations are exposed to mixtures of POPs originated either from local or remote sources. Toxaphene is ubiquitous in air, water, soil, and biological matrices, as well as in major environmental compartments. Toxaphene has effects on various organs such as thyroid, bone, skin, kidneys, and blood cells and especially, revealed strong toxicity to liver. In this study, we identified genes related to hepatotoxiciy induced by toxaphene in human hepatocellular carcinoma (HepG2) cells using microarray and gene ontology (GO) analysis. Through microarray analysis, we identified 1,647 up- and 2,251 down-regulated genes changed by more than 1.5-fold and P-values 0.001 by toxaphene. And after GO analysis, we determined several key pathways which known as related to hepatotoxicity such as MAPK signaling pathway, complement and coagulation cascades, tight junction. Thus, our present study suggests that genes expressed by toxaphene may provide a clue for hepatotoxic mechanism of toxaphene.

Phospholipidosis (PL), a disorder characterized by an accumulation of phospholipids in lysosome-derived multilamellar vesicles owing to abnormal lipid metabolism. Amiodarone (AM), an antiarrhythmic drug, can induce pulmonary PL. First, to evaluate potential mechanisms of phospholipidosis, we found lipid metabolism--related genes by microarray. PPARG, FADS2, and SCD out of these genes were key genes in lipid metabolism and PPAR signaling by AM. The messenger RNA (mRNA) levels of PPARG, FADS2, and SCD were upregulated by AM. The PPARγ antagonist GW9662 was used to investigate the possible involvement of PPARγ as a mediator of AM-induced PL, and FADS2 and SCD small interfering RNAs (siRNAs) were used to examine the involvement of FADS2 and SCD in AM-induced PL. The inhibition of PPARγ by GW9662 significantly attenuated the AM-induced upregulation of SCD and slightly decreased the AM-induced upregulation of FADS2. And the pretreatment of GW9662 significantly decreased the AM-induced uptake of the fluorescent phospholipid analog NBD-PC. The siRNA-mediated gene silencing of FADS2 and SCD also decreased the AM-induced NBD-PC uptake. These results suggest that the activation of the PPARγ signaling pathway, including FADS2 and SCD, may play an important role in AM-induced PL. PPARG, FADS2, and SCD are AM-induced PL-related genes and may serve as potential biomarkers for PL caused by pulmonary toxicity. We also provide evidence for a possible mechanism of PL, the accumulation of phospholipid in the induction of FADS2 and SCD by PPARγ, in AM-induced pulmonary toxicity.

Chlordane is a bioaccumulative, persistent, and toxic pollutant. Chlordane is one of the 12 priority of Persistent Organic Pollutants (POPs) intended for global action by the United Nations Environment Program (UNEP) Governing Council. POPs are organic compounds resistant to environmental degradation through chemical, biological, and photolytic processes. Chlordane is ubiquitous in air, water, soil, and biological matrices, as well as in major environmental compartments. Chlordane has effects on various organs such as thyroid, bone, skin, kidneys, and blood cells and especially, revealed strong toxicity to liver. In this study, we identified genes related to hepatotoxiciy induced by chlordane in human hepatocellular carcinoma (HepG2) cells using microarray and gene ontology (GO) analysis. Through microarray analysis, we identified 524 up- and 440 down-regulated genes changed by more than 2.0-fold and P-values 0.05 by chlordane. And after GO analysis, we determined several key pathways which known as related to hepatotoxicity such as metabolism of xenobiotics by cytochrome P450, cell cycle, and apoptosis. Thus, our present study suggests that genes expressed by chlordane may provide a clue for hepatotoxic mechanism of chlordane.

Environmental chemicals have attracted attention owing to their effects on thyroid functions, because thyroid hormones (THs) play key roles in the development of mammalian organs such as the brain and heart. Carbaryl, which is used as an insecticide, is a cholinesterase inhibitor and is toxic to humans. It is classified as a likely human carcinogen by the United States Environmental Protection Agency (EPA). It induces thyroid dysfunction by acting as a thyroid receptor (TR) antagonist and altering the circulating levels of THs; it increases triiodothryonine (T3) levels. Vinclozolin is a fungicide and is known as an endocrine disruptor. Vinclozolin decreases circulating thyroxine (T4) levels and increases thyroid stimulating hormone (TSH) levels. We examined the changes in gene expression profiles in human thyroid follicular carcinoma FTC-238 cells that were exposed to carbaryl and vinclozolin and various chemicals by using a human oligonucleotide chip. Several genes altered by carbaryl and vinclozolin belonged to the gene ontology (GO) categories of cell cycle, apoptosis, development, and metabolism. Further, we identified 106 classifiers represent in the contrast the reaction in thyroid systems by carbaryl and vinclozolin. These classifiers are potential biomarkers of the final symptoms (i.e., hyperthyroidism and hypothyroidism) that result from disruption of THs production. In conclusion, our study suggests potential biomarkers and biological functions related to thyroid dysfunction and biological functions to be investigated in response to the exposure of environmental chemicals such as carbaryl and vinclozolin.

The cuplike structure of calix[4]arenes is one of the most attractive features, which has been observed both in the solid state and in solution. The newly synthesized 5,11,17,23-tetrakis(3-mercaptopropyl)calix[4]arene (1) and 25,26,27,28-tetrakis(5-mercaptopenthoxy)calix[4]arene containing aryl sulfide rings (2), have four alkyl thiol linkages, which allow the calixarenes to attach onto the gold surface. Surface plasmon resonance (SPR) spectroscopy allows us to monitor the binding of calixarene derivatives on the gold surface. The 1 and 2 bind very effectively on the gold surface and self-assembled layers of 1 and 2 produce significant change in SPR signals in 30 min. Calixarenes layers are used as platforms for molecular recognition, where complementary binding sites are easily and selectively introduced. The aromatic molecules used in this study are anthracene, pyrene, coronene and rubrene. The host-guest properties of these aromatic molecules and the calixarene cavity exhibit selectivity of these aromatic molecules. The anthracene, pyrene and coronene have moderate binding affinity to the cavity, and the rubrene does not bind at all.

Polyimide containing the chalcone moiety is expected to show the high photodimerization rate and stable alignment characteristics. We introduced the chalcone moiety as a side chain into the polyimide backbone to apply to the photo-alignment layer. The tilted angle of incident light produced out-of-the-plane orientation of chalcone side chain. The orientation effects align the LC in LCD, which possesses the various pretilt angles depending on the length of side chains.

The photoalignment of liquid crystal (LC) molecules located onto polyimide films with chalcone derivatives using linearly polarized UV (LPUV) light is investigated. The LPUV light irradiation generated dimerization products of the chalcones followed by isomerization of the chalcone derivatives. The alignment directions of LC molecules were either homeotropic or planar with respect to plane of polyimide film, depending upon the alkyl chain length attached on the chalcones.

We synthesized chalcone derivatives and introduced them as a side chain unit in the backbone of polyimide for photo-alignment layers. The rate of photoreaction was followed by the disappearance of the CCCO bond in the chalcone moiety using UV–visible spectroscopy. The absorption peak at around 340 nm decreased significantly in less than a few minutes at room temperature. We studied the effect of the length of alkyl chain in chalcone derivatives and found that the alignment properties are very much dependent on the chain length.

Photosensitive polyimide containing chalcone moiety as a photoalignment layer in LCD is synthesized. Chalcone monomer is prepared through William's reaction and DOCDA-DAP is polymerized via one-step imidization followed by introducing the prepared chalcone moiety. The solution and film of the photosensitive polyimide are irradiated with UV light and characterized by UV-vis. and FT-IR spectroscopies.

The photo-alignment with the linear-polarized UV (LP-UV) light was applied to the surface modified polyimide film with chalcone derivatives for the vertical alignment of liquid crystal molecules. The LP-UV light irradiation caused either dimerization or isomerization of chalcone derivatives. The long alkyl-chains attached on the chalcone derivatives were aligned homeotropically and so are LC-molecules.

The photosensitive PI film composing of DOCDA/DAP-Chalcone [5-2,5-dioxotetrahydrofuryl]-3-methyl-3-cyclohexene-1,2-dicarboxylic anhydride/1,4-diaminophenol/4-n-propyl-4-(3-propylene hydroxide) chalcone] induces orientation of liquid crystal alignment perpendicular to the polarization direction. The pretilt angle of liquid crystal was about 1°, It will be applied to the ferroelectric liquid crystal display.

It has been known that the chalcone dimerizes efficiently. We modified BPDA-PDA (poly(surface with sulfuric acid and aqueous KOH solution. The modified surface provides the binding sites for photo-ractive materials. A chalcone derivative has been synthesized, which possesses reactive functional group to the modified surface. The synthesis of the chalcone derivative was confirmed. The photoreactions of the chalcone derivative were followed by UV-visible spectroscopy. The isomerization occurs with irradiation of UV light and finishes in 5 min. Succeedingly the photo-dimerization occurs.

Inhalation is an important route of aldehyde exposure, and lung is one of the main targets of aldehyde toxicity. Octanal is distributed ubiquitously in the environment and is a component of indoor air pollutants. We investigated whether octanal exposure enhances the inflammatory response in the human respiratory system by increasing the expression and release of cytokines and chemokines. The effect of octanal in transcriptomic modulation was assessed in the human alveolar epithelial cell line A549 using oligonucleotide arrays. We identified a set of genes differentially expressed upon octanal exposure that may be useful for monitoring octanal pulmonary toxicity. These genes were classified according to the Gene Ontology functional category and Kyoto Encyclopedia of Genes and Genomes analysis to explore the biological processes related to octanal-induced pulmonary toxicity. The results show that octanal affects the expression of several chemokines and inflammatory cytokines and increases the levels of interleukin 6 (IL-6) and IL-8 released. In conclusion, octanal exposure modulates the expression of cytokines and chemokines important in the development of lung injury and disease. This suggests that inflammation contributes to octanal-induced lung damage and that the inflammatory genes expressed should be studied in detail, thereby laying the groundwork for future biomonitoring studies.

Assessing the potential carcinogenicity of human toxins represents an ongoing challenge. Chronic rodent bioassays predict human cancer risk with limited reliability, and are expensive and time-consuming. To identify alternative prediction methods, we evaluated a transcriptomics-based human in vitro model to classify carcinogens by their modes of action. The aim of this study was to determine the transcriptomic response and identify specific molecular signatures of polycyclic aromatic hydrocarbons (PAHs), which can be used as predictors of carcinogenicity of environmental toxins in human in vitro systems. We found that characteristic molecular signatures facilitate identification and prediction of carcinogens. To evaluate the change in gene expression levels, human hepatocellular carcinoma (HepG2) cells were exposed to nine different PAHs (benzo[a]pyrene, dibenzo[a,h]anthracene, 3-methylcholanthrene, naphthalene, chrysene, phenanthrene, benzo[a]anthracene, benzo[k]fluoranthene, and indeno[1,2,3-c,d]pyrene) for 48 h. Unsupervised gene expression analysis resulted in a characteristic molecular signature for each toxin, and a supervised analysis identified 31 outlier genes as distinct molecular signatures distinguishing carcinogens from noncarcinogens. Further analysis and multi-classification revealed 430 genes as surrogate markers for predicting carcinogenic potencies of each PAH with 100% accuracy. Our results suggest that these expression signatures can be used as predictable and discernible surrogate markers for detecting and predicting PAH exposure, and their carcinogenic potential. Furthermore, the use of these markers can be more widely applied in combination with traditional techniques for assessing and predicting toxic exposure to PAHs.

Thyroid peroxidase (TPO) plays an important role in thyroid hormone biosynthesis, as it catalyzes all of the essential steps in iodide organification. TPO activity can be detected using the guaiacol assay; however, this assay is complex and very time-consuming. Therefore, we focused on devising a simplified method using microarrays to detect changes in TPO activity, which is a target for disruption of the thyroid hormone axis. These experiments have systematically assessed the potential utility of transcriptomic end points as enhancements to the guaiacol assay. Previously, we demonstrated that benzophenone-2, benzophenone, perfluorooctane sulfonate, bisphenol A bis ether, and vinclozolin decreased TPO activity, and that dibutyl phthalate, carbaryl, dibenzo(a,h)anthracene, benzo(a)pyrene, and methylmercury increased TPO activity. In this work, we used human oligonucleotide chips to examine changes in the gene expression profile of FTC-238 human follicular thyroid carcinoma cells expressing human recombinant TPO, after exposure of the cells to TPO activity-disrupting agents. We identified 362 classifiers that could predict the effect of the toxicants on TPO activity with about 70% accuracy. These classifiers are potential markers for predicting the effects of chemicals on thyroid hormone production.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that require metabolic activation to exert their carcinogenic effects. This study investigated the 3,4-diol-1,2-epoxide formation of benz[a]anthracene (BA) and its toxic effects in a human in vitro hepatocyte culture system. Both mRNA and protein expression of metabolic enzymes which can activate PAHs to carcinogenic forms increased after BA exposure in HepG2 cells and our quantitative analysis showed that the formation of BA-3,4-diol-1,2-epoxide in medium extracts increased in a time-dependent manner. We also performed several comparative studies which show that much lower concentrations of BA-3,4-diol-1,2-epoxide had stronger cytotoxicity and genotoxicity than higher doses of BA. These results suggest that BA is activated as the major carcinogenic metabolite 3,4-diol-1,2-epoxide, in human in vitro culture systems by metabolic enzymes and that this metabolite has stronger cytotoxic and genotoxic effects than its parent compound.

Whereas benzene (BZ) is a well-known human carcinogen, toluene (TOL) and o-xylene (o-XY) are not; however, all three compounds are important environmental pollutants. Although BZ, TOL, and o-XY have been shown to induce apoptosis in vitro, their mechanism of toxicity remains unclear. In this study, we sought to identify the apoptotic pathway(s) activated by BZ, TOL, and o-XY in human HL-60 promyelocytic leukemia cells. Cell cycle analysis by propidium iodide (PI) staining and flow cytometric analyses of Annexin V/PI double-stained cells revealed similar patterns of apoptosis following BZ, TOL, and o-XY exposure. Though reactive oxygen species (ROS) production contributes significantly to BZ metabolite-induced apoptotic cell death, we hypothesized that BZ, TOL, and o-XY can themselves trigger ROS production, leading to the activation of apoptotic signaling. Dose-dependent increases in ROS production and significant tail moments were observed in HL-60 cells exposed to all three compounds. Real-time RT-PCR revealed increased HMOX1 and Noxa expression in BZ-, TOL-, and o-XY-treated HL-60 cells, confirming the results of previous microarray analyses. Similar expression profiles were found in human K562 erythromyeloblastoid leukemia cells and human U937 leukemic monocyte lymphoma cells. Pretreatment with the ROS scavenger N-acetyl cysteine decreased the effects of exposure to BZ, TOL, and o-XY. In summary, this study provides useful insights into the mechanism of BZ-, TOL-, and o-XY-induced apoptosis in leukemia cells.

Various phospholipases are thought to be associated with the in vitro apoptosis of thymocytes. In the present study, the in vivo phospholipase D (PLD) activity of rat thymus was studied after whole-body X-irradiation or injection of dexamethasone (DEX). Using exogenous [14C]dipalmitoyl phosphatidylcholine (PC) as the substrate, an elevation of oleate-activated PLD activity was observed during thymic atrophy. The activity increases were sevenfold at 48 hr after 5-Gy irradiation and fourfold at 72 hr after injection of 5 mg/kg DEX. The elevation of PLD activity appeared to parallel extensive thymus shrinkage. An increased level of thymic phosphatidic acid (PA), the presumed physiological product of PLD action on PC, was also detected. By comparing the acyl chains of PA with those of other phospholipids, PA appeared to originate from PC. To assess the role of PLD during thymic atrophy, thymocytes and stromal cells were isolated. Although thymocytes themselves exhibited significant PLD activation, the major elevation in PLD activity (greater than fourfold) was found in isolated stromal cells. PLD was also activated during in vitro phagocytosis of apoptotic thymocytes by the macrophage-like cell line P388D1. This in vitro phagocytosis was significantly inhibited by PLD action blockers, such as 2,3-diphosphoglycerate and 1-butanol. These observations strongly suggest that the alteration of oleate-activated PLD activity is part of an in vivo event in the progression of thymic atrophy, including phagocytic clearance of apoptotic thymocytes.

Compared to other liquid crystalline mesophases, the Blue Phase exhibits extremely fast switching via induced birefringence by an external field. However, the pure Blue Phase is characterized by a rather narrow temperature range on the order of a few K. For display applications, one very promising way to broaden the stable temperature range is achieved by polymer-stabilization of the Blue Phase. A crucial prerequisite for efficient stabilization is the optimal material selection/matching of reactive mesogens RMs and the chiral host. New material concepts will be introduced and discussed.

Thyroperoxidase (TPO) is a large heme-containing glycoprotein that catalyzes the transfer of iodine to thyroglobulin during thyroid hormone (TH) synthesis. Previously, we established an in vitro assay for TPO activity based on human recombinant TPO (hrTPO) stably transfected into human follicular thyroid carcinoma (FTC-238) cells. It is important to determine whether environmental chemicals can disrupt TPO activity because it is an important factor in the TH axis. In this study, we used our assay to examine the changes in TPO activity in response to various chemicals, including benzophenones (BPs), polycyclic aromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs). Overall, BPs, PAHs, and POPs slightly altered TPO activity at low doses, as compared with the positive controls methimazole (MMI), genistein, and 2,2',4,4'-tetrahydroxy BP. Benzophenone, benzhydrol, 3-methylchloranthracene, pyrene, benzo(k)fluoranthene, benzo(e)pyrene, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and heptachlor decreased TPO activity, while 2,4-dihydroxy BP, 2,2'-dihydroxy-4-methoxy BP, and dibenzo(a,h)anthracene increased TPO activity. From these data, we can predict the disruption of TPO activity by various chemicals as a sensitive TH end point. TPO activity should be considered when enacting measures to regulate environmental exposure to thyroid-disrupting chemicals.

Polyimide containing the chalcone moiety is expected to show the high photodimerization rate and stable alignment characteristics. We introduced the chalcone moiety as a side chain into the polyimide backbone to apply to the photo-alignment layer. The photochemical reaction with the tilted incident light produced out-of -the plane orientation of chalcone side chain. The orientation effects align the LC in LCD, which possesses the various pretilt angles depending on the length of side chains.