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Lu D, Wang Z, Chen Z, Fan J, Zhai J, Fang D, Cai H, Liu X, Wu H, Cai K. Olmesartan Attenuates Single-Lung Ventilation Induced Lung Injury via Regulating Pulmonary Microbiota. Front Pharmacol 2022; 13:822615. [PMID: 35401192 PMCID: PMC8984607 DOI: 10.3389/fphar.2022.822615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Single-lung ventilation (SLV) associated acute lung injury is similar to ischemia reperfusion (IR) injury which is usually occurred during lung surgery. Olmesartan (Olm), a novel angiotensin receptor blocker (ARB), has been reported to ameliorate organ IR injury. Several recent studies have shown that lung microbiota may be involved in pulmonary diseases, but the effect of pulmonary microbiota in SLV-induced lung injury has not been reported. This study aims to determine the mechanism of how Olm attenuates SLV induced lung injury. Our data showed that 7 days Olm treatment before modeling markedly alleviated SLV-induced lung injury by suppressing inflammation and reactive oxygen species. Bronchoalveolar lavage fluid samples from the injured side were collected for 16S rRNA gene-based sequencing analysis and 53 different bacteria at the genus and species levels were identified. Furthermore, the injured lung samples were collected for metabolomics analysis using liquid chromatography-mass spectrometry analyses to explore differential metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze the correlation between differential metabolites and lung microbiota. A total of 38 pathways were identified according to differential metabolites and 275 relevant pathways were enriched via analyzing the microbial community, 24 pathways were both identified by analyzing either metabolites or microbiota, including pyrimidine metabolism, purine metabolism, aminoacyl-tRNA biosynthesis and ATP-binding cassette transporter. Besides classical blockage of the renin-angiotensin II system, Olm could also alleviate SLV-induced lung injury by rewiring the interaction between pulmonary microbiota and metabolites.
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Zamanian Z, Yousefinejad S, Dehghan SF, Rahmani A. Hemato-Biochemical Responses Of Rats Co-Exposed To Heat Stress And Trichloroethylene Vapors. RUSSIAN OPEN MEDICAL JOURNAL 2021. [DOI: 10.15275/rusomj.2021.0405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Aim — The present study was aimed to measure some hemato-biochemical parameters of male Sprague-Dawley rats co-exposed to different levels of heat stress and Trichloroethylene (TCE) exposure. Methods — All male rats were randomly divided into nine equal groups of 5 animals each. They were exposed to heat stress and TCE vapors in a subacute manner (8 hr/day for 10 days) according to experimental design. Blood samples were taken from the heart of all animals at the end of the 10th day of exposure. Hematology and biochemical parameters were determined using the automated hematology analyzer and an automated biochemistry, respectively. Results — The values of WBC, RBC and HB significantly decreased after co-exposure 250 ppm TCE and extreme heat stress; although, this exposure condition lead to statistically significant increase in mean levels of MCV, RDW, ALP, CPK and LDH. Our findings indicated that there were the subtractive and independent interactions for the hematological parameters and the additive, subtractive and independent interactions for biochemical parameters based on the exposure level to trichloroethylene and heat stress. Conclusion — Heat stress may increase sensitivity of workers to trichloroethylene and the simultaneous effects of exposure provide the circumstances for the occurrence of a variety of disorders.
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Prichystalova R, Caron-Beaudoin E, Richardson L, Dirkx E, Amadou A, Zavodna T, Cihak R, Cogliano V, Hynes J, Pelland-St-Pierre L, Verner MA, van Tongeren M, Ho V. An approach to classifying occupational exposures to endocrine disrupting chemicals by sex hormone function using an expert judgment process. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2021; 31:753-768. [PMID: 32704083 DOI: 10.1038/s41370-020-0253-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 06/11/2023]
Abstract
Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the endocrine system and cause adverse effects. We aimed to classify the effects of 24 known EDCs, prevalent in certain occupations, according to four modes of action (estrogenic, antiestrogenic, androgenic, and/or antiandrogenic). A literature search, stratified into four types of literature was conducted (namely: national and international agency reports; review articles; primary studies; ToxCastTM). The state of the evidence of each EDC on sex hormone function was summarized and reviewed by an expert panel. For each mode of action, the experts evaluated the likelihood of endocrine disruption in five categories: "No", "Unlikely", "Possibly", "Probably", and "Yes". Seven agents were categorized as "Yes," or having strong evidence for their effects on sex hormone function (antiandrogenic: lead, arsenic, butylbenzyl phthalate, dibutyl phthalate, dicyclohexyl phthalate; estrogenic: nonylphenol, bisphenol A). Nine agents were categorized as "Probable," or having probable evidence (antiandrogenic: bis(2-ethylhexyl)phthalate, nonylphenol, toluene, bisphenol A, diisononyl phthalate; androgenic: cadmium; estrogenic: copper, cadmium and; anti-estrogenic: lead). Two agents (arsenic, polychlorinated biphenyls) had opposing conclusions supporting both "probably" estrogenic and antiestrogenic effects. This synthesis will allow researchers to evaluate the health effects of selected EDCs with an added level of precision related to the mode of action.
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Affiliation(s)
- R Prichystalova
- Faculty of Safety Engineering, Technical University of Ostrava, Ostrava, Czech Republic
| | - E Caron-Beaudoin
- Department of Occupational and Environmental Health, Université de Montréal, Montréal, QC, Canada
| | - L Richardson
- Centre de recherche du CHUM (CRCHUM), Montréal, QC, Canada
| | - E Dirkx
- Centre de recherche du CHUM (CRCHUM), Montréal, QC, Canada
| | - A Amadou
- Département Prévention Cancer Environnement, Centre Léon Bérard, Lyon, France
- Inserm UA 08 Radiations: Défense, Santé, Environement, Lyon, France
| | - T Zavodna
- Institute of Experimental Medicine of the CAS, Prague, Czech Republic
| | - R Cihak
- Výzkumný ústav organických syntéz a.s., Centre for Ecology, Toxicology and Analytics, Rybitví, Czech Republic
| | - V Cogliano
- National Center for Environmental Health Hazard Assessment, US Environmental Protection Agency, Washington, DC, USA
| | - J Hynes
- JH Tox Consulting, Maastricht, Netherlands
| | - L Pelland-St-Pierre
- Department of Social and Preventive Medicine, Université de Montréal, Montréal, QC, Canada
| | - M A Verner
- Department of Occupational and Environmental Health, Université de Montréal, Montréal, QC, Canada
- Centre de recherche en santé publique (CReSP), Université de Montréal, Montréal, QC, Canada
| | - M van Tongeren
- Faculty of Science and Engineering, Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK
| | - V Ho
- Centre de recherche du CHUM (CRCHUM), Montréal, QC, Canada.
- Department of Social and Preventive Medicine, Université de Montréal, Montréal, QC, Canada.
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Luo YS, Furuya S, Soldatov VY, Kosyk O, Yoo HS, Fukushima H, Lewis L, Iwata Y, Rusyn I. Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene in Cytochrome P450 2E1 Knockout and Humanized Transgenic Mice. Toxicol Sci 2019; 164:489-500. [PMID: 29897530 DOI: 10.1093/toxsci/kfy099] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar olefins that can cause liver and kidney toxicity. Adverse effects of these chemicals are associated with metabolism to oxidative and glutathione conjugation moieties. It is thought that CYP2E1 is crucial to the oxidative metabolism of TCE and PCE, and may also play a role in formation of nephrotoxic metabolites; however, inter-species and inter-individual differences in contribution of CYP2E1 to metabolism and toxicity are not well understood. Therefore, the role of CYP2E1 in metabolism and toxic effects of TCE and PCE was investigated using male and female wild-type [129S1/SvlmJ], Cyp2e1(-/-), and humanized Cyp2e1 [hCYP2E1] mice. To fill in existing gaps in our knowledge, we conducted a toxicokinetic study of TCE (600 mg/kg, single dose, i.g.) and a subacute study of PCE (500 mg/kg/day, 5 days, i.g.) in 3 strains. Liver and kidney tissues were subject to profiling of oxidative and glutathione conjugation metabolites of TCE and PCE, as well as toxicity endpoints. The amounts of trichloroacetic acid formed in the liver was hCYP2E1≈ 129S1/SvlmJ > Cyp2e1(-/-) for both TCE and PCE; levels in males were about 2-fold higher than in females. Interestingly, 2- to 3-fold higher levels of conjugation metabolites were observed in TCE-treated Cyp2e1(-/-) mice. PCE induced lipid accumulation only in liver of 129S1/SvlmJ mice. In the kidney, PCE exposure resulted in acute proximal tubule injury in both sexes in all strains (hCYP2E1 ≈ 129S1/SvlmJ > Cyp2e1(-/-)). In conclusion, our results demonstrate that CYP2E1 is an important, but not exclusive actor in the oxidative metabolism and toxicity of TCE and PCE.
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Affiliation(s)
- Yu-Syuan Luo
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
| | - Shinji Furuya
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
| | - Valerie Y Soldatov
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Oksana Kosyk
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Hong Sik Yoo
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Hisataka Fukushima
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
| | - Lauren Lewis
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
| | - Yasuhiro Iwata
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843
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Liu M, Wang H, Zhang J, Yang X, Li B, Wu C, Zhu Q. NF-κB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice. J Immunotoxicol 2018. [PMID: 29534626 DOI: 10.1080/1547691x.2017.1420712] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Both NF-κB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two systems has not yet been established. The present study aimed to clarify the role of NF-κB in complement activation and renal injury in TCE-sensitized BALB/c mice. Mice were sensitized by an initial subcutaneous injection and repeated focal applications of TCE to dorsal skin at specified timepoints. NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was injected (intraperitoneal) before the final two focal TCE challenges. In the experiments, mice had their blood and kidneys collected. Kidney function was evaluated via blood urea nitrogen (BUN) and creatinine (Cr) content; renal histology was examined using transmission electron microscopy (TEM). Kidney levels of phospho-p65 were assessed by Western blot and kidney mRNA levels of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α, and p65 by real-time quantitative PCR. Presence of C3 and C5b-9 membrane attack complexes in the kidneys was evaluated via immunohistochemistry. The results showed there was significant swelling, vacuolar degeneration in mitochondria, shrinkage of microvilli, disappearance of brush borders, segmental foot process fusion, and glomerular basement membrane thickening (or disrobing) in kidneys from TCE-sensitized mice. In conjunction with these changes, serum BUN and Cr levels were increased and IL-1β, IL-6, IL-17, and TNFα mRNA levels were elevated. Levels of p65 and phospho-p65 protein were also up-regulated, and there was significant C3 and C5b-9 deposition. PDTC pretreatment attenuated TCE-induced up-regulation of p65 and its phosphorylation, complement deposition, cytokine release, and renal damage. These results provide the first evidence that NF-κB pathway has an important role in TCE-induced renal damage mediated by enhanced complement activation in situ.
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Affiliation(s)
- Min Liu
- a Department of Occupational Health and Environment Health (School of Public Health) , Anhui Medical University , Hefei , Anhui , China
| | - Hui Wang
- b Department of Nutrition , Chaohu Hospital of Anhui Medical University , Hefei , Anhui , China.,c Institute of Dermatology , Anhui Medical University , Hefei , Anhui , China
| | - Jiaxiang Zhang
- a Department of Occupational Health and Environment Health (School of Public Health) , Anhui Medical University , Hefei , Anhui , China.,c Institute of Dermatology , Anhui Medical University , Hefei , Anhui , China
| | - Xiaodong Yang
- a Department of Occupational Health and Environment Health (School of Public Health) , Anhui Medical University , Hefei , Anhui , China
| | - Bodong Li
- a Department of Occupational Health and Environment Health (School of Public Health) , Anhui Medical University , Hefei , Anhui , China
| | - Changhao Wu
- d Faculty of Health and Medical Sciences , University of Surrey , Guildford , UK
| | - Qixing Zhu
- c Institute of Dermatology , Anhui Medical University , Hefei , Anhui , China
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Klaunig JE, Li X, Wang Z. Role of xenobiotics in the induction and progression of fatty liver disease. Toxicol Res (Camb) 2018; 7:664-680. [PMID: 30090613 PMCID: PMC6062016 DOI: 10.1039/c7tx00326a] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 05/09/2018] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is a major cause of chronic liver pathology in humans. Fatty liver disease involves the accumulation of hepatocellular fat in hepatocytes that can progress to hepatitis. Steatohepatitis is categorized into alcoholic (ASH) or non-alcoholic (NASH) steatohepatitis based on the etiology of the insult. Both pathologies involve an initial steatosis followed by a progressive inflammation of the liver and eventual hepatic fibrosis (steatohepatitis) and cirrhosis. The involvement of pharmaceuticals and other chemicals in the initiation and progression of fatty liver disease has received increased study. This review will examine not only how xenobiotics initiate hepatic steatosis and steatohepatitis but also how the presence of fatty liver may modify the metabolism and pathologic effects of xenobiotics. The feeding of a high fat diet results in changes in the expression of nuclear receptors that are involved in adaptive and adverse liver effects following xenobiotic exposure. High fat diets also modulate cellular and molecular pathways involved in inflammation, metabolism, oxidative phosphorylation and cell growth. Understanding the role of hepatic steatosis and steatohepatitis on the sequelae of toxic and pathologic changes seen following xenobiotic exposure has importance in defining proper and meaningful human risk characterization of the drugs and other chemical agents.
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Affiliation(s)
- James E Klaunig
- Indiana University , School of Public Health , Bloomington , Indiana , USA .
| | - Xilin Li
- Indiana University , School of Public Health , Bloomington , Indiana , USA .
| | - Zemin Wang
- Indiana University , School of Public Health , Bloomington , Indiana , USA .
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Blossom SJ, Fernandes L, Bai S, Khare S, Gokulan K, Yuan Y, Dewall M, Simmen FA, Gilbert KM. Opposing Actions of Developmental Trichloroethylene and High-Fat Diet Coexposure on Markers of Lipogenesis and Inflammation in Autoimmune-Prone Mice. Toxicol Sci 2018; 164:313-327. [PMID: 29669109 PMCID: PMC6016708 DOI: 10.1093/toxsci/kfy091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Trichloroethylene (TCE) is a widespread environmental pollutant associated with immunotoxicity and autoimmune disease. Previous studies showed that mice exposed from gestation through early life demonstrated CD4+ T cell alterations and autoimmune hepatitis. Determining the role of one environmental risk factor for any disease is complicated by the presence of other stressors. Based on its known effects, we hypothesized that developmental overnutrition in the form of a moderately high-fat diet (HFD) consisting of 40% kcal fat would exacerbate the immunotoxicity and autoimmune-promoting effects of low-level (<10 μg/kg/day) TCE in autoimmune-prone MRL+/+ mice over either stressor alone. When female offspring were evaluated at 27 weeks of age we found that a continuous exposure beginning at 4 weeks preconception in the dams until 10 weeks of age in offspring that TCE and HFD promoted unique effects that were often antagonistic. For a number of adiposity endpoints, TCE significantly reversed the expected effects of HFD on expression of genes involved in fatty acid synthesis/insulin resistance, as well as mean pathology scores of steatosis. Although none of the animals developed pathological signs of autoimmune hepatitis, the mice generated unique patterns of antiliver antibodies detected by western blotting attributable to TCE exposure. A majority of cytokines in liver, gut, and splenic CD4+ T cells were significantly altered by TCE, but not HFD. Levels of bacterial populations in the intestinal ileum were also altered by TCE exposure rather than HFD. Thus, in contrast to our expectations this coexposure did not promote synergistic effects.
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Affiliation(s)
- Sarah J Blossom
- Department of Pediatrics, Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202
| | - Lorenzo Fernandes
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Shasha Bai
- Department of Pediatrics, Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202
| | - Sangeeta Khare
- Division of Microbiology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079
| | - Kuppan Gokulan
- Division of Microbiology, National Center for Toxicological Research, U.S. FDA, Jefferson, Arkansas 72079
| | | | | | - Frank A Simmen
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Kathleen M Gilbert
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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Role of selective blocking of bradykinin B1 receptor in attenuating immune liver injury in trichloroethylene-sensitized mice. Cytokine 2018; 108:71-81. [PMID: 29579546 DOI: 10.1016/j.cyto.2018.03.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 03/02/2018] [Accepted: 03/19/2018] [Indexed: 12/15/2022]
Abstract
Trichloroethylene (TCE) is able to induce trichloroethylene hypersensitivity syndrome (THS) with multi-system immune injuries. In our previous study, we found kallikrein-kinin system (KKS) activation, including the bradykinin B1 receptor (B1R), which contributed to immune organ injury in TCE sensitized mice. However, the mechanism of B1R mediating immune dysfunction is not clarified. The present study initiates to investigate the potential mechanism of B1R on liver injury. We establish a TCE sensitized BALB/c mouse model to explore the mechanism with or without a B1R inhibitor R715. We found B1R expression was increased in TCE sensitization-positive mice. As expect, hepatocyte intracellular organelles and mitochondria disappeared, glycogen particles reduced significantly as well in TCE sensitization-positive mice via the transmission electron microscopic examination, meanwhile, R715 alleviated the deteriorate above. The blockade of B1R resulted in a significant decreased p-ERK1/2 and increased p-AKT expression. The expression of CD68 kupffer cell and its relative cytokine, including IL-6 and TNF-α, increased in TCE sensitization-positive mice and decreased in R715 pretreatment TCE sensitization-positive mice. Together, the results demonstrate B1R plays a key role in ERK/MAPK and PI3K/AKT signal pathway activation and inflammation cytokine expression in immune liver injury induced by TCE. B1R exerts a pivotal role in the development of TCE induced liver injury.
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9
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The effects of methionine on TCE-induced DNA methylation and mRNA expression changes in mouse liver. Mol Cell Toxicol 2017. [DOI: 10.1007/s13273-017-0006-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Ledda C, Loreto C, Zammit C, Marconi A, Fago L, Matera S, Costanzo V, Sanzà GF, Palmucci S, Ferrante M, Costa C, Fenga C, Biondi A, Pomara C, Rapisarda V. Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review). Mol Med Rep 2017; 15:511-533. [PMID: 28000892 PMCID: PMC5364850 DOI: 10.3892/mmr.2016.6046] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/01/2016] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the second leading worldwide cause of cancer‑associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well‑established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non‑infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non‑specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non‑infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Caterina Ledda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Carla Loreto
- Human Anatomy and Histology, Department of Biomedical and Biotechnology Sciences, University of Catania, I-95123 Catania, Italy
| | - Christian Zammit
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
| | - Andrea Marconi
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Lucrezia Fago
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Serena Matera
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Valentina Costanzo
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
| | - Giovanni Fuccio Sanzà
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Stefano Palmucci
- Division of Radiology, ‘Policlinico-Vittorio Emanuele’ University Hospital, University of Catania, I-95123 Catania, Italy
| | - Margherita Ferrante
- Hygiene and Public Health, Department of Medical Sciences, Surgical and Advanced Technologies ‘GF Ingrassia’, University of Catania, I-95123 Catania, Italy
| | - Chiara Costa
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Concettina Fenga
- Occupational Medicine, Department of the Environment, Safety, Territory, Food and Health Sciences, University of Messina, I-98125 Messina, Italy
| | - Antonio Biondi
- General Surgery, Department of General Surgery and Medical-Surgical Specialties, University of Catania, I-95123 Catania, Italy
| | - Cristoforo Pomara
- Anatomy Department, Faculty of Medicine and Surgery, University of Malta, MSD-2080 Msida, Malta
- Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, I-71122 Foggia, Italy
| | - Venerando Rapisarda
- Occupational Medicine, Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania, Italy
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11
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Cichocki JA, Guyton KZ, Guha N, Chiu WA, Rusyn I, Lash LH. Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps. J Pharmacol Exp Ther 2016; 359:110-23. [PMID: 27511820 PMCID: PMC5034707 DOI: 10.1124/jpet.116.232629] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 08/09/2016] [Indexed: 01/18/2023] Open
Abstract
Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure.
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Affiliation(s)
- Joseph A Cichocki
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
| | - Kathryn Z Guyton
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
| | - Neela Guha
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
| | - Weihsueh A Chiu
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
| | - Lawrence H Lash
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas (J.A.C., W.A.C., I.R.); International Agency for Research on Cancer, Lyon, France (K.Z.G., N.G.); Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan (L.H.L.)
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12
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Yanagiba Y, Suda M, Toyooka T, Wang RS. [Chemical management and occupational cholangiocarcinoma among workers in printing industry]. SANGYO EISEIGAKU ZASSHI = JOURNAL OF OCCUPATIONAL HEALTH 2016; 58:78-83. [PMID: 26983494 DOI: 10.1539/sangyoeisei.wadai15005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
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13
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Rapisarda V, Loreto C, Malaguarnera M, Ardiri A, Proiti M, Rigano G, Frazzetto E, Ruggeri MI, Malaguarnera G, Bertino N, Malaguarnera M, Catania VE, Di Carlo I, Toro A, Bertino E, Mangano D, Bertino G. Hepatocellular carcinoma and the risk of occupational exposure. World J Hepatol 2016; 8:573-90. [PMID: 27168870 PMCID: PMC4858622 DOI: 10.4254/wjh.v8.i13.573] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 04/01/2016] [Accepted: 04/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.
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Affiliation(s)
- Venerando Rapisarda
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Carla Loreto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Michele Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Annalisa Ardiri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Proiti
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giuseppe Rigano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Evelise Frazzetto
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Maria Irene Ruggeri
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Nicoletta Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Mariano Malaguarnera
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Vito Emanuele Catania
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Isidoro Di Carlo
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Adriana Toro
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Emanuele Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Dario Mangano
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Gaetano Bertino
- Venerando Rapisarda, Dario Mangano, Occupational Medi-cine Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
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Tamada H, Naito H, Kitamori K, Hayashi Y, Yamagishi N, Kato M, Nakajima T. Efficacy of Dietary Lipid Control in Healing High-Fat and High-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats. PLoS One 2016; 11:e0145939. [PMID: 26727365 PMCID: PMC4699821 DOI: 10.1371/journal.pone.0145939] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/10/2015] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic steatohepatitis is related to lifestyle, particularly to dietary habits. We developed diet-induced fibrotic steatohepatitis model stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats showing steatosis, hepatic inflammation, and severe fibrosis induced by high-fat and -cholesterol (HFC) diet feeding. We aimed to clarify the efficacy of dietary intervention on the disease before and after the appearance of fibrosis. Male SHRSP5/Dmcr rats were divided into 9 groups; of these, 6 groups were fed control or HFC diet for several weeks and the remaining 3 groups represented the dietary intervention groups, which were fed the control diet after HFC diet feeding for 2 (before the appearance of fibrosis) or 8 (after the appearance of fibrosis) weeks. Dietary intervention before the appearance of fibrosis significantly improved the steatosis and reset the increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum total cholesterol (TC) levels. However, dietary intervention after the appearance of fibrosis was unable to reset the levels of hepatic TC, serum ALT, and fibrogenesis-related markers and had only a minor influence on hepatic fibrosis, although it reset the increased expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). It was noted that dietary intervention improved the increased AST levels; however, aggregated CD68-positive cells were still observed around the fibrosis area, which may be related to the findings of inflammatory cytokine mRNAs. Taken together, dietary intervention for fibrotic steatohepatitis improved steatosis, although it could not completely improve fibrosis.
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Affiliation(s)
- Hazuki Tamada
- Department of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Nagoya, Japan
| | - Kazuya Kitamori
- Department of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Yumi Hayashi
- Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nozomi Yamagishi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masashi Kato
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
- * E-mail:
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15
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Yoo HS, Cichocki JA, Kim S, Venkatratnam A, Iwata Y, Kosyk O, Bodnar W, Sweet S, Knap A, Wade T, Campbell J, Clewell HJ, Melnyk SB, Chiu WA, Rusyn I. The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene. Toxicol Sci 2015; 147:339-49. [PMID: 26136231 DOI: 10.1093/toxsci/kfv134] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects.
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Affiliation(s)
- Hong Sik Yoo
- *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina
| | - Joseph A Cichocki
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Sungkyoon Kim
- Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Abhishek Venkatratnam
- *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina; Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Yasuhiro Iwata
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Oksana Kosyk
- *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina
| | - Wanda Bodnar
- *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina
| | - Stephen Sweet
- Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas
| | - Anthony Knap
- Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas
| | - Terry Wade
- Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas
| | - Jerry Campbell
- The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina; and
| | - Harvey J Clewell
- The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina; and
| | - Stepan B Melnyk
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Weihsueh A Chiu
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA;
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16
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Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver. PLoS One 2014; 9:e116179. [PMID: 25549359 PMCID: PMC4280179 DOI: 10.1371/journal.pone.0116179] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 12/03/2014] [Indexed: 12/31/2022] Open
Abstract
Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.
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Jiang Y, Chen J, Tong J, Chen T. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver. PLoS One 2014. [PMID: 25549359 DOI: 10.1371/-journal.pone.0116179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.
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Affiliation(s)
- Yan Jiang
- Department of Physiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Jiahong Chen
- Department of Toxicology, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Jian Tong
- Department of Toxicology, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Tao Chen
- Department of Toxicology, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
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Wang Y, Borlak J, Tong W. Toxicogenomics – A Drug Development Perspective. GENOMIC BIOMARKERS FOR PHARMACEUTICAL DEVELOPMENT 2014:127-155. [DOI: 10.1016/b978-0-12-397336-8.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Arciello M, Gori M, Maggio R, Barbaro B, Tarocchi M, Galli A, Balsano C. Environmental pollution: a tangible risk for NAFLD pathogenesis. Int J Mol Sci 2013; 14:22052-22066. [PMID: 24213605 PMCID: PMC3856051 DOI: 10.3390/ijms141122052] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/18/2013] [Accepted: 10/24/2013] [Indexed: 12/13/2022] Open
Abstract
The liver is crucial for human life, and the health of this organ often mirrors the health of the individual. The liver can be the target of several diseases, the most prevalent of which, as a consequence of development and changes in human lifestyles, is the nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease that embraces many histo-pathologic conditions and is highly linked to metabolic derangements. Technological progress and industrialization have also had the consequence of releasing pollutants in the environment, for instance pesticides or solvents, as well as by-products of discharge, such as the particulate matter. In the last decade, a growing body of evidence has emerged, shedding light on the potential impact of environmental pollutants on liver health and, in particular, on NAFLD occurrence. These contaminants have a great steatogenic potential and need to be considered as tangible NAFLD risk factors. There is an urgent need for a deeper comprehension of their molecular mechanisms of action, as well as for new lines of intervention to reduce their worldwide diffusion. This review wishes to sensitize the community to the effects of several environmental pollutants on liver health.
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Affiliation(s)
- Mario Arciello
- Francesco Balsano Foundation, via G.B. Martini 6, Rome 00198, Italy; E-Mails: (M.A.); (M.G.); (R.M.); (B.B.)
| | - Manuele Gori
- Francesco Balsano Foundation, via G.B. Martini 6, Rome 00198, Italy; E-Mails: (M.A.); (M.G.); (R.M.); (B.B.)
- Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Via Tronto 10, Ancona 60020, Italy
| | - Roberta Maggio
- Francesco Balsano Foundation, via G.B. Martini 6, Rome 00198, Italy; E-Mails: (M.A.); (M.G.); (R.M.); (B.B.)
| | - Barbara Barbaro
- Francesco Balsano Foundation, via G.B. Martini 6, Rome 00198, Italy; E-Mails: (M.A.); (M.G.); (R.M.); (B.B.)
| | - Mirko Tarocchi
- Gastroenterology Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Viale Pieraccini 6, Florence 50139, Italy; E-Mails: (M.T.); (A.G.)
| | - Andrea Galli
- Gastroenterology Unit, Department of Experimental and Clinical Biochemical Sciences, University of Florence, Viale Pieraccini 6, Florence 50139, Italy; E-Mails: (M.T.); (A.G.)
| | - Clara Balsano
- Francesco Balsano Foundation, via G.B. Martini 6, Rome 00198, Italy; E-Mails: (M.A.); (M.G.); (R.M.); (B.B.)
- Institute of Molecular Biology and Pathology (IBPM)-National Research Council (CNR), Piazzale Aldo Moro 7, Rome 00185, Italy
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Zhang J, Zha W, Wang F, Jiang T, Xu S, Yu J, Zhou C, Shen T, Wu C, Zhu Q. Complement Activation and Liver Impairment in Trichloroethylene-Sensitized BALB/c Mice. Int J Toxicol 2013; 32:431-41. [DOI: 10.1177/1091581813511337] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Our recent studies have shown that trichloroethylene (TCE) was able to induce multisystem injuries in the form of occupational medicamentosa-like dermatitis, including skin, kidney, and liver damages. However, the role of complement activation in the immune-mediated liver injury is not known. This study examined the role of complement activation in the liver injury in a mouse model of TCE-induced sensitization. Treatment of female BALB/c mice with TCE under specific dosing protocols resulted in skin inflammation and sensitization. Skin edema and erythema occurred in TCE-sensitized groups. Trichloroethylene sensitization produced liver histopathological lesions, increased serum alanine aminotransferase, aspartate transaminase activities, and the relative liver weight. The concentrations of serum complement components C3a-desArg, C5a-desArg, and C5b-9 were significantly increased in 24-hour, 48-hour, and 72-hour sensitization-positive groups treated with TCE and peaked in the 72-hour sensitization-positive group. Depositions of C3a, C5a, and C5b-9 into the liver tissue were also revealed by immunohistochemistry. Immunofluorescence further verified high C5b-9 expression in 24-hour, 48-hour, and 72-hour sensitization-positive groups in response to TCE treatment. Reverse transcription–polymerase chain reaction detected C3 messenger RNA expression in the liver, and this was significantly increased in 24-hour and 48-hour sensitization-positive groups with a transient reduction at 72 hours. These results provide the first experimental evidence that complement activation may play a key role in the generation and progression of immune-mediated hepatic injury by exposure to TCE.
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Affiliation(s)
- Jiaxiang Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Wansheng Zha
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Feng Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Tao Jiang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Shuhai Xu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Junfeng Yu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Chengfan Zhou
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Tong Shen
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Changhao Wu
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Qixing Zhu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, People’s Republic of China
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Hibino Y, Wang H, Naito H, Zhao N, Wang D, Jia X, Li H, Song X, Liu L, Huang Y, Ito Y, Huang H, Kamijima M, Nakajima T. Sex differences in metabolism of trichloroethylene and trichloroethanol in guinea pigs. J Occup Health 2013; 55:443-9. [PMID: 24025858 DOI: 10.1539/joh.13-0091-oa] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Trichloroethylene (TRI) has the potential to cause generalized dermatitis complicated with hepatitis. The guinea pig maximization test (GPMT) also suggests that both TRI and its metabolite trichloroethanol (TCE) exhibit immunogenicity and possible sex differences in guinea pigs. However, TRI and TCE metabolisms in guinea pigs have not been elucidated in detail. The first issue to clarify may be the sex differences in relation to the immunogenicity. METHODS We collected urine from Hartley male and female guinea pigs 24 hours after intracutaneous injection of TRI, TCE or trichloroacetic acid (TCA) during a GPMT and measured the urinary metabolites by gas chromatography-mass spectrometry. RESULTS After TRI treatment, the amount of TCA was significantly greater in females than males, while there was no sex difference in the total amount (TCA + TCE). TCA was only detected in urine after TCA treatment. Interestingly, not only TCE but also TCA was detected in urine of both sexes after TCE treatment, and the amount of TCA was also greater in females than males. An additional experiment showed that TCE treatment did not result in the detection of urinary TCA in cytochrome P450 (CYP)2E1-null mice TCEbut did in wild-type mice, suggesting the involvement of CYP2E1 in the metabolism from TCE to TCA. The constitutive expression of CYP2E1 in the liver of guinea pigs was greater in females than males. CONCLUSIONS The sex difference in urinary TCA excretion after TRI and TCE treatments may be due to variation of the constitutive expression of CYP2E1.
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Affiliation(s)
- Yui Hibino
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine
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Fang ZZ, Krausz KW, Tanaka N, Li F, Qu A, Idle JR, Gonzalez FJ. Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum. Arch Toxicol 2013; 87:1975-1987. [PMID: 23575800 DOI: 10.1007/s00204-013-1053-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 03/26/2013] [Indexed: 01/14/2023]
Abstract
Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor α (PPARα). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPARα target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPARα target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum.
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Affiliation(s)
- Zhong-Ze Fang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Naoki Tanaka
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Fei Li
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Aijuan Qu
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Jeffrey R Idle
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
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Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, Cave MC. Toxicant-associated steatohepatitis. Toxicol Pathol 2013; 41:343-60. [PMID: 23262638 PMCID: PMC5114851 DOI: 10.1177/0192623312468517] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.
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Affiliation(s)
- Banrida Wahlang
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Juliane I. Beier
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather B. Clair
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather J. Bellis-Jones
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - K. Cameron Falkner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Craig J. McClain
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
| | - Matt C. Cave
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
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Jia X, Naito H, Yetti H, Tamada H, Kitamori K, Hayashi Y, Wang D, Yanagiba Y, Wang J, Ikeda K, Yamori Y, Nakajima T. Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats. Dig Dis Sci 2013; 58:2212-22. [PMID: 23824403 PMCID: PMC3731517 DOI: 10.1007/s10620-013-2747-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 06/05/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified. METHODS Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet. RESULTS Unlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor. CONCLUSIONS The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.
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Affiliation(s)
- Xiaofang Jia
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Hisao Naito
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Husna Yetti
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Hazuki Tamada
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan ,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, 463-8521 Japan
| | - Kazuya Kitamori
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan ,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, 463-8521 Japan
| | - Yumi Hayashi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Dong Wang
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Yukie Yanagiba
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Juncai Wang
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan
| | - Katsumi Ikeda
- School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, Nishinomiya, 663-8179 Japan
| | - Yukio Yamori
- Institute for World Health Development, Mukogawa Women’s University, Nishinomiya, 663-8143 Japan
| | - Tamie Nakajima
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550 Japan ,College of Life and Health Sciences, Chubu University, Kasugai, 487-8501 Japan
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Caldwell JC. DEHP: Genotoxicity and potential carcinogenic mechanisms—A review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2012; 751:82-157. [DOI: 10.1016/j.mrrev.2012.03.001] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 03/22/2012] [Accepted: 03/22/2012] [Indexed: 10/28/2022]
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Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver. PPAR Res 2012; 2012:201284. [PMID: 22792086 PMCID: PMC3388330 DOI: 10.1155/2012/201284] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 03/19/2012] [Accepted: 03/21/2012] [Indexed: 12/05/2022] Open
Abstract
Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR) α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα) and humanized PPARα (hPPARα) mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control), 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg), DEHP (977, 1953 mg/kg), and DEHA (926, 1853 mg/kg), respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR.
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The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model. Life Sci 2012; 90:934-43. [PMID: 22569299 DOI: 10.1016/j.lfs.2012.04.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 04/17/2012] [Accepted: 04/21/2012] [Indexed: 11/24/2022]
Abstract
AIMS Eicosapentaenoic acid (EPA) can ameliorate certain liver lesions involved in non-alcoholic steatohepatitis (NASH). A previous study has found that stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats fed a high fat-cholesterol (HFC) diet developed fibrotic steatohepatitis with histological similarities to NASH. This study evaluated the potential effects and mechanisms of action of EPA supplementation using this rodent model. MAIN METHODS Male rats were randomly assigned to groups that were fed with either the stroke-prone (SP) diet or HFC diet with or without EPA for 2, 8 and 14 weeks, respectively. The liver histopathology, biochemical features, mRNA and protein levels, and nuclear factor-κB (NF-κB) DNA binding activity were determined. KEY FINDINGS The SP diet-fed rats presented normal livers. Conversely, the HFC diet-fed rats developed microvesicular/macrovesicular steatosis, inflammation, ballooning degeneration and severe fibrosis. At 2 weeks, the administration of EPA inhibited hepatic inflammatory recruitment by blocking the phosphorylation of inhibitor of κB-α (IκBα), which antagonizes the NF-κB activation pathway. The dietary supplementation of EPA for 8 weeks ameliorated hepatic triglyceride accumulation and macrovesicular steatosis by inhibiting the HFC diet-induced decrease in the protein levels of enzymes involved in fatty acid β-oxidation including carnitine palmitoyltransferase 1, very long chain acyl-CoA dehydrogenase and peroxisomal bifunctional protein. Although the administration of EPA elicited no histologically detectable effects on severe fibrosis at 14 weeks, it restored an HFC diet-induced decline in hepatic adenosine triphosphate (ATP) levels and suppressed ballooning degeneration, suggesting that EPA may inhibit HFC diet-induced ATP loss and cell death. SIGNIFICANCE Initial amelioration of the inflammation and steatosis in the rats after EPA supplementation indicates a possibility to treat steatohepatitis. Additionally, this study provides new insights into the roles of EPA in hepatic ATP depletion and subsequent hepatocellular injury during severe fibrosis.
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28
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Current World Literature. Curr Opin Nephrol Hypertens 2012; 21:106-18. [DOI: 10.1097/mnh.0b013e32834ee42b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Rusyn I, Corton JC. Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl) phthalate. Mutat Res 2011; 750:141-158. [PMID: 22198209 DOI: 10.1016/j.mrrev.2011.12.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 12/06/2011] [Accepted: 12/12/2011] [Indexed: 12/28/2022]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator agent that is widely used as a plasticizer to soften polyvinylchloride plastics and non-polymers. Both occupational (e.g., by inhalation during its manufacture and use as a plasticizer of polyvinylchloride) and environmental (medical devices, contamination of food, or intake from air, water and soil) routes of exposure to DEHP are of concern for human health. There is sufficient evidence for carcinogenicity of DEHP in the liver in both rats and mice; however, there is little epidemiological evidence on possible associations between exposure to DEHP and liver cancer in humans. Data are available to suggest that liver is not the only target tissue for DEHP-associated toxicity and carcinogenicity in both humans and rodents. The debate regarding human relevance of the findings in rats or mice has been informed by studies on the mechanisms of carcinogenesis of the peroxisome proliferator class of chemicals, including DEHP. Important additional mechanistic information became available in the past decade, including, but not limited to, sub-acute, sub-chronic and chronic studies with DEHP in peroxisome proliferator-activated receptor (PPAR) α-null mice, as well as experiments utilizing several transgenic mouse lines. Activation of PPARα and the subsequent downstream events mediated by this transcription factor represent an important mechanism of action for DEHP in rats and mice. However, additional data from animal models and studies in humans exposed to DEHP from the environment suggest that multiple molecular signals and pathways in several cell types in the liver, rather than a single molecular event, contribute to the cancer in rats and mice. In addition, the toxic and carcinogenic effects of DEHP are not limited to liver. The International Agency for Research on Cancer working group concluded that the human relevance of the molecular events leading to cancer elicited by DEHP in several target tissues (e.g., liver and testis) in rats and mice can not be ruled out and DEHP was classified as possibly carcinogenic to humans (Group 2B).
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Affiliation(s)
- Ivan Rusyn
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431, USA.
| | - J Christopher Corton
- Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA
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Nakagawa T, Ramdhan DH, Tanaka N, Naito H, Tamada H, Ito Y, Li Y, Hayashi Y, Yamagishi N, Yanagiba Y, Aoyama T, Gonzalez FJ, Nakajima T. Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice. Arch Toxicol 2011; 86:63-74. [PMID: 21499893 DOI: 10.1007/s00204-011-0704-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Accepted: 03/31/2011] [Indexed: 01/12/2023]
Abstract
Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPARα). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARα, but not human PPARα. This study aimed to clarify whether milligram-order APFO can activate human PPARα, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0 mg/kg APFO for 6 weeks, orally, respectively. Both doses activated mouse and human PPARα to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Pparα-null and hPPARα mice, but conversely decreased those in mPPARα ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Pparα-null mice; and microvesicular steatosis and hydropic degenerations in hPPARα and Pparα-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPARα, β- and ω-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPARα in a different manner, which may reflect histopathologically different types of hepatic damage.
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Affiliation(s)
- Tomohiko Nakagawa
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Showa-ku, Aichi, Japan
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31
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Bradford BU, Lock EF, Kosyk O, Kim S, Uehara T, Harbourt D, DeSimone M, Threadgill DW, Tryndyak V, Pogribny IP, Bleyle L, Koop DR, Rusyn I. Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice. Toxicol Sci 2011; 120:206-17. [PMID: 21135412 PMCID: PMC3044200 DOI: 10.1093/toxsci/kfq362] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 11/17/2010] [Indexed: 12/11/2022] Open
Abstract
Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be uncovered by exploring responses to TCE using a diverse panel of inbred mouse strains. TCE (2100 mg/kg) or corn oil vehicle was administered by gavage to 6- to 8-week-old male mice of 15 mouse strains. Serum and liver were collected at 2, 8, and 24 h postdosing and were analyzed for TCE metabolites, hepatocellular injury, and gene expression of liver. TCE metabolism, as evident from the levels of individual oxidative and conjugative metabolites, varied considerably between strains. TCE treatment-specific effect on the liver transcriptome was strongly dependent on genetic background. Peroxisome proliferator-activated receptor-mediated molecular networks, consisting of the metabolism genes known to be induced by TCE, represent some of the most pronounced molecular effects of TCE treatment in mouse liver that are dependent on genetic background. Conversely, cell death, liver necrosis, and immune-mediated response pathways, which are altered by TCE treatment in liver, are largely genetic background independent. These studies provide better understanding of the mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that may define susceptibility or resistance.
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Affiliation(s)
| | - Eric F. Lock
- Department of Statistics and Operations Research, and
| | - Oksana Kosyk
- Department of Environmental Sciences and Engineering
| | - Sungkyoon Kim
- Department of Environmental Sciences and Engineering
| | - Takeki Uehara
- Department of Environmental Sciences and Engineering
| | - David Harbourt
- Department of Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Michelle DeSimone
- Department of Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599
| | - David W. Threadgill
- Department of Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599
- Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695
| | | | - Igor P. Pogribny
- National Center for Toxicological Research, Jefferson, Arkansas 72079
| | - Lisa Bleyle
- Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239
| | - Dennis R. Koop
- Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239
| | - Ivan Rusyn
- Department of Environmental Sciences and Engineering
- Department of Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599
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Hayashi Y, Ito Y, Yamagishi N, Yanagiba Y, Tamada H, Wang D, Ramdhan DH, Naito H, Harada Y, Kamijima M, Gonzales FJ, Nakajima T. Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice. Toxicology 2011; 289:1-10. [PMID: 21354252 DOI: 10.1016/j.tox.2011.02.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 02/18/2011] [Accepted: 02/18/2011] [Indexed: 02/02/2023]
Abstract
Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) α, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPARα. Male and female Sv/129 wild-type (mPPARα), Pparα-null and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPARα mice. In hPPARα mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPARα and at the high dose in hPPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPARα mice, but not in Pparα-null and hPPARα ones. Above the medium dose in mPPARα mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium- and/or high-dose DEHP increased the levels of maternal PPARα target genes in mPPARα and hPPARα mice. Taken together, PPARα expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPARα mice and not in hPPARα mice.
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Affiliation(s)
- Yumi Hayashi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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