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      Di(2-ethylhexyl) phthalate-induced toxicity and peroxisome proliferator-activated receptor alpha: a review

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          Abstract

          The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.

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          Peroxisome proliferator-activated receptor alpha target genes.

          Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that belong to the superfamily of nuclear hormone receptors. They mediate the effects of small lipophilic compounds such as long-chain fatty acids and their derivatives on transcription of genes commonly called PPAR target genes. Here we review the involvement of PPARalpha in peroxisomal and mitochondrial fatty acid oxidation, microsomal fatty acid hydroxylation, lipoprotein, bile and amino acid metabolism, glucose homeostasis, biotransformation, inflammation control, hepato-carcinogenesis and other pathways, through a detailed analysis of the different known or putative PPARalpha target genes.
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            Identification of polymer types and additives in marine microplastic particles using pyrolysis-GC/MS and scanning electron microscopy

            Any assessment of plastic contamination in the marine environment requires knowledge of the polymer type and the additive content of microplastics. Sequential pyrolysis-gas chromatography coupled to mass spectrometry (Pyr-GC/MS) was applied to simultaneously identify polymer types of microplastic particles and associated organic plastic additives (OPAs). In addition, a scanning electron microscope equipped with an energy-dispersive X-ray microanalyser was used to identify the inorganic plastic additives (IPAs) contained in these particles. A total of ten particles, which were optically identified as potentially being plastics, were extracted from two sediment samples collected from Norderney, a North Sea island, by density separation in sodium chloride. The weights of these blue, white and transparent fragments varied between 10 and 350 μg. Polymer types were identified by comparing the resulting pyrograms with those obtained from the pyrolysis of selected standard polymers. The particles consisted of polyethylene (PE), polypropylene, polystyrene, polyamide, chlorinated PE and chlorosulfonated PE. The polymers contained diethylhexyl phthalate, dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, dimethyl phthalate, benzaldehyde and 2,4-di-tert-butylphenol. Sequential Py-GC/MS was found to be an appropriate tool for identifying marine microplastics for polymer types and OPAs. The IPAs identified were titanium dioxide nanoparticles (TiO2-NPs), barium, sulphur and zinc. When polymer-TiO2 composites are degraded in the marine environment, TiO2-NPs are probably released. Thus, marine microplastics may act as a TiO2-NP source, which has not yet been considered.
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              Inflammation and cancer

              Infection and inflammation account for approximately 25% of cancer-causing factors. Inflammation-related cancers are characterized by mutagenic DNA lesions, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and 8-nitroguanine. Our previous studies demonstrated the formation of 8-oxodG and 8-nitroguanine in the tissues of cancer and precancerous lesions due to infection (e.g., Opisthorchis viverrini-related cholangiocarcinoma, Schistosoma haematobium-associated bladder cancer, Helicobacter pylori-infected gastric cancer, human papillomavirus-related cervical cancer, Epstein-Barr virus-infected nasopharyngeal carcinoma) and pro-inflammatory factors (e.g., asbestos, nanomaterials, and inflammatory diseases such as Barrett’s esophagus and oral leukoplakia). Interestingly, several of our studies suggested that inflammation-associated DNA damage in cancer stem-like cells leads to cancer development with aggressive clinical features. Reactive oxygen/nitrogen species from inflammation damage not only DNA but also other biomacromolecules, such as proteins and lipids, resulting in their dysfunction. We identified oxidatively damaged proteins in cancer tissues by 2D Oxyblot followed by MALDI-TOF/TOF. As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species. Dysfunction of anti-oxidative proteins due to this damage might increase oxidative stress. Such damage in biomacromolecules may form a vicious cycle of oxidative stress, leading to cancer development. Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers. We examined epigenetic alterations, DNA methylation and microRNA dysregulation, in Epstein-Barr virus-related nasopharyngeal carcinoma in the endemic area of Southern China and found several differentially methylated tumor suppressor gene candidates by using a next-generation sequencer. Among these candidates, we revealed higher methylation rates of RAS-like estrogen-regulated growth inhibitor (RERG) in biopsy specimens of nasopharyngeal carcinoma more conveniently by using restriction enzyme-based real-time PCR. This result may help to improve cancer screening strategies. We profiled microRNAs of nasopharyngeal carcinoma tissues using microarrays. Quantitative RT-PCR analysis confirmed the concordant downregulation of miR-497 in cancer tissues and plasma, suggesting that plasma miR-497 could be used as a diagnostic biomarker for nasopharyngeal carcinoma. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses. These changes may be useful biomarkers in liquid biopsy for early detection and prevention of cancer.
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                Author and article information

                Contributors
                yukey@med.nagoya-cu.ac.jp
                kamijima@med.nagoya-cu.ac.jp
                tnasu23@med.nagoya-u.ac.jp
                Journal
                Environ Health Prev Med
                Environ Health Prev Med
                Environmental Health and Preventive Medicine
                BioMed Central (London )
                1342-078X
                1347-4715
                6 July 2019
                6 July 2019
                2019
                : 24
                : 47
                Affiliations
                [1 ]ISNI 0000 0001 0728 1069, GRID grid.260433.0, Department of Occupational and Environmental Health, , Nagoya City University Graduate School of Medical Sciences, ; Nagoya, 467-8601 Japan
                [2 ]ISNI 0000 0000 8868 2202, GRID grid.254217.7, College of Life and Health Sciences, , Chubu University, ; 1200 Matsumoto-cho, Kasugai, Aichi 487-8501 Japan
                Author information
                http://orcid.org/0000-0003-1617-1595
                Article
                802
                10.1186/s12199-019-0802-z
                6612219
                31279339
                7a16e22d-0c6c-4807-8f0d-9f1ae74bac51
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 March 2019
                : 28 June 2019
                Funding
                Funded by: Japan Society for the Promotion of Science
                Award ID: B. 14370121, B. 17390169
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science
                Award ID: C.25460808
                Award Recipient :
                Funded by: Health and Labor Sciences Research Grants from the Ministry of Health Labour and Welfare, Japan
                Award ID: 200939055A
                Award Recipient :
                Funded by: Grants-in-Aid from Food Safety Commission, Japan
                Award ID: No. 1002
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2019

                Occupational & Environmental medicine
                di(2-ethylhexyl) phthalate,carcinogenesis,reproductive toxicity,developmental toxicity,science policy

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