- Email: [email protected]
How dangerous are phthalate plasticizers? Integrated approach to toxicity based on metabolism, electron transfer, reactive oxygen species and cell signaling
Medical Hypotheses 74 (2010) 626–628
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Editorial
How dangerous are phthalate plasticizers? Integrated approach to toxicity based on metabolism, electron transfer, reactive oxygen species and cell signaling a r t i c l e
i n f o
Article history: Received 20 November 2009 Accepted 24 November 2009
s u m m a r y Phthalate plasticizers are the most abundant man-made pollutants that have recently received wide-spread attention. There is uncertainty concerning the toxicity to humans. During the debate, scant attention has been paid to adverse effects at the molecular level which is the focus of this article. Most metabolic reports are concerned only with ester hydrolysis. In addition to that aspect, an important study deals with formation of catechol carboxylic acids which have the potential to redox cycle with the o-quinone counterparts. This electron transfer (ET) process is capable of generating reactive oxygen species (ROS) which are well known toxic agents at elevated levels. Substantial numbers of investigations find the presence of ROS leading to oxidative stress (OS) in living systems containing phthalates. Insults occur to various organs, including the reproductive system, pulmonary, central nervous system, immune system and liver. Toxic reactions are also reported involving inflammation, mitochondria and carcinogenicity. Generally, OS evidently plays a role. Of relevance are prior reviews which document extensive evidence for association of ET–ROS–OS with organ toxicity, and other deleterious reactions. In addition, cell signaling has been related to the physiological effects of phthalates. Various signaling processes participate together with involvement of ROS and association with biological effects. Suggestions for future work are offered. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Phthalate plasticizers are the most abundant man-made pollutants that have recently received wide-spread attention, including public media, concerning toxic affects. There has been uncertainty from the science community about the danger to humans, and the usual protestations from manufacturers that safety is satisfactory. In this debate, there has been scant attention paid to the scientific literature as to the fundamental aspects of toxicity. This article addresses the problem based on toxicity at the molecular level that deals with fundamental aspects, such as metabolism, electron transfer (ET), reactive oxygen species (ROS), oxidative stress (OS) and cell signaling. Based on ET, ROS and OS, a comprehensive unifying mechanism was proposed for various toxins (toxicants), including those involving the reproductive system [1,2], kidneys [3], liver [4], cardiovascular system [5], nervous system [6], mitochondria [7], abused drugs [8], ear [9], the immune system [10] and various other categories, including human illnesses [11a]. The same theme was applied to anti-infective agents [12], anticancer drugs [13], and carcinogens [14]. Involvement of ROS in toxicity is supported by the beneficial effects of antioxidants (AOs). The preponderance of bioactive substances or their metabolites incorporate ET functionalities, which, we believe, play an important role in physiological responses. These main groups include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). In 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.11.032
vivo redox cycling with oxygen can occur giving rise to OS through generation of ROS, such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide). In some cases, ET results in interference with normal electrical effects (e.g., in respiration or neurochemistry). Generally, active entities possessing ET groups display reduction potentials in the physiologically responsive range (i.e., more positive than 0.5 V). There is a plethora of experimental evidence supporting the OS theoretical framework, including generation of the common ROS, lipid peroxidation, degradation products of oxidation, depletion of AOs, effect of exogenous AOs, DNA oxidation and cleavage products, as well as electrochemical data. The comprehensive, unifying mechanism is in keeping with the frequent observations that many ET substances display a variety of activities (e.g., multiple-drug properties and toxic effects). The toxic groups include a wide variety of structurally diverse substances. The data reveal that the mechanistic framework serves as a common thread for the vast majority of toxins. However, it should be emphasized that physiological activity is often complex and multifaceted. A number of original references may be found in the reviews and articles cited; in many cases, references are representative. Metabolism A key element of evidence involves metabolism in connection with reproductive toxicity [1]. Most metabolic studies report enzymatic hydrolysis of the ester with little attention to nuclear
Editorial / Medical Hypotheses 74 (2010) 626–628
involvement. One investigation is quite illuminating, dealing with both hydrolysis and aromatic hydroxylation by oxidases [15]. From the processes, a number of products ensued, including 3,4- and 4,5dihydroxyphthalic acids, in addition to 3,4-dihydroxybenzoic acid from decarboxylation. All incorporate the formation of catechol which exhibits the potential for subsequent oxidation to ET o-quinone, a familiar function for redox cycling to ROS. Note that there is a close similarity to the hydrolytic and hydroxylation products observed in metabolism of toxic thalidomide [1]. Only a small amount of the ET catalyst is needed to generate large quantities of ROS. Toxicity (ET–ROS–OS) A recent investigation focused on leakage of the plasticizer from blood storage bags and resulting physiological consequences [16]. The effect of oxidative injury caused by the phthalates is discussed as a potential mechanism for increases in inflammation resulting from long term leakage. The OS might well arise from ROS generated via redox cycling by the catechol metabolites [1,15]. The relationship of ET–ROS–OS with unwanted effects has been reported for many other toxic species. It is significant that adverse effects associated with phthalates include birth defects [1,2], inflammation, respiratory disease and malignancy [16]. Reviews of mechanisms involving pulmonary toxins [17], carcinogens [14] and inflammatory agents [11b] provide extensive evidence for involvement of ET–ROS–OS. An investigation of phthalate degradation products from metabolism by yeast revealed the presence of a toxic hazard causing OS [18,19]. There appears to be involvement of OS in the pathogenesis of rat testis atrophy induced by phthalate [20]. Increased generation of ROS was accompanied by constant decrease in the AOs, GSH and ascorbic acid. The OS apparently injured the mitochondria and induced apoptosis. In a study of OS associated with phthalate administration in rats, the ester showed an inhibiting effect on SOD (AO) activity in the testes [21]. There are reports of phthalate toxicity in other organs. Exposure in rats resulted in liver impairment as evidenced by mitochondrial proliferation, triglyceride accumulation and severe hepatocellular changes involving increased liver weight, elevated enzyme levels, impaired metabolism and altered liver histology [22]. Data that support participation of ROS in liver toxicity are documented in a book [4]. Phthalate exposure in rats resulted in neurobehavioral toxicity [23]. The adverse effects included depressed surface righting, shortened forepaw grip time, and enhanced spatial learning and reference memory. Cognitive abilities may be altered. A review relates toxicity in the nervous system to exposure to ROS [6]. Phthalates can damage hemocytes and decrease the cellular immunity of prawns [24]. Results indicate that the immune reactions were variable due to the different toxic effects of the pollutants, including mortality. A significant finding is an increase in superoxide production. There is considerable evidence for a relationship of ROS with immunotoxicity [10]. Cell signaling (ET–ROS): Electrochemistry and toxicity Another important observation is the release of pro-inflammatory cytokines from exposure to phthalates [16]. Considerable evidence links inflammation to generation of ROS [11b]. The participation of cytokines points to a role for cell signaling. A number of proteins included in the proteomic signatures from exposure of mussels to phthalate participate in pathways relevant to the unifying mechanism [25]. The processes include cell signaling, oxy radical involvement and oxidative pathways. Disturbed signaling pathways which orchestrate genital development might play an important role in the toxic process induced by phthalate in new-
627
born rats [25]. The altered signaling processes include sonic hedgehog, bone morphogenetic proteins, fibroblast growth factor and the transforming growth factor-beta superfamily [26]. The results show that the reproductive system and development conditions were damaged. A recent review deals with the fundamental aspects of cell signaling which is regarded as proceeding via long redox chains in which initiation, propagation, and termination occur involving conduits with unshared electrons [27]. ROS have been of recent interest in this scenario, as are precursors of ROS, and other molecules of ET functionality. A current school of thought divides messengers into two categories: ROS and electrons. Free electrons, known to travel appreciable distances, are ideal for signal transduction due to rapid transfer. Suppliers of electrons in the propagation step include amino acids (tyrosine, tryptophan, histidine, cysteine, methionine, disulfide bonds). Conduits for ET participation in propagation include various peptides, DNA, mitochondria, water, and other materials with nonbonding electrons. Future work Experiments should be performed to isolate and identify the proposed quinone metabolite. A similar approach involves addition to the metabolizing system of o-phenylenediamine which readily condenses with o-quinone to form easily identified condensation products. Quinones are sometimes difficult to isolate due to facile reaction with protein nucleophiles. The most important approach entails research to determine toxicity of phthalates to the fetus, involving amount and duration required. Some research on this aspect is already available. These types of injuries should be compared with those arising from human fetuses, e.g., from accidental exposure. There is extensive literature documenting the beneficial effects of AOs toward toxic species. Investigation of this aspect should be carried out with the possibility of clinically useful results. For many, delving into the signal transduction literature reveals a maze of baffling complexity. Recently, attempts have been made to organize and rationalize. One approach to simplify involves the new mechanics [28], whereas another is based on the hypothesis of radicals and electrochemistry (electron transfer and molecular electrostatic potential) [29]. References [1] Kovacic P, Jacintho JD. Reproductive toxins: Pervasive theme of oxidative stress and electron transfer. Curr Med Chem 2001;8:823–47. [2] Kovacic P, Somanathan R. Mechanism of teratogenesis: Electron transfer reactive oxygen species and antioxidants. Birth Defects Res 2006;78:308–25. [3] Kovacic P, Sacman A, Wu-Weiss M. Nephrotoxins: Widespread role of oxidative stress and electron transfer. Curr Med Chem 2002;9:823–47. [4] Poli G, Cheeseman KH, Dianzani MU, Slater TF. Free radicals in the pathogenesis of liver injury. New York: Pergamon; 1989. pp. 1–300. [5] Kovacic P, Thurn LA. Cardiovascular toxins from the perspective of oxidative stress and electron transfer. Curr Vasc Pharm 2005;3:107–17. [6] Kovacic P, Somanathan R. Neurotoxicity: The broad framework of electron transfer, oxidative stress and protection by antioxidants. Curr Med Chem 2005;5:249–58. [7] Kovacic P, Pozos RS, Somanathan R, Shangari R, O’Brien PJ. Mechanism of mitochondrial uncouplers, inhibitors, and toxins: Focus on electron transfer, free radicals, and structure-activity relationships. Curr Med Chem 2005;12:2601–23. [8] Kovacic P, Cooksy AL. Unifying mechanism for toxicity and addiction by abused drugs: electron transfer and reactive oxygen species. Med Hypotheses 2005;64:357–66. [9] Kovacic P, Somanathan R. Ototoxicity and noise trauma: Electron transfer, reactive oxygen species, cell signaling, electrical effects, and protection by antioxidants: Practical medical features. Med Hypotheses 2008;70:914–23. [10] Kovacic P, Somanathan R. Integrated approach to immunotoxicity: Electron transfer, reactive oxygen species, antioxidants, cell signaling and receptors. J Recept Signal Transduct Res 2008;28:323–46. [11] (a) Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. New York: Oxford University Press; 2002. pp. 1–895;
628
[12] [13] [14] [15] [16]
[17]
[18]
[19] [20]
[21]
[22]
Editorial / Medical Hypotheses 74 (2010) 626–628 (b) Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. New York: Oxford University Press; 2002. p. 677. Kovacic P, Becvar LE. Mode of action of anti-infective agents: Focus on oxidative stress and electron transfer. Curr Pharm Des 2000;6:143–67. Kovacic P, Osuana JA. Mechanisms of anti-cancer agents: Emphasis on oxidative stress and electron transfer. Curr Pharm Des 2000;6:277–309. Kovacic P, Jacintho JD. Mechanisms of carcinogenesis: Focus on oxidative stress and electron transfer. Curr Med Chem 2001;8:773–96. Eaton RW, Ribbons DW. Metabolism of dibutylphthalate by micrococcus sp. Strain 12B. J Bacteriol 1982;151:48–57. Rael LT, Bar-Or R, Ambruso R, Mains W, Slone S, Craun L, et al. Phthalate esters used as plasticizers in packed red blood cell storage bags may lead to progressive toxin exposure and the release of pro-inflammatory cytokines. Oxid Med Cell Longev 2009;2:166–71. Kovacic P, Somanathan R. Pulmonary toxicity and environmental contamination: Radicals, electron transfer, and protection by antioxidants. Rev Environ Contam Toxicol 2009;201:41–69. Ahn JY, Kim YH, Min J, Lee J. Accelerated degradation of dipentyl phthalate by fusarium oxysporum f. sp. Pisi cutinase and toxicity evaluation of its degradation products using bioluminescent bacteria. Curr Microbiol 2006;52:340–4. Kim YH, Lee J. Enzymatic degradation of dibutyl phthalate and toxicity of its degradation products. Biotechnol Lett 2005;27:635–9. Kasahara E, Sato EF, Miyoshi M, Konaka R, Hiramoto K, Sasaki J, et al. Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl) phthalate. Biochem J 2002;365:849–56. Wang Y, Song L, Chen J, He J, Liu R, Zhu Z, et al. Effects of di-butyl phthalate on sperm motility and oxidative stress in rats. Zhonghua Nan Ke Xue 2004;10: 253–6. Pereira C, Mapuskar K, Rao CV. Chronic toxicity of diethyl phthalate in male Wister rats – a dose – response study. Regul Toxicol Pharmacol 2006;45: 169–77.
[23] Li Y, Zhuang M, Shi N. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure. J Appl Toxicol 2009;29:603–11. [24] Chen WL, Sung HH. The toxic effect of phthalate on immune responses of giant freshwater prawn (Macrobrachium rosenbergii) via oral treatment. Aquat Toxicol 2005;74:160–71. [25] Apraiz I, Mi J, Cristobal S. Identification of proteomic signatures of exposure to marine pollutants in mussels (Mytilus edulis). Mol Cell Proteomics 2006;5:1274–85. [26] Zhu YJ, Jiang JT, Ma L, Zhang J, Hong Y, Liao K, et al. Molecular and toxicologic research in newborn hypospadiac male rats following in utero exposure to din-butyl phthalate (DBP). Toxicology 2009;260:120–5. [27] Kovacic P, Pozos RS. Cell signaling (mechanism and reproductive toxicity): Redox chains, radicals, electrons, relays, conduit, electrochemistry, and other medical implications. Birth Defects Res, Part C 2006;78:333–44. [28] Hlavacek WS, Faeder JR. The complexity of cell signaling and the need for a new mechanics. Sci Signal 2009;2:Pe46. [29] Kovacic P. Simplifying the complexity of cell signaling in medicine and the life sciences: Radicals and electrochemistry. Med Hypotheses 2009, in press, doi:10.1016/j.mehy.2009.10.032.
Peter Kovacic Department of Chemistry, San Diego State University, 5500 Campanile Drive, San Diego CA 92182-1030, USA Tel.: +1 619 594 5545; fax: +1 619 594 4634 E-mail address: [email protected]
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Editorial
How dangerous are phthalate plasticizers? Integrated approach to toxicity based on metabolism, electron transfer, reactive oxygen species and cell signaling a r t i c l e
i n f o
Article history: Received 20 November 2009 Accepted 24 November 2009
s u m m a r y Phthalate plasticizers are the most abundant man-made pollutants that have recently received wide-spread attention. There is uncertainty concerning the toxicity to humans. During the debate, scant attention has been paid to adverse effects at the molecular level which is the focus of this article. Most metabolic reports are concerned only with ester hydrolysis. In addition to that aspect, an important study deals with formation of catechol carboxylic acids which have the potential to redox cycle with the o-quinone counterparts. This electron transfer (ET) process is capable of generating reactive oxygen species (ROS) which are well known toxic agents at elevated levels. Substantial numbers of investigations find the presence of ROS leading to oxidative stress (OS) in living systems containing phthalates. Insults occur to various organs, including the reproductive system, pulmonary, central nervous system, immune system and liver. Toxic reactions are also reported involving inflammation, mitochondria and carcinogenicity. Generally, OS evidently plays a role. Of relevance are prior reviews which document extensive evidence for association of ET–ROS–OS with organ toxicity, and other deleterious reactions. In addition, cell signaling has been related to the physiological effects of phthalates. Various signaling processes participate together with involvement of ROS and association with biological effects. Suggestions for future work are offered. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Phthalate plasticizers are the most abundant man-made pollutants that have recently received wide-spread attention, including public media, concerning toxic affects. There has been uncertainty from the science community about the danger to humans, and the usual protestations from manufacturers that safety is satisfactory. In this debate, there has been scant attention paid to the scientific literature as to the fundamental aspects of toxicity. This article addresses the problem based on toxicity at the molecular level that deals with fundamental aspects, such as metabolism, electron transfer (ET), reactive oxygen species (ROS), oxidative stress (OS) and cell signaling. Based on ET, ROS and OS, a comprehensive unifying mechanism was proposed for various toxins (toxicants), including those involving the reproductive system [1,2], kidneys [3], liver [4], cardiovascular system [5], nervous system [6], mitochondria [7], abused drugs [8], ear [9], the immune system [10] and various other categories, including human illnesses [11a]. The same theme was applied to anti-infective agents [12], anticancer drugs [13], and carcinogens [14]. Involvement of ROS in toxicity is supported by the beneficial effects of antioxidants (AOs). The preponderance of bioactive substances or their metabolites incorporate ET functionalities, which, we believe, play an important role in physiological responses. These main groups include quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). In 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.11.032
vivo redox cycling with oxygen can occur giving rise to OS through generation of ROS, such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide). In some cases, ET results in interference with normal electrical effects (e.g., in respiration or neurochemistry). Generally, active entities possessing ET groups display reduction potentials in the physiologically responsive range (i.e., more positive than 0.5 V). There is a plethora of experimental evidence supporting the OS theoretical framework, including generation of the common ROS, lipid peroxidation, degradation products of oxidation, depletion of AOs, effect of exogenous AOs, DNA oxidation and cleavage products, as well as electrochemical data. The comprehensive, unifying mechanism is in keeping with the frequent observations that many ET substances display a variety of activities (e.g., multiple-drug properties and toxic effects). The toxic groups include a wide variety of structurally diverse substances. The data reveal that the mechanistic framework serves as a common thread for the vast majority of toxins. However, it should be emphasized that physiological activity is often complex and multifaceted. A number of original references may be found in the reviews and articles cited; in many cases, references are representative. Metabolism A key element of evidence involves metabolism in connection with reproductive toxicity [1]. Most metabolic studies report enzymatic hydrolysis of the ester with little attention to nuclear
Editorial / Medical Hypotheses 74 (2010) 626–628
involvement. One investigation is quite illuminating, dealing with both hydrolysis and aromatic hydroxylation by oxidases [15]. From the processes, a number of products ensued, including 3,4- and 4,5dihydroxyphthalic acids, in addition to 3,4-dihydroxybenzoic acid from decarboxylation. All incorporate the formation of catechol which exhibits the potential for subsequent oxidation to ET o-quinone, a familiar function for redox cycling to ROS. Note that there is a close similarity to the hydrolytic and hydroxylation products observed in metabolism of toxic thalidomide [1]. Only a small amount of the ET catalyst is needed to generate large quantities of ROS. Toxicity (ET–ROS–OS) A recent investigation focused on leakage of the plasticizer from blood storage bags and resulting physiological consequences [16]. The effect of oxidative injury caused by the phthalates is discussed as a potential mechanism for increases in inflammation resulting from long term leakage. The OS might well arise from ROS generated via redox cycling by the catechol metabolites [1,15]. The relationship of ET–ROS–OS with unwanted effects has been reported for many other toxic species. It is significant that adverse effects associated with phthalates include birth defects [1,2], inflammation, respiratory disease and malignancy [16]. Reviews of mechanisms involving pulmonary toxins [17], carcinogens [14] and inflammatory agents [11b] provide extensive evidence for involvement of ET–ROS–OS. An investigation of phthalate degradation products from metabolism by yeast revealed the presence of a toxic hazard causing OS [18,19]. There appears to be involvement of OS in the pathogenesis of rat testis atrophy induced by phthalate [20]. Increased generation of ROS was accompanied by constant decrease in the AOs, GSH and ascorbic acid. The OS apparently injured the mitochondria and induced apoptosis. In a study of OS associated with phthalate administration in rats, the ester showed an inhibiting effect on SOD (AO) activity in the testes [21]. There are reports of phthalate toxicity in other organs. Exposure in rats resulted in liver impairment as evidenced by mitochondrial proliferation, triglyceride accumulation and severe hepatocellular changes involving increased liver weight, elevated enzyme levels, impaired metabolism and altered liver histology [22]. Data that support participation of ROS in liver toxicity are documented in a book [4]. Phthalate exposure in rats resulted in neurobehavioral toxicity [23]. The adverse effects included depressed surface righting, shortened forepaw grip time, and enhanced spatial learning and reference memory. Cognitive abilities may be altered. A review relates toxicity in the nervous system to exposure to ROS [6]. Phthalates can damage hemocytes and decrease the cellular immunity of prawns [24]. Results indicate that the immune reactions were variable due to the different toxic effects of the pollutants, including mortality. A significant finding is an increase in superoxide production. There is considerable evidence for a relationship of ROS with immunotoxicity [10]. Cell signaling (ET–ROS): Electrochemistry and toxicity Another important observation is the release of pro-inflammatory cytokines from exposure to phthalates [16]. Considerable evidence links inflammation to generation of ROS [11b]. The participation of cytokines points to a role for cell signaling. A number of proteins included in the proteomic signatures from exposure of mussels to phthalate participate in pathways relevant to the unifying mechanism [25]. The processes include cell signaling, oxy radical involvement and oxidative pathways. Disturbed signaling pathways which orchestrate genital development might play an important role in the toxic process induced by phthalate in new-
627
born rats [25]. The altered signaling processes include sonic hedgehog, bone morphogenetic proteins, fibroblast growth factor and the transforming growth factor-beta superfamily [26]. The results show that the reproductive system and development conditions were damaged. A recent review deals with the fundamental aspects of cell signaling which is regarded as proceeding via long redox chains in which initiation, propagation, and termination occur involving conduits with unshared electrons [27]. ROS have been of recent interest in this scenario, as are precursors of ROS, and other molecules of ET functionality. A current school of thought divides messengers into two categories: ROS and electrons. Free electrons, known to travel appreciable distances, are ideal for signal transduction due to rapid transfer. Suppliers of electrons in the propagation step include amino acids (tyrosine, tryptophan, histidine, cysteine, methionine, disulfide bonds). Conduits for ET participation in propagation include various peptides, DNA, mitochondria, water, and other materials with nonbonding electrons. Future work Experiments should be performed to isolate and identify the proposed quinone metabolite. A similar approach involves addition to the metabolizing system of o-phenylenediamine which readily condenses with o-quinone to form easily identified condensation products. Quinones are sometimes difficult to isolate due to facile reaction with protein nucleophiles. The most important approach entails research to determine toxicity of phthalates to the fetus, involving amount and duration required. Some research on this aspect is already available. These types of injuries should be compared with those arising from human fetuses, e.g., from accidental exposure. There is extensive literature documenting the beneficial effects of AOs toward toxic species. Investigation of this aspect should be carried out with the possibility of clinically useful results. For many, delving into the signal transduction literature reveals a maze of baffling complexity. Recently, attempts have been made to organize and rationalize. One approach to simplify involves the new mechanics [28], whereas another is based on the hypothesis of radicals and electrochemistry (electron transfer and molecular electrostatic potential) [29]. References [1] Kovacic P, Jacintho JD. Reproductive toxins: Pervasive theme of oxidative stress and electron transfer. Curr Med Chem 2001;8:823–47. [2] Kovacic P, Somanathan R. Mechanism of teratogenesis: Electron transfer reactive oxygen species and antioxidants. Birth Defects Res 2006;78:308–25. [3] Kovacic P, Sacman A, Wu-Weiss M. Nephrotoxins: Widespread role of oxidative stress and electron transfer. Curr Med Chem 2002;9:823–47. [4] Poli G, Cheeseman KH, Dianzani MU, Slater TF. Free radicals in the pathogenesis of liver injury. New York: Pergamon; 1989. pp. 1–300. [5] Kovacic P, Thurn LA. Cardiovascular toxins from the perspective of oxidative stress and electron transfer. Curr Vasc Pharm 2005;3:107–17. [6] Kovacic P, Somanathan R. Neurotoxicity: The broad framework of electron transfer, oxidative stress and protection by antioxidants. Curr Med Chem 2005;5:249–58. [7] Kovacic P, Pozos RS, Somanathan R, Shangari R, O’Brien PJ. Mechanism of mitochondrial uncouplers, inhibitors, and toxins: Focus on electron transfer, free radicals, and structure-activity relationships. Curr Med Chem 2005;12:2601–23. [8] Kovacic P, Cooksy AL. Unifying mechanism for toxicity and addiction by abused drugs: electron transfer and reactive oxygen species. Med Hypotheses 2005;64:357–66. [9] Kovacic P, Somanathan R. Ototoxicity and noise trauma: Electron transfer, reactive oxygen species, cell signaling, electrical effects, and protection by antioxidants: Practical medical features. Med Hypotheses 2008;70:914–23. [10] Kovacic P, Somanathan R. Integrated approach to immunotoxicity: Electron transfer, reactive oxygen species, antioxidants, cell signaling and receptors. J Recept Signal Transduct Res 2008;28:323–46. [11] (a) Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. New York: Oxford University Press; 2002. pp. 1–895;
628
[12] [13] [14] [15] [16]
[17]
[18]
[19] [20]
[21]
[22]
Editorial / Medical Hypotheses 74 (2010) 626–628 (b) Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. New York: Oxford University Press; 2002. p. 677. Kovacic P, Becvar LE. Mode of action of anti-infective agents: Focus on oxidative stress and electron transfer. Curr Pharm Des 2000;6:143–67. Kovacic P, Osuana JA. Mechanisms of anti-cancer agents: Emphasis on oxidative stress and electron transfer. Curr Pharm Des 2000;6:277–309. Kovacic P, Jacintho JD. Mechanisms of carcinogenesis: Focus on oxidative stress and electron transfer. Curr Med Chem 2001;8:773–96. Eaton RW, Ribbons DW. Metabolism of dibutylphthalate by micrococcus sp. Strain 12B. J Bacteriol 1982;151:48–57. Rael LT, Bar-Or R, Ambruso R, Mains W, Slone S, Craun L, et al. Phthalate esters used as plasticizers in packed red blood cell storage bags may lead to progressive toxin exposure and the release of pro-inflammatory cytokines. Oxid Med Cell Longev 2009;2:166–71. Kovacic P, Somanathan R. Pulmonary toxicity and environmental contamination: Radicals, electron transfer, and protection by antioxidants. Rev Environ Contam Toxicol 2009;201:41–69. Ahn JY, Kim YH, Min J, Lee J. Accelerated degradation of dipentyl phthalate by fusarium oxysporum f. sp. Pisi cutinase and toxicity evaluation of its degradation products using bioluminescent bacteria. Curr Microbiol 2006;52:340–4. Kim YH, Lee J. Enzymatic degradation of dibutyl phthalate and toxicity of its degradation products. Biotechnol Lett 2005;27:635–9. Kasahara E, Sato EF, Miyoshi M, Konaka R, Hiramoto K, Sasaki J, et al. Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl) phthalate. Biochem J 2002;365:849–56. Wang Y, Song L, Chen J, He J, Liu R, Zhu Z, et al. Effects of di-butyl phthalate on sperm motility and oxidative stress in rats. Zhonghua Nan Ke Xue 2004;10: 253–6. Pereira C, Mapuskar K, Rao CV. Chronic toxicity of diethyl phthalate in male Wister rats – a dose – response study. Regul Toxicol Pharmacol 2006;45: 169–77.
[23] Li Y, Zhuang M, Shi N. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure. J Appl Toxicol 2009;29:603–11. [24] Chen WL, Sung HH. The toxic effect of phthalate on immune responses of giant freshwater prawn (Macrobrachium rosenbergii) via oral treatment. Aquat Toxicol 2005;74:160–71. [25] Apraiz I, Mi J, Cristobal S. Identification of proteomic signatures of exposure to marine pollutants in mussels (Mytilus edulis). Mol Cell Proteomics 2006;5:1274–85. [26] Zhu YJ, Jiang JT, Ma L, Zhang J, Hong Y, Liao K, et al. Molecular and toxicologic research in newborn hypospadiac male rats following in utero exposure to din-butyl phthalate (DBP). Toxicology 2009;260:120–5. [27] Kovacic P, Pozos RS. Cell signaling (mechanism and reproductive toxicity): Redox chains, radicals, electrons, relays, conduit, electrochemistry, and other medical implications. Birth Defects Res, Part C 2006;78:333–44. [28] Hlavacek WS, Faeder JR. The complexity of cell signaling and the need for a new mechanics. Sci Signal 2009;2:Pe46. [29] Kovacic P. Simplifying the complexity of cell signaling in medicine and the life sciences: Radicals and electrochemistry. Med Hypotheses 2009, in press, doi:10.1016/j.mehy.2009.10.032.
Peter Kovacic Department of Chemistry, San Diego State University, 5500 Campanile Drive, San Diego CA 92182-1030, USA Tel.: +1 619 594 5545; fax: +1 619 594 4634 E-mail address: [email protected]