五氯酚是一種過去常用在工業、農業及家庭環境中的抑黴劑、除草劑、殺蟲劑以及抗菌劑。工業級的五氯酚含有多氯聯苯戴奧辛以及多氯聯苯呋喃，具有免疫抑制的影響，並且免疫系統也是多氯聯苯戴奧辛/多氯聯苯呋喃的主要標的。雖然暴露五氯酚或是四氯聯苯戴奧辛對免疫反應的影響已經被研究過，但是共暴露五氯酚以及四氯聯苯戴奧辛造成的毒性影響仍然沒有被報導過。四氯對苯二酚被認為是五氯酚引起的活性氧物種所造成基因毒性的主要原因。然而，五氯酚與四氯對苯二酚引起的免疫毒性影響之機制仍然是不清楚的。此研究的其一目的是評估小鼠經腹腔注射卵白蛋白致敏化後，透過胃管灌食法單獨暴露五氯酚或四氯聯苯戴奧辛以及五氯酚合併暴露四氯聯苯戴奧辛對小鼠的免疫細胞之影響(part I study)。其二目的是檢驗五氯酚以及四氯對苯二酚引起脾臟細胞的活性氧物種產生以及對脾臟細胞的傷害(part II study)。在part I study，於第7天以及第14天取出脾臟及血漿樣品作免疫毒性評估。結果指出單獨暴露四氯聯苯戴奧辛的小鼠脾臟/體重比以及脾臟細胞數量減少，合併處理五氯酚則會降低減少的程度。單獨或合併暴露四氯聯苯戴奧辛皆會抑制卵白蛋白誘發的細胞激素，包括IL-2、 IFN-γ、IL-4、IL-5以及IL-10。此外，單獨暴露五氯酚會抑制免疫球蛋白IgG及IgM，而四氯聯苯戴奧辛的抑制影響比五氯酚更大。共同暴露五氯酚及暴露四氯聯苯戴奧辛的組別則發現五氯酚能拮抗四氯聯苯戴奧辛引起的IFN-γ和IL-10抑制。Part II study的研究結果則指出，對於脾臟細胞，四氯對苯二酚的毒性大於五氯酚並且高劑量的四氯對苯二酚會透過引起大量的活性氧物種誘發持續性的ERK磷酸化表現，最後導致細胞壞死性死亡。利用N-acetyl-cysteine抑制活性氧物種生成可部分恢復粒線體膜電位、抑制ERK磷酸化、提升caspase-3活性及PARP cleavage，最後使細胞壞死轉成細胞凋亡。因此，本研究證實五氯酚，不需四氯聯苯戴奧辛存在，即具有免疫毒性，並且五氯酚能拮抗四氯聯苯戴奧辛引起的IFN-γ抑制。研究結果也指出，持續活化的ERK對於四氯對苯二酚引起的細胞懷死是必需的，並且活性氧物種在四氯對苯二酚引起不同的細胞死亡機制中扮演重要的角色。

Pentachlorophenol (PCP) was a commonly used fungicide, herbicide, insecticide, and bactericide in industrial, agricultural, and domestic settings. Technical grade PCP, which was with contaminated with polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), had immunosuppressive effects and that the immune system was the major target of PCDD/PCDFs toxicity. Although the immune response after exposure to PCP or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been studied, the immunotoxic effects of exposure to both PCP and TCDD have not yet been reported. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant species (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to evaluate the effects on immune cells from mice intraperitoneally immunized with ovalbumin (OVA) and subsequently treated with PCP or TCDD alone or in combination by gavage (part I study) and to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes (part II study). In part I study, the animals were terminated on Day 7 and 14, and the spleen and plasma samples were collected for immunotoxicity evaluation. The results indicate that the spleen/body weight ratio and splenocyte number was reduced by TCDD alone and this reduction was enhanced when TCDD was combined with PCP. Exposure to TCDD alone or in conjunction with PCP suppressed many OVA-stimulated cytokines, including IL-2, IFN-γ, IL-4, IL-5, and IL-10. Furthermore, the immunoglobulins IgG and IgM were suppressed in mice administered by PCP alone, but the suppressive effects were greater in mice treated with TCDD alone or in combination with PCP. Co-exposure to PCP and TCDD resulted in an antagonistic effect on TCDD-induced suppression of IFN-γ and IL-10. In part II study, our results indicated that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. Thus, this study demonstrates that PCP alone, regardless of the presence of TCDD, is immunotoxic and TCDD-induced IFN-γ suppression can be antagonized by PCP. The results in this study also indicated that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.

Ahlborg UG, Lindgren JE, Mercier M (1974) Metabolism of pentachlorophenol. Archives of toxicology 32(4):271-81
Ahlborg UG, Thunberg TM (1980) Chlorinated phenols: occurrence, toxicity, metabolism, and environmental impact. Critical reviews in toxicology 7(1):1-35 doi:10.3109/10408448009017934
Akhiani AA, Werlenius O, Aurelius J, et al. (2014) Role of the ERK pathway for oxidant-induced parthanatos in human lymphocytes. PloS one 9(2):e89646 doi:10.1371/journal.pone.0089646
Akool el S, Gauer S, Osman B, et al. (2012) Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling. Biochemical pharmacology 83(2):286-95 doi:10.1016/j.bcp.2011.11.001
Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI (2000) N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport 11(11):2491-3
Appelt U, Sheriff A, Gaipl US, Kalden JR, Voll RE, Herrmann M (2005) Viable, apoptotic and necrotic monocytes expose phosphatidylserine: cooperative binding of the ligand Annexin V to dying but not viable cells and implications for PS-dependent clearance. Cell death and differentiation 12(2):194-6 doi:10.1038/sj.cdd.4401527
Aruoma OI, Halliwell B, Gajewski E, Dizdaroglu M (1991) Copper-ion-dependent damage to the bases in DNA in the presence of hydrogen peroxide. The Biochemical journal 273 ( Pt 3):601-4
Aruoma OI, Halliwell B, Hoey BM, Butler J (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free radical biology & medicine 6(6):593-7
Aydin S, Ozaras R, Uzun H, et al. (2002) N-acetylcysteine reduced the effect of ethanol on antioxidant system in rat plasma and brain tissue. The Tohoku journal of experimental medicine 198(2):71-7
Bai J, Cederbaum AI (2001) Mitochondrial catalase and oxidative injury. Biological signals and receptors 10(3-4):189-99 doi:46887
Blakley BR, Yole MJ, Brousseau P, Boermans H, Fournier M (1998) Effect of pentachlorophenol on immune function. Toxicology 125(2-3):141-8
Bluestone JA, Abbas AK (2003) Natural versus adaptive regulatory T cells. Nature reviews Immunology 3(3):253-7 doi:10.1038/nri1032
Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proceedings of the National Academy of Sciences of the United States of America 92(16):7162-6
Carstens CP, Blum JK, Witte I (1990) The role of hydroxyl radicals in tetrachlorohydroquinone induced DNA strand break formation in PM2 DNA and human fibroblasts. Chemico-biological interactions 74(3):305-14
Chang HJ, Wang S, Li HW, Lin KH, Chao CC, Lai YC (2010) Polychlorinated dibenzo-p-dioxins and dibenzofuran contents in fish and sediment near a pentachlorophenol contaminated site. Journal of environmental science and health Part A, Toxic/hazardous substances & environmental engineering 45(8):923-31 doi:10.1080/10934521003772303
Chang WC, Jeng JH, Shieh CC, et al. (2003) Skin tumor-promoting potential and systemic effects of pentachlorophenol and its major metabolite tetrachlorohydroquinone in CD-1 Mice. Molecular carcinogenesis 36(4):161-70 doi:10.1002/mc.10113
Chen HM, Lee YH, Chen RJ, Chiu HW, Wang BJ, Wang YJ (2013) The immunotoxic effects of dual exposure to PCP and TCDD. Chemico-biological interactions 206(2):166-174 doi:10.1016/j.cbi.2013.09.005
Chen MW, Wu YL, Li HW, Wang LC, Chien GP (2010) Partition of polychlorinated dibenzo-p-dioxins and dibenzofurans distribution in water in both suspended solid and dissolved phases. Journal of environmental science and health Part A, Toxic/hazardous substances & environmental engineering 45(2):183-91 doi:10.1080/10934520903429840
Chen SY, Chiu LY, Maa MC, Wang JS, Chien CL, Lin WW (2011) zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation. Autophagy 7(2):217-28
Chen YR, Wang X, Templeton D, Davis RJ, Tan TH (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. The Journal of biological chemistry 271(50):31929-36
Chhabra RS, Maronpot RM, Bucher JR, Haseman JK, Toft JD, Hejtmancik MR (1999) Toxicology and carcinogenesis studies of pentachlorophenol in rats. Toxicological sciences : an official journal of the Society of Toxicology 48(1):14-20
Collins JJ, Bodner K, Aylward LL, et al. (2009) Mortality rates among workers exposed to dioxins in the manufacture of pentachlorophenol. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 51(10):1212-9 doi:10.1097/JOM.0b013e3181badd4e
Collison LW, Workman CJ, Kuo TT, et al. (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566-9 doi:10.1038/nature06306
Columbano A (1995) Cell death: current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. Journal of cellular biochemistry 58(2):181-90 doi:10.1002/jcb.240580207
Cooper GS, Jones S (2008) Pentachlorophenol and cancer risk: focusing the lens on specific chlorophenols and contaminants. Environmental health perspectives 116(8):1001-8 doi:10.1289/ehp.11081
Corcoran GB, Fix L, Jones DP, et al. (1994) Apoptosis: molecular control point in toxicity. Toxicology and applied pharmacology 128(2):169-81 doi:10.1006/taap.1994.1195
Dahlhaus M, Almstadt E, Appel KE (1994) The pentachlorophenol metabolite tetrachloro-p-hydroquinone induces the formation of 8-hydroxy-2-deoxyguanosine in liver DNA of male B6C3F1 mice. Toxicology letters 74(3):265-74
Daniel V, Huber W, Bauer K, Opelz G (1995) Impaired in-vitro lymphocyte responses in patients with elevated pentachlorophenol (PCP) blood levels. Archives of environmental health 50(4):287-92 doi:10.1080/00039896.1995.9935956
Daniel V, Huber W, Bauer K, et al. (2001) Association of elevated blood levels of pentachlorophenol (PCP) with cellular and humoral immunodeficiencies. Archives of environmental health 56(1):77-83 doi:10.1080/00039890109604057
Davies KJ (1999) The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. IUBMB life 48(1):41-7 doi:10.1080/713803463
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239-52
De Flora S, Izzotti A, D'Agostini F, Balansky RM (2001) Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 22(7):999-1013
de Groot RP, Coffer PJ, Koenderman L (1998) Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cellular signalling 10(9):619-28
Degterev A, Yuan J (2008) Expansion and evolution of cell death programmes. Nature reviews Molecular cell biology 9(5):378-90 doi:10.1038/nrm2393
Dypbukt JM, Ankarcrona M, Burkitt M, et al. (1994) Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines. The Journal of biological chemistry 269(48):30553-60
Eaton DL, Klaassen CD (2003) Principles of Toxicology. In: Klaassen CD, Watkins JBr (eds) Casarett and Doull's essentials of Toxicology. vol 1. The McGraw-Hill Companies, Inc., USA, p 6-20
Ercal N, Treeratphan P, Hammond TC, Matthews RH, Grannemann NH, Spitz DR (1996) In vivo indices of oxidative stress in lead-exposed C57BL/6 mice are reduced by treatment with meso-2,3-dimercaptosuccinic acid or N-acetylcysteine. Free radical biology & medicine 21(2):157-61
Exon JH, Koller LD (1983) Effects of chlorinated phenols on immunity in rats. International journal of immunopharmacology 5(2):131-6
Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM (1998) The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell death and differentiation 5(7):551-62 doi:10.1038/sj.cdd.4400404
Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. Journal of immunology (Baltimore, Md : 1950) 148(7):2207-16
Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicology and applied pharmacology 140(1):173-9 doi:10.1006/taap.1996.0210
Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochimica et biophysica acta 1757(9-10):1371-87 doi:10.1016/j.bbabio.2006.06.014
Fiers W, Beyaert R, Declercq W, Vandenabeele P (1999) More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18(54):7719-30 doi:10.1038/sj.onc.1203249
Gate L, Lunk A, Tew KD (2003) Resistance to phorbol 12-myristate 13-acetate-induced cell growth arrest in an HL60 cell line chronically exposed to a glutathione S-transferase pi inhibitor. Biochemical pharmacology 65(10):1611-22
Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends in biochemical sciences 32(1):37-43 doi:10.1016/j.tibs.2006.11.001
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science (New York, NY) 281(5381):1309-12
Griendling KK (2005) ATVB in focus: redox mechanisms in blood vessels. Arteriosclerosis, thrombosis, and vascular biology 25(2):272-3 doi:10.1161/01.ATV.0000153515.72375.3b
Guo YL, Baysal K, Kang B, Yang LJ, Williamson JR (1998) Correlation between sustained c-Jun N-terminal protein kinase activation and apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells. The Journal of biological chemistry 273(7):4027-34
Han KS, Kang HJ, Kim EY, et al. (2001) 1,2-bis(2-Aminophenoxy)ethane-N,N,N',N'-tetraacetic acid induces caspase-mediated apoptosis and reactive oxygen species-mediated necrosis in cultured cortical neurons. Journal of neurochemistry 78(2):230-9
Hetz CA, Torres V, Quest AF (2005) Beyond apoptosis: nonapoptotic cell death in physiology and disease. Biochemistry and cell biology = Biochimie et biologie cellulaire 83(5):579-88 doi:10.1139/o05-065
Hirt UA, Leist M (2003) Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells. Cell death and differentiation 10(10):1156-64 doi:10.1038/sj.cdd.4401286
Holler N, Zaru R, Micheau O, et al. (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature immunology 1(6):489-95 doi:10.1038/82732
Holsapple MP, McNerney PJ, Barnes DW, White KL, Jr. (1984) Suppression of humoral antibody production by exposure to 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin. J Pharmacol Exp Ther 231(3):518-26
Holsapple MP, McNerney PJ, McCay JA (1987) Effects of pentachlorophenol on the in vitro and in vivo antibody response. Journal of toxicology and environmental health 20(3):229-39 doi:10.1080/15287398709530977
Ichijo H (1999) From receptors to stress-activated MAP kinases. Oncogene 18(45):6087-93 doi:10.1038/sj.onc.1203129
Inouye K, Ito T, Fujimaki H, et al. (2003) Suppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the high-affinity antibody response in C57BL/6 mice. Toxicological sciences : an official journal of the Society of Toxicology 74(2):315-24 doi:10.1093/toxsci/kfg132 [doi]
kfg132 [pii]
Ito T, Inouye K, Fujimaki H, Tohyama C, Nohara K (2002) Mechanism of TCDD-induced suppression of antibody production: effect on T cell-derived cytokine production in the primary immune reaction of mice. Toxicological sciences : an official journal of the Society of Toxicology 70(1):46-54
Jakobson I, Yllner S (1971) Metabolism of 14 C-pentachlorophenol in the mouse. Acta pharmacologica et toxicologica 29(5):513-24
Juhl U, Witte I, Butte W (1985) Metabolism of pentachlorophenol to tetrachlorohydroquinone by human liver homogenate. Bulletin of environmental contamination and toxicology 35(5):596-601
Kamboj A, Kiran R, Sandhir R (2006) Carbofuran-induced neurochemical and neurobehavioral alterations in rats: attenuation by N-acetylcysteine. Experimental brain research 170(4):567-75 doi:10.1007/s00221-005-0241-5
Kang DH, Fox C (2001) Th1 and Th2 cytokine responses to academic stress. Research in nursing & health 24(4):245-57
Kao CM, Chai CT, Liu JK, Yeh TY, Chen KF, Chen SC (2004) Evaluation of natural and enhanced PCP biodegradation at a former pesticide manufacturing plant. Water research 38(3):663-72 doi:10.1016/j.watres.2003.10.030
Kao CM, Chen SC, Liu JK, Wu MJ (2001) Evaluation of TCDD biodegradability under different redox conditions. Chemosphere 44(6):1447-54
Kerkvliet NI (1995) Immunological effects of chlorinated dibenzo-p-dioxins. Environmental health perspectives 103 Suppl 9:47-53
Kerkvliet NI (2002) Recent advances in understanding the mechanisms of TCDD immunotoxicity. International immunopharmacology 2(2-3):277-91
Kerkvliet NI (2012) TCDD: an environmental immunotoxicant reveals a novel pathway of immunoregulation--a 30-year odyssey. Toxicol Pathol 40(2):138-42 doi:0192623311427710 [pii]
10.1177/0192623311427710 [doi]
Kerkvliet NI, Baecher-Steppan L, Claycomb AT, Craig AM, Sheggeby GG (1982) Immunotoxicity of technical pentachlorophenol (PCP-T): depressed humoral immune responses to T-dependent and T-independent antigen stimulation in PCP-T exposed mice. Fundamental and applied toxicology : official journal of the Society of Toxicology 2(2):90-9
Kerkvliet NI, Brauner JA, Baecher-Steppan L (1985a) Effects of dietary technical pentachlorophenol exposure on T cell, macrophage and natural killer cell activity in C57Bl/6 mice. International journal of immunopharmacology 7(2):239-47
Kerkvliet NI, Brauner JA, Matlock JP (1985b) Humoral immunotoxicity of polychlorinated diphenyl ethers, phenoxyphenols, dioxins and furans present as contaminants of technical grade pentachlorophenol. Toxicology 36(4):307-24
Kooijman R, Devos S, Hooghe-Peters E (2010) Inhibition of in vitro cytokine production by human peripheral blood mononuclear cells treated with xenobiotics: implications for the prediction of general toxicity and immunotoxicity. Toxicology in vitro : an international journal published in association with BIBRA 24(6):1782-9 doi:10.1016/j.tiv.2010.07.007
Koppal T, Drake J, Butterfield DA (1999) In vivo modulation of rodent glutathione and its role in peroxynitrite-induced neocortical synaptosomal membrane protein damage. Biochimica et biophysica acta 1453(3):407-11
Kroemer G, Galluzzi L, Vandenabeele P, et al. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell death and differentiation 16(1):3-11 doi:10.1038/cdd.2008.150
Krysko O, De Ridder L, Cornelissen M (2004) Phosphatidylserine exposure during early primary necrosis (oncosis) in JB6 cells as evidenced by immunogold labeling technique. Apoptosis : an international journal on programmed cell death 9(4):495-500 doi:10.1023/b:appt.0000031452.75162.75
Laiosa MD, Wyman A, Murante FG, et al. (2003) Cell proliferation arrest within intrathymic lymphocyte progenitor cells causes thymic atrophy mediated by the aryl hydrocarbon receptor. Journal of immunology (Baltimore, Md : 1950) 171(9):4582-91
Lang D, Mueller-Ruchholtz W (1991) Human lymphocyte reactivity after in vitro exposure to technical and analytical grade pentachlorophenol. Toxicology 70(3):271-82
Law WM, Lau WN, Lo KL, Wai LM, Chiu SW (2003) Removal of biocide pentachlorophenol in water system by the spent mushroom compost of Pleurotus pulmonarius. Chemosphere 52(9):1531-7 doi:10.1016/s0045-6535(03)00492-2
Lee CC, Guo YL, Kuei CH, et al. (2006a) Human PCDD/PCDF levels near a pentachlorophenol contamination site in Tainan, Taiwan. Chemosphere 65(3):436-48 doi:10.1016/j.chemosphere.2006.01.063
Lee CC, Lin WT, Liao PC, Su HJ, Chen HL (2006b) High average daily intake of PCDD/Fs and serum levels in residents living near a deserted factory producing pentachlorophenol (PCP) in Taiwan: influence of contaminated fish consumption. Environmental pollution (Barking, Essex : 1987) 141(2):381-6 doi:10.1016/j.envpol.2005.08.032
Li C, Zheng M, Zhang B, et al. (2012) Long-term persistence of polychlorinated dibenzo-p-dioxins and dibenzofurans in air, soil and sediment around an abandoned pentachlorophenol factory in China. Environmental pollution (Barking, Essex : 1987) 162:138-43 doi:10.1016/j.envpol.2011.11.015
Lin PH, La DK, Upton PB, Swenberg JA (2002) Analysis of DNA adducts in rats exposed to pentachlorophenol. Carcinogenesis 23(2):365-9
Lin PH, Nakamura J, Yamaguchi S, Upton PB, La DK, Swenberg JA (2001) Oxidative damage and direct adducts in calf thymus DNA induced by the pentachlorophenol metabolites, tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone. Carcinogenesis 22(4):627-34
Lin YP, Zhu BZ, Yang MC, et al. (2004) Bcl-2 overexpression inhibits tetrachlorohydroquinone-induced apoptosis in NIH3T3 cells: a possible mechanism for tumor promotion. Molecular carcinogenesis 40(1):24-33 doi:10.1002/mc.20021
Lotzova E (1993) Definition and functions of natural killer cells. Nat Immun 12(4-5):169-76
Maheshwari A, Misro MM, Aggarwal A, Sharma RK (2012) N-acetyl-L-cysteine modulates multiple signaling pathways to rescue male germ cells from apoptosis induced by chronic hCG administration to rats. Apoptosis : an international journal on programmed cell death 17(6):551-65 doi:10.1007/s10495-012-0703-8
Mandal PK (2005) Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. Journal of comparative physiology B, Biochemical, systemic, and environmental physiology 175(4):221-30 doi:10.1007/s00360-005-0483-3
Marshall NB, Vorachek WR, Steppan LB, Mourich DV, Kerkvliet NI (2008) Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of immunology (Baltimore, Md : 1950) 181(4):2382-91
Matsuda N, Morita N, Matsuda K, Watanabe M (1998) Proliferation and differentiation of human osteoblastic cells associated with differential activation of MAP kinases in response to epidermal growth factor, hypoxia, and mechanical stress in vitro. Biochemical and biophysical research communications 249(2):350-4 doi:10.1006/bbrc.1998.9151
McConnachie PR, Zahalsky AC (1991) Immunological consequences of exposure to pentachlorophenol. Archives of environmental health 46(4):249-53 doi:10.1080/00039896.1991.9937456
Menghini R (1988) Genotoxicity of active oxygen species in mammalian cells. Mutation research 195(3):215-30
Muir J, Eduljee G (1999) PCP in the freshwater and marine environment of the European Union. The Science of the total environment 236(1-3):41-56
Mukerjee D, Papke O, Karmaus W (1989) Indoor air contamination with polychlorinated dibenzo-p-dioxins and dibenzofurans. Toxicology and industrial health 5(5):731-45
Nakagawa T, Shimizu S, Watanabe T, et al. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434(7033):652-8 doi:10.1038/nature03317
Nnodu U, Whalen MM (2008) Pentachlorophenol decreases ATP levels in human natural killer cells. Journal of applied toxicology : JAT 28(8):1016-20 doi:10.1002/jat.1367
Nohara K, Fujimaki H, Tsukumo S, Inouye K, Sone H, Tohyama C (2002) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on T cell-derived cytokine production in ovalbumin (OVA)-immunized C57Bl/6 mice. Toxicology 172(1):49-58 doi:S0300483X01005820 [pii]
North CM, Crawford RB, Lu H, Kaminski NE (2009) Simultaneous in vivo time course and dose response evaluation for TCDD-induced impairment of the LPS-stimulated primary IgM response. Toxicological sciences : an official journal of the Society of Toxicology 112(1):123-32 doi:10.1093/toxsci/kfp187
Nose K, Shibanuma M, Kikuchi K, Kageyama H, Sakiyama S, Kuroki T (1991) Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. European journal of biochemistry / FEBS 201(1):99-106
Okeke BC, Paterson A, Smith JE, Watson-Craik IA (1997) Comparative biotransformation of pentachlorophenol in soils by solid substrate cultures of Lentinula edodes. Applied microbiology and biotechnology 48(4):563-9
Pocernich CB, La Fontaine M, Butterfield DA (2000) In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. Neurochemistry international 36(3):185-91
Raha S, Robinson BH (2001) Mitochondria, oxygen free radicals, and apoptosis. American journal of medical genetics 106(1):62-70 doi:10.1002/ajmg.1398
Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C (2003) The significance of unstable chromosomes in colorectal cancer. Nature reviews Cancer 3(9):695-701 doi:10.1038/nrc1165
Ramos B, Lahti JM, Claro E, Jackowski S (2003) Prevalence of necrosis in C2-ceramide-induced cytotoxicity in NB16 neuroblastoma cells. Molecular pharmacology 64(2):502-11 doi:10.1124/mol.64.2.502
Reed A, Dzon L, Loganathan BG, Whalen MM (2004) Immunomodulation of human natural killer cell cytotoxic function by organochlorine pesticides. Hum Exp Toxicol 23(10):463-71
Reigner BG, Bois FY, Tozer TN (1992) Assessment of pentachlorophenol exposure in humans using the clearance concept. Human & experimental toxicology 11(1):17-26
Roberts HJ (1990) Pentachlorophenol-associated aplastic anemia, red cell aplasia, leukemia and other blood disorders. The Journal of the Florida Medical Association 77(2):86-90
Robertson JD, Orrenius S (2000) Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Critical reviews in toxicology 30(5):609-27 doi:10.1080/10408440008951122
Safe S (1997) Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds. Teratogenesis, carcinogenesis, and mutagenesis 17(4-5):285-304
Sai-Kato K, Umemura T, Takagi A, Hasegawa R, Tanimura A, Kurokawa Y (1995) Pentachlorophenol-induced oxidative DNA damage in mouse liver and protective effect of antioxidants. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 33(10):877-82
Sakon S, Xue X, Takekawa M, et al. (2003) NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. The EMBO journal 22(15):3898-909 doi:10.1093/emboj/cdg379
Schecter A, Birnbaum L, Ryan JJ, Constable JD (2006) Dioxins: an overview. Environmental research 101(3):419-28 doi:10.1016/j.envres.2005.12.003
Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. The EMBO journal 10(8):2247-58
Shelton JG, Steelman LS, Lee JT, et al. (2003) Effects of the RAF/MEK/ERK and PI3K/AKT signal transduction pathways on the abrogation of cytokine-dependence and prevention of apoptosis in hematopoietic cells. Oncogene 22(16):2478-92 doi:10.1038/sj.onc.1206321
Silverstone AE, Frazier DE, Jr., Fiore NC, Soults JA, Gasiewicz TA (1994) Dexamethasone, beta-estradiol, and 2,3,7,8-tetrachlorodibenzo-p-dioxin elicit thymic atrophy through different cellular targets. Toxicology and applied pharmacology 126(2):248-59 doi:10.1006/taap.1994.1114
Soderstrom TS, Poukkula M, Holmstrom TH, Heiskanen KM, Eriksson JE (2002) Mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in activated T cells abrogates TRAIL-induced apoptosis upstream of the mitochondrial amplification loop and caspase-8. Journal of immunology (Baltimore, Md : 1950) 169(6):2851-60
Staples JE, Murante FG, Fiore NC, Gasiewicz TA, Silverstone AE (1998) Thymic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are strictly dependent on aryl hydrocarbon receptor activation in hemopoietic cells. Journal of immunology (Baltimore, Md : 1950) 160(8):3844-54
Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends in cell biology 12(6):258-66
Tait SW, Green DR (2012) Mitochondria and cell signalling. Journal of cell science 125(Pt 4):807-15 doi:10.1242/jcs.099234
Tran SE, Holmstrom TH, Ahonen M, Kahari VM, Eriksson JE (2001) MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. The Journal of biological chemistry 276(19):16484-90 doi:10.1074/jbc.M010384200
Umemura T, Kai S, Hasegawa R, Sai K, Kurokawa Y, Williams GM (1999) Pentachlorophenol (PCP) produces liver oxidative stress and promotes but does not initiate hepatocarcinogenesis in B6C3F1 mice. Carcinogenesis 20(6):1115-20
Umemura T, Sai-Kato K, Takagi A, Hasegawa R, Kurokawa Y (1996) Oxidative DNA damage and cell proliferation in the livers of B6C3F1 mice exposed to pentachlorophenol in their diet. Fundamental and applied toxicology : official journal of the Society of Toxicology 30(2):285-9
Vakifahmetoglu H, Olsson M, Zhivotovsky B (2008) Death through a tragedy: mitotic catastrophe. Cell death and differentiation 15(7):1153-62 doi:10.1038/cdd.2008.47
van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31(1):1-9
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nature reviews Molecular cell biology 11(10):700-14 doi:10.1038/nrm2970
Villena J, Henriquez M, Torres V, et al. (2008) Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells. Free radical biology & medicine 44(6):1146-60 doi:10.1016/j.freeradbiomed.2007.12.017
Vorderstrasse BA, Kerkvliet NI (2001) 2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules. Toxicology and applied pharmacology 171(2):117-25 doi:10.1006/taap.2000.9119
Vorderstrasse BA, Steppan LB, Silverstone AE, Kerkvliet NI (2001) Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression. Toxicology and applied pharmacology 171(3):157-64 doi:10.1006/taap.2000.9122 [doi]
S0041-008X(00)99122-1 [pii]
Vos JG, Moore JA, Zinkl JG (1973) Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals. Environmental health perspectives 5:149-62
Wang BJ, Guo YL, Chang HY, et al. (2010) N-acetylcysteine inhibits chromium hypersensitivity in coadjuvant chromium-sensitized albino guinea pigs by suppressing the effects of reactive oxygen species. Experimental dermatology 19(8):e191-200 doi:10.1111/j.1600-0625.2009.01045.x
Wang J, Yu S, Jiao S, et al. (2012) Characterization of TCHQ-induced genotoxicity and mutagenesis using the pSP189 shuttle vector in mammalian cells. Mutation research 729(1-2):16-23 doi:10.1016/j.mrfmmm.2011.08.010
Wang YJ, Ho YS, Chu SW, Lien HJ, Liu TH, Lin JK (1997) Induction of glutathione depletion, p53 protein accumulation and cellular transformation by tetrachlorohydroquinone, a toxic metabolite of pentachlorophenol. Chemico-biological interactions 105(1):1-16
Wang YJ, Ho YS, Jeng JH, Su HJ, Lee CC (2000) Different cell death mechanisms and gene expression in human cells induced by pentachlorophenol and its major metabolite, tetrachlorohydroquinone. Chemico-biological interactions 128(3):173-88
Wang YJ, Lee CC, Chang WC, Liou HB, Ho YS (2001) Oxidative stress and liver toxicity in rats and human hepatoma cell line induced by pentachlorophenol and its major metabolite tetrachlorohydroquinone. Toxicology letters 122(2):157-69
Wang YJ, Yang MC, Pan MH (2008) Dihydrolipoic acid inhibits tetrachlorohydroquinone-induced tumor promotion through prevention of oxidative damage. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 46(12):3739-48 doi:10.1016/j.fct.2008.09.064
Waring P, Lambert D, Sjaarda A, Hurne A, Beaver J (1999) Increased cell surface exposure of phosphatidylserine on propidium iodide negative thymocytes undergoing death by necrosis. Cell death and differentiation 6(7):624-37 doi:10.1038/sj.cdd.4400540
Wassom JS, Huff JE, Loprieno N (1977) A review of the genetic toxicology of chlorinated dibenzo-p-dioxins. Mutation research 47(3-4):141-60
Wispriyono B, Matsuoka M, Igisu H (2002) Effects of pentachlorophenol and tetrachlorohydroquinone on mitogen-activated protein kinase pathways in Jurkat T cells. Environmental health perspectives 110(2):139-43
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science (New York, NY) 270(5240):1326-31
Yan CY, Greene LA (1998) Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 18(11):4042-9
Yoshida T, Ikuta K, Sugaya H, et al. (1996) Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5R alpha-deficient mice. Immunity 4(5):483-94
Zachwieja J, Zaniew M, Bobkowski W, et al. (2005) Beneficial in vitro effect of N-acetyl-cysteine on oxidative stress and apoptosis. Pediatric nephrology (Berlin, Germany) 20(6):725-31 doi:10.1007/s00467-004-1806-4
Zhang DW, Shao J, Lin J, et al. (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science (New York, NY) 325(5938):332-6 doi:10.1126/science.1172308
Zhao W, Ramos KS (1998) Cytotoxic response profiles of cultured rat hepatocytes to selected aromatic hydrocarbons. Toxicology in vitro : an international journal published in association with BIBRA 12(2):175-82
Zhao X, Pang X, Chaisuwan N (2011) Developing a qPCR method to quantify AhR-PCP-DNA complex for detection of environmental trace-level PCP. Ecotoxicology (London, England) 20(5):1148-53 doi:10.1007/s10646-011-0678-1
Zheng MH, Zhang B, Bao ZC, Yang H, Xu XB (2000) Analysis of pentachlorophenol from water, sediments, and fish bile of Dongting lake in China. Bulletin of environmental contamination and toxicology 64(1):16-9