Environmental toxicity, oxidative stress and apoptosis: Ménage à Trois

Mutation Research 674 (2009) 3–22

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Environmental toxicity, oxidative stress and apoptosis: Ménage à Trois Rodrigo Franco a,∗ , Roberto Sánchez-Olea b , Elsa M. Reyes-Reyes c , Mihalis I. Panayiotidis d a

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, P. O. Box 12233, 111. T.W. Alexander Drive, Research Triangle Park, NC 27709, United States Biophysics Department, Physics Institute, Autonomous University of San Luis Potosi, SLP 78290, Mexico c Department of Biochemistry, University of Louisville, Kentucky, KY 40202, United States d School of Public Health, University of Nevada-Reno, MS-274, Reno, NV 89557, United States b

a r t i c l e

i n f o

Article history: Received 26 November 2008 Accepted 27 November 2008 Available online 9 December 2008 Keywords: Cell death Environmental stress Environmental toxicants Environmental agents ROS Free radicals Oxidative stress Glutathione Metals Pesticides Ionizing radiation Ultraviolet radiation Particulate matter Asbestos Cigarette smoke DNA damage Endoplasmic reticulum stress SAPK MAPK p53 Dioxins

a b s t r a c t Apoptosis is an evolutionary conserved homeostatic process involved in distinct physiological processes including organ and tissue morphogenesis, development and senescence. Its deregulation is also known to participate in the etiology of several human diseases including cancer, neurodegenerative and autoimmune disorders. Environmental stressors (cytotoxic agents, pollutants or toxicants) are well known to induce apoptotic cell death and to contribute to a variety of pathological conditions. Oxidative stress seems to be the central element in the regulation of the apoptotic pathways triggered by environmental stressors. In this work, we review the established mechanisms by which oxidative stress and environmental stressors regulate the apoptotic machinery with the aim to underscore the relevance of apoptosis as a component in environmental toxicity and human disease progression. Published by Elsevier B.V.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apoptotic signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative stress and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: GSH, reduced glutathione; GSSG, glutathione disulfide; GS• , thyil radical; ROS, reactive oxygen species; RNS, reactive nitrogen species; RS, reactive species of both oxygen and nitrogen; ␥-GCS, ␥-glutamylcysteine synthetase; GPX, glutathione peroxidase; GR, glutathione reductase; GST, glutathione S-transferase, GSNO, nitrosoglutathione; NAC, N-acetyl-l-cysteine; NO, nitric oxide; • OH, hydroxyl radical; H2 O2 , hydrogen peroxide; • O2 − , superoxide anion; • ONOO- , peroxynitrite; IRA, ionizing radiation-induced apoptosis; CO, carbon monoxide; • LOO, lipid peroxides; Sb, antimony; As, arsenic; Be, beryllium; Cd, cadmium; Cr, chromium; Co, cobalt; Cu, copper; Pb, lead; Hg, mercury; Ni, nickel; V, vanadium; Ca2+ , calcium; SOD, superoxide dismutase; DSB, double-strand breaks; SSB, single-strand breaks; FasL, Fas ligand; SAPKs, stress-activated protein kinases; MAPKs, mitogen-activated protein kinases; TNF, tumor necrosis factor; UV, ultraviolet; ATM, ataxia talangiectasia mutated gene; ASK-1, apoptosis-signal regulating kinase-1; ER, endoplasmic reticulum; JNK, c-jun N-terminal kinase; MMP, mitochondrial membrane potential; MPTP, mitochondrial permeability transition pore; PM, particulate matter; NADPH, nicotinamine adenine dinucleotide phosphate; PKC, protein kinase C; DNA-PK, DNA-dependent protein kinase; FADD, Fas-associated death domain; PI3K, phosphoinositide 3-kinase; NF-kB, nuclear factor-kappa-light-chain-enhancer of activated B cells. ∗ Corresponding author. Tel.: +919 541 1564; fax: +919 541 1367. E-mail address: [email protected] (R. Franco). 1383-5718/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.mrgentox.2008.11.012

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5.

Molecular mechanisms involved in apoptosis induced by environmental stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Antimony (Sb) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Arsenic (As) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Beryllium (Be) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Cadmium (Cd) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5. Chromium (Cr) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6. Cobalt (Co) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.7. Copper (Cu) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.8. Lead (Pb) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.9. Mercury (Hg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.10. Nickel (Ni) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.11. Vanadium (V) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Particulate matter and smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Carbon monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Dioxins, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and the role of the arylhydrocarbon receptor (Ahr) 4.7. Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Ultraviolet radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The environment represents a key contributor to human health and disease. Exposure to many substances such as pollutants and chemicals (environmental stressors), have detrimental effects on health and are considered to contribute substantially to most diseases of major public health significance. Environmental diseases are those in general aroused or exacerbated by exposure to environmental stressors and include cancer, chronic lung disease, diabetes and neurodegeneration. Thus, it is now evident that research towards understanding how environmental risk factors influence the development and progression of disease will lead to further improvements in public health. A key for Environmental Sciences is identifying and understanding the basic biological processes that are altered or regulated by environmental factors, and that stimulate disease processes to begin, or the course of the disease to be substantially altered. For this, basic biology research with potential for future translation into the clinic must be pursued to understand the fundamental changes caused by exposure to environmental agents that will drive the scientific basis for health decisions. Cells respond and adapt to environmental signals such as toxicants or stressors through multiple mechanisms that involve communication pathways or signal transduction processes [1]. Although a large amount of toxicological studies have been performed to understand the biological basis of the cellular response to environmental stress, there is still a lack of evidence for a clear mechanistic explanation of these effects. Environmental stressors are well known to mediate a wide variety of toxic effects such as DNA damage or genotoxicity. However, it has been recognized that many of the toxic effects induced by environmental stressors are mediated by regulation/induction of apoptosis and redox signaling [2–6], whose deregulation has been associated to the etiology of several environmental diseases [7]. Although redox signaling has been largely linked to the activation of distinct apoptotic pathways in response to environmental stress, the direct molecular mechanisms involved have remained largely elusive. The overall impact of environmental changes on the mechanisms of cell death progression is poorly understood yet the consequences of modifying/regulating them can result in a poten-

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tial increased risk of developing diseases, including cancer and neurodegeneration, associated to changes in apoptotic cell death rates.

2. Apoptotic signaling Apoptosis is a highly organized process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations [8]. Initial stages of apoptosis are characterized by initiator caspase activation, alterations in the cellular redox potential, cell shrinkage, loss of membrane lipid asymmetry and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by activation of execution caspases and endonucleases, apoptotic body formation and cell fragmentation [8,9]. The signaling cascades that regulate the progression of apoptosis have been extensively studied and characterized. In general both extrinsic and intrinsic pathways have been described for the activation of apoptosis (Fig. 1). Induction of apoptosis via the extrinsic pathway is triggered by the activation of death receptors such as those activated by Fas ligand or FasL (Fas (CD95/Apo-1); by the TNFrelated apoptosis-inducing ligand or TRAIL (DR4, DR5); and by tumor necrosis factor (TNFR1). Activation of CD95, DR4 and DR5 leads primarily to the formation of the death-inducing signaling complex (DISC) formed by the recruitment of the Fas-associated death domain (FADD), caspase 8 (and in some cases caspase 10 [10]) and the cellular FLICE-inhibitory protein (FLIP). Initiator caspase 8 is processed, activated and further amplifies the apoptotic cascade by activation of executioner caspases. When upon death receptor activation, cells have lower levels of DISC formation and active caspase-8 (Type II cells), the progression of the cell death program relies on an amplification loop induced by cleavage of the Bcl-2-family protein Bid by caspase 8 and subsequent release of cytochrome c from mitochondria [11,12]. In contrast, TNFR1 signaling results in the formation of two signaling complexes. TNF-induced complex 1 formation induces the recruitment of RIP (receptor-interacting protein), TRADD (TNFR-associated death domain protein) and TRAF-1/2 (TNFR-associated factor). This complex lacks FADD and procaspase-8 but is reported to translocate to the cytosol, where FADD, caspase-8/10 and FLIP are finally recruited

R. Franco et al. / Mutation Research 674 (2009) 3–22

Fig. 1. Environmental stress, oxidative stress and apoptosis. Exposure to environmental stressors has been recognized to contribute to the progression of human diseases such as immunosuppression, cancer and neurodegeneration. It has been also demonstrated that many of the toxic effects elicited by exposure to these environmental stressors are mediated by the regulation of apoptosis (programmed cell death) and redox (reduction/oxidation) signaling [2–7]. Environmental stressors have been shown to induce apoptosis by activating a wide variety of signaling pathways mediated by mitochondria, DNA damage and/or endoplasmic reticulum stress (intrinsic pathways) as well as by activation/modulation of death receptors (extrinsic pathways) [5,63,241,418–420]. Apoptosis induced by environmental toxicants is widely associated with alterations in redox homeostasis which include both the depletion of antioxidant defenses (such as GSH) and the increase accumulation of reactive species (RS) of oxygen or nitrogen. Environmental stressors have been reported to exert their prooxidant effects through a direct damage of the mitochondria or indirectly via activation of distinct apoptotic pathways such as death receptor activation, ER-stress and/or DNA damage. Environmental stressors such as metals and radiation are known to exert direct prooxidant effects via different biochemical oxido/reduction mechanisms. Although different environmental stressors induce redox signaling via different pathways according to their specific metabolism and reactivity, it is in general acknowledged that toxic effects of environmental stressors are mediated by triggering apoptosis and oxidative stress [5,65,68,241,312].

to form the traddosome or complex II where activation of caspase-8 takes place [13]. The intrinsic pathway of apoptosis is also referred to as the mitochondrial pathway. It is activated by a wide variety of cytotoxic stimuli or environmental stressors. Although the mechanisms by which these stimuli trigger apoptosis seem to differ, they all convey in the release of proapoptotic proteins from the mitochondria including cytochrome c. Activation of the mitochondria pathway and the release of cytochrome c is associated with the opening of the mitochondrial permeability transition pore (MPTP, composed of the voltage-dependent anion-channel [VDAC], the adenine–nucleotide translocator [ANT], and cyclophilin D) and loss of the mitochondrial membrane potential (MMP). However the exact mechanisms and causative roles that these latter processes have on cytochrome c release are still controversial [14,15]. Distinct mitochondrial components and mitochondrial released proteins such as AIF, EndoG, ANT, cyclophilin D, Bit1, p53AIP, GRIM-19, DAP3, Nur77/TR3/NGFB1, HtrA2/Omi and Smac/Diablo have been proposed to participate in the mitochondrial pathway to apoptosis. However, recent reports have challenged their role in apoptosis [16]. The intrinsic pathway is also regulated by the Bcl-2 family of proteins. The BH3-only proteins Bad, Bid, Bim, NOXA, and PUMA (members of the Bcl-2 family of proteins) regulate the antiapoptotic Bcl-2 proteins (Bcl-2 and Bcl-xl) to promote apoptosis. Bcl-2 and Bcl-xl inhibit Bax and Bak. Induction and/or activation of BH3-only proteins de-repress Bax and Bak by direct binding and inhibition of Bcl-2 and other antiapoptotic family members. Bax and Bak are crucial for inducing permeabilization of the outer mitochondrial membrane and the release of cytochrome c. This leads to the recruitment of APAF1 into the apoptosome and activation of caspase-9 that in turn stimulates the activation of execution caspases [15,17,18].

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Another intrinsic pathway for apoptosis induction is that activated by stress to the endoplasmic reticulum (ER). Because the ER requires several factors for its optimum protein folding capacities, including ATP, Ca2+ and an oxidizing environment, it is highly sensitive to stresses that perturb cellular energy levels, the redox state or Ca2+ concentration. Such stresses result in the accumulation and aggregation of unfolded proteins which are toxic to cells and, consequently, numerous pathophysiological conditions are associated with ER stress, including ischaemia, neurodegenerative diseases and diabetes. To date the mechanisms involved in ER stress-induced apoptosis are still under debate. Severe ER stress has been proposed to lead to the activation of JNK (c-jun N-terminal kinase) kinase and induction of C/EBP homologous protein (CHOP) which by impairment of the anti-apoptotic function of Bcl-2 leads to the activation of Bim, Bax and Bak, transmission of the signal from the ER to the mitochondria and execution of death by activation of caspases [19,20]. An interplay between the mitochondria- and the ER stress-pathways of apoptosis has been increasingly recognized [21]. DNA is the main target of environmental genotoxins such as alkylating compounds, polycyclic aromatic hydrocarbons, biphenyls, heterocyclic amines, ultraviolet (UV) light and ionizing radiation. Specific DNA lesions or damage are known to trigger apoptosis. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA crosslinks and DNA double-strand breaks (DSBs). Apoptosis induced by many genotoxic compounds including environmental stressors is the consequence of blockage of DNA replication, which leads to collapse of replication forks and DSB formation. DSBs are detected by ATM (ataxia telangiectasia mutated gene) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to the CHK1, CHK2 checkpoint kinases and p53. p53 induces the transcriptional activation of proapoptotic factors such as FAS, PUMA and Bax. However, non-transcriptional regulation of apoptosis by p53, and p53-independent pathways have also been described. p53 backup systems also exist that involve CHK1/CHK2, E2F1 activation and p73 up-regulation, leading to Bax, PUMA and NOXA transcription. DNA damage-induced apoptosis can also be triggered by inhibition of RNA synthesis, which leads to a decline in the level of MKP1 (mitogen-activated protein kinase phosphatase) causing sustained activation of JNK and AP-1, which stimulates death-receptor activation. DNA damage-induced apoptosis seems to signal through the intrinsic mitochondrial pathway of apoptosis. Direct mitochondrial roles for p53, histone H1.2 release, Nur77 and caspase-2 activation have also been described. Other proteins such as DAXX, FADD and Nu77 also appear to play important roles in DNA damage-induced cell death [22,23]. Once activated, initiator caspases converge in the activation of execution caspases 3, 6 and 7 which further cleave different cellular substrates leading to the organized demise of the cell. Although compensatory roles have been described for caspase-dependent apoptosis [10,24], caspases have non-redundant roles in apoptosis [25,26]. In fact, they have also been recently shown to participate in the regulation of the initiator phase of apoptosis by positive feedback loops under specific circumstances [27–30]. Although caspases have always been considered the central players in apoptosis, several other enzymes have been shown to play important regulatory roles in the regulation of cell death. A wide variety of enzymes such as protein kinases, phosphatases, calpains, transcription factors and several other adaptor or scaffolding proteins have been described to participate in several pathways of apoptosis in distinct ways [17,31–42]. Among these, p53 and stress activated kinases need more attention because of their central involvement in environmental stress-induced apoptosis. Induction of apoptosis is an essential function of p53 as a tumor suppressor in response to DNA-damage, ER-stress, UV and ionizing radiation and hypoxia. p53 activity is highly governed through complex networks of post-translational modifications, including phosphorylation, acety-

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lation, ubiquitination, sumoylation, neddylation, glutathionylation and cytoplasmic sequestration, etc. p53 can activate a variety of downstream targets in a sequence-specific manner to induce apoptosis. p53 activates genes involved in both extrinsic and intrinsic pathways through transcription-dependent mechanisms or induces apoptosis through transcription-independent mechanisms. For example, p53 has been shown to regulate apoptosis through the up-regulation of death receptors located at the plasma membrane (Fas, DR4, and DR5). At the level of the mitochondria, overexpression of Bcl-2 protects cells from p53-dependent apoptosis. p53 has been shown to regulate proapoptotic Bax, PUMA, Noxa, Bid, Apaf-1 and caspase 6. Finally, p53 has also been shown to transcriptionally repress Bcl-2, Bcl-xl, and survivin [43,44]. Stress conditions have been shown to induce apoptosis via transcriptionindependent p53 activation which involves its translocation to the mitochondria in response to genotoxic, hypoxic, and oxidative stresses. Translocation of p53 to the mitochondria induces apoptosis via cytochrome c release and activation of the intrinsic pathway which in turn is also regulated by Bcl-2 protein family members. In fact, it has been shown that p53 antagonizes Bcl-2, Bcl-xl and Mcl-1 antiapoptotic activities and thus, allowing proapoptotic Bax, Bak and Bid to trigger apoptosis. Activation of Bax and induction of the mitochondrial apoptotic pathway have been shown to depend on p53 localization in the cytosol which correlates with the same localization reported for Bax [45,46]. Mitogen-activated protein kinases (MAPKs) such as ERK, p38 and JNK (these last two also named stress-activated protein kinases, SAPK) have been widely reported as central players of stressinduced apoptosis. More importantly they are very well known for their regulation by oxidative stress and reactive species (RS). MAPKs are all serine/threonine kinases that are directed by a proline residue and are activated by threonine/tyrosine phosphorylation events. They all operate in a cascade fashion with a MAPK kinase kinase (MAPKKK) phosphorylating and activating a MAPK kinase (MAPKK) and the MAPKK phosphorylating and activating a MAPK. Inhibition of MAPKs has been demonstrated to protect against apoptosis induced by different conditions of stress. However, many examples also exist about the protective effects of MAPKs activity against apoptotic cell death. For JNK, its activation kinetics has been proposed to determine its role in induction or inhibition of apoptosis. Sustained activation of JNK has been proposed to have a role in promoting apoptosis. Moreover, the dynamic balance between mitogen (growth factor)-activated ERK and stress-activated JNK-p38 pathways seems to be important in determining whether a cell survives or undergoes apoptosis. In general, MAPK activation seems to regulate the intrinsic mitochondrial pathway via regulation of the Bcl-2 family members, regulation of p53 and transcriptional regulation of many other genes via transcription factors such as c-Jun, ATF2, p53, and c-Myc [37,47–51]. Apoptosis signal-regulating kinase 1 (ASK-1) is a MAPKKK that triggers the phosphorylation/activation of JNK and p38 in response to stress-induced apoptotic signals. ASK-1 is regulated by the redox status of the cell via thioredoxin/glutaredoxin-mediated inhibition. Thioredoxin/glutaredoxin oxidation leads to activation of ASK-1 by autophosphorylation/homodimerization and recruits homodimer TRAF-2 which in turn activates MAPKK and MAPK. ASK-1 not only acts as an apoptotic redox sensor but also integrates multiple death signals from cell surface receptors and organelles such as ER. Finally, other proteins such as DAXX have been reported to regulate ASK-1 mediated apoptotic signaling [50,52,53].

3. Oxidative stress and apoptosis Environmental stressors are well known to induce oxidative stress and alterations in the cellular redox balance (see Fig. 2). In

Fig. 2. Environmental toxicants induce alterations in redox homeostasis. Exposure to environmental stressors has been widely demonstrated to induce alterations in the cellular redox balance by different mechanisms interconnected. (1) Environmental toxicants can directly attack the mitochondria inducing the generation of ROS. ROS can further induce the depletion of antioxidant defenses and mediate other oxido/reduction reactions that promote oxidative stress. (2) Environmental agents can directly deplete the cellular antioxidant defenses. For example, depletion of intracellular GSH (and the concomitant reduction in GSH/GSSG ratio) has been shown to occur by the direct conjugation/reaction of environmental agents to GSH, or indirectly by the activity of GSH-transferases. Depletion of these antioxidant defenses facilitates the accumulation of ROS and other oxido/reduction reactions by environmental toxicants. (3) Environmental stressors have also been reported to induce oxidative stress by mediating a variety of oxido/reduction reactions and/or through different metabolic pathways such as those mediated by detoxifying enzymes. These phenomena can in turn promote mitochondrial damage, ROS formation and depletion of antioxidant molecules in the cell.

addition oxidative stress has been widely shown to regulate apoptosis. However, the complexity of redox signaling is evidenced by several reports showing that oxidative stress exerts both agonistic and antagonistic effects on apoptotic signaling. In fact oxidative stress has been demonstrated to mediate cell proliferation and differentiation, which are considered the opposite of cell death by apoptosis. It is now clear that not only the extent and duration of redox signals are important to determine subsequent cell fate, but also the intracellular localization of the redox signaling and the surrounding cellular environment. Earlier studies suggested that long exposure to oxidative stress leads to cell death, whereas low or transient exposure leads to survival/differentiation. However, several examples exist that contradict the generalization of this hypothesis. In this section, a brief overview is provided in order to give a general perspective of the mechanisms by which oxidative stress and reactive species of oxygen (ROS) and nitrogen (RNS) (in many cases referred to as free radicals) regulate apoptosis. Excellent and thorough reviews exist that give a better understanding of the complexity of these phenomena [2,54,55]. A free radical is defined as a molecule with one or more unpaired electrons in an outermost valence shell. Reactive oxygen species (ROS) include O2 -derived free radicals: superoxide anion radical (• O2 − ) and the hydroxyl radical (• OH− ), as well as nonradical derivatives of O2 such as hydrogen peroxide (H2 O2 ). ROS production is the result of an aerobic environment. • O2 − arises during mitochondrial respiration through reduction of molecular O2 by semiubiquinone. Mitochondria have been largely demonstrated to be the major source for ROS generation during apoptosis induced by both intrinsic and extrinsic signaling. It is estimated that 1-2% of O2 consumed by mitochondria is converted to • O2 − although it can be produced as well through various enzymatic oxidation reactions catalyzed by cytochromes P450, other oxidoreductases and also by NADPH oxidase. • O2 − reacts at diffusion-controlled rates with nitric oxide (NO) produced by NO-synthases leading to the formation of a wide diversity of oxidizing and nitrosating/nitrating species or reactive nitrogen species (RNS). • O2 − can also be dismutated nonenzymatically or enzymatically with the aid of superoxide dismutases (SODs)

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to O2 and hydrogen peroxide (H2 O2 ). SODs exist as Mn (mitochondrial), CuZn (cytoplasmic), and extracellular forms. H2 O2 is also utilized by myeloperoxidases (MPx) to produce hypochlorous acid and other noxious chlorine derived oxidants. Additionally, H2 O2 can be reduced to • OH− through Fenton type reactions, where Fe2+ or Cu2+ act as reducing agents. H2 O2 is reduced to H2 O by GSH peroxidases (GPX) and catalase. The selenium-containing GPX degrade organic peroxides at the expense of GSH. The GSH/GSH reductase (GR) and thioredoxin (Trx)/thioredoxin reductase systems regenerate cellular GSH or reduced Trx, respectively, at the expense of NADPH. GSH per se is the most important antioxidant molecule in the cell and due to its high cytosolic concentration it can also directly scavenge ROS such as • O2 − , • OH− and NO. Other antioxidant molecules (such as ascorbate, vitamin E) and enzymes (such as phospholipid hydroperoxide, peroxiredoxins, glutaredoxins) act as secondary defenses against oxidative stress. Oxidative stress arises if detoxification systems and antioxidants are compromised or if ROS production is excessive, resulting in DNA, protein, and lipid oxidation [2,54,56]. Polyunsaturated fatty acids are constituents of glycerophospholipids and other lipids in plasma and organelle membranes and are the major targets of intracellular oxidizing agents. Lipid peroxidation occurs through a radical-mediated abstraction of a bis-allylic hydrogen atom from either the polyunsaturated ω-3 or ω-6 fatty acids, the delocalized radical reacts then with O2 through radical coupling leading to the formation of lipid peroxyl radicals (LOO• ). LOO• starts a series of radical chain reactions abstracting a hydrogen atom from a polyunsaturated lipid to generate L• . LOO• generates a number of lipid hydroperoxide products such as malondialdehyde (MDA), 4-hydroperoxy-2-nonenal (HPNE), 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE). These aldehyde products can react with individual nucleotides and nucleophilic amino acids, thus inducing several signaling effects. Most highly reactive aldehydes are inactivated by conjugation to GSH, oxidation by aldehyde dehydrogenases and reduction by aldoketoreductases [54]. Although oxidative stress has been largely linked to the activation of distinct apoptotic enzymes, the direct mechanisms involved have remained largely elusive. Recently, post-translational oxidative protein modifications (OPMs), through subtle oxidative events that involve targeted amino acids in proteins, have been shown to regulate the activity of a wide variety of proteins such as kinases (ASK, JNK), phosphatases (PTEN, mitogen-activated protein kinase phosphatases), proteases (caspases), molecular adaptors and chaperones (heat shock proteins and PDI), and transcription factors (Nrf2, NF-kB, AP-1, p53, HIF-1␣) involved in apoptosis. OPMs in general can be classified as reversible and irreversible modifications. ROS also damage the peptide backbone and individual amino acids in proteins. Hydrogen atoms are abstracted from the ␣-carbon in peptide chains and side chains of aromatic residues, and the resulting radicals are trapped by O2 . Oxidative protein damage can be irreversible when protein carbonyls result from breakdown of the peptide backbone. The regulatory role of oxidative stress in signal transduction in physiological settings must exhibit substrate specificity and thus produce reversible oxidations. Highly reactive oxidant species such as ozone, hypochlorous acid, • ONOO− , nitrogen dioxide, and • OH− are thought to oxidize biomolecules without preference or specificity. Herein, oxidative modifications, such as the 3-nitrotyrosine and protein carbonyls caused by these oxidants, are not easily reduced. OPMs by these species may lead to the aberrant activation of signal transduction cascades, often resulting in pathophysiology. Physiological oxidants such as NO, • O2 − and H2 O2 , have been implicated in reversible OPMs at the cysteine level that underlie homeostatic control and diverse biological responses. In addition to cysteines, methionine, tryptophan, and tyrosine residues are also prone to oxidative modification. Cysteine residues can be modified through alternative redox-based modifi-

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cations (nitrosylation, SNO; hydroxylation, SOH; glutathionylation, SSG; disulfide bond formation, S-S) that may enable differential effects on protein function. Cysteines are also targeted by alkylating species (such as acrolein), HNE, avicins (formed endogenously or encountered through environmental insults) and by acylation. Transition metals may catalyze S-nitrosylation of cysteinyl moieties. H2 O2 also oxidizes cysteines, leading to the formation of SOH, which can further be oxidized to sulfinic (SO2 H) and sulfonic acids. Sulfenic acids are by-products of nitrosylation and targets of glutathionylation. Glutathionylation refers to the formation of protein mixed disulfides between the cysteine of glutathione and a cysteine moiety of a protein. A wide variety of enzymes regulate these OPMs including sulfiredoxins, thioredoxins, peroxiredoxins, glutaredoxins and GSNO reductases or GSH-dependent formaldehyde dehydrogenase [57,58]. Oxidative stress-induced apoptosis has been largely associated to the activation of the intrinsic pathways of apoptosis at the level of the mitochondria. One important target of ROS is the mitochondrial DNA (mtDNA) due to the close proximity to the electron transport chain and the lack of protective histones. Oxidative mtDNA damage induced by ROS leads to lethal cell injury due to mitochondrial genomic instability leading to respiratory dysfunction through the disruption of electron transport, mitochondrial membrane potential, and ATP generation. ROS in the mitochondria can also directly oxidize and inactivate proteins such as mitochondrial aconitase and complex I NADH oxidase leading to further ROS overload. Lipid peroxidation at the level of the mitochondria also impairs mitochondrial metabolism and induction of the MPTP. Finally, cytochrome c which is bound to the inner mitochondrial membrane by an association with the anionic phospholipid cardiolipin has been shown to be released via oxidation of cardiolipin during apoptosis which precedes its release to the cytosol [59]. Oxidative DNA damage and oxidative-induced ER stress are other important apoptotic signaling cascades activated by oxidative stress (see previous section). Oxidative damage to DNA leads to the formation of lesions such as 8-oxo-deoxyguanosine, 8-oxodeoxyadenosine, and deoxythymidine glycol which are selectively excised from DNA by DNA glycosylases. It is generally accepted that oxidative stress and ROS cause DNA damage, whereby insufficient cellular repair mechanisms contribute to apoptosis. The response to oxidative DNA damage appears to involve p53 which has been proposed to sense oxidative damage to DNA [60]. ROS and RNS have been shown to directly trigger the activation of distinct signaling cascades induced by ER stress including activation of JNK and dissociation of the TRAF2–ASK1 complex, transcriptional activation of CHOP, and caspase activation. Protein disulfide isomerase (PDI) which is the most abundant chaperone in the ER facilitates the folding and disulfide bond formation of its protein substrates. PDI is regulated not only by post-translational oxidative modifications (nitrosylation and glutathionylation) but also by the ER oxidase (ERO1), which restores reduced PDI to an oxidized state through disulfide exchange with ERO1. ERO1 activity is also regulated through modulation of noncatalytic cysteine residues and has been shown to be inhibited under oxidized conditions in the ER [61]. Redox imbalance in the ER lumen is the most frequent cause of ER stress-induced apoptosis, which involves the impairment of oxidative protein folding, the accumulation of unfolded/misfolded proteins in the lumen and the initiation of the unfolded protein response. In the ER, changes in the luminal redox state are sensed by secretory proteins to be folded (via ER chaperone Bip), and also directly by transmembrane proteins involved in signaling such as ATF6. Several antioxidant protective systems such as glutathione, ascorbate, flavin adenine dinucleotide (FAD), tocopherol and vitamin K exist in the ER. Formation of disulfide bonds is required for the proper folding of secretory and membrane proteins in the ER and thus, redox imbalance leads to the accumulation of

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unfolded/misfolded proteins in the ER lumen. Redox-sensitive thiols in the ryanodine receptor calcium channel are also targets for oxidoreduction that regulates the open probability of the channel. More recently, the InsP3 receptor (InsP3R) has also been demonstrated to be regulated by ER luminal redox status through a direct interaction with ERp44, a thioredoxin family member [62]. 4. Molecular mechanisms involved in apoptosis induced by environmental stressors We have summarized above the general pathways involved in the activation of apoptosis and how these signaling pathways can be modulated by oxidative stress. Environmental stressors are widely known to induce oxidative stress and studies so far have demonstrated a clear correlation between environmental stress, oxidative stress and apoptosis. We next overview the molecular mechanisms by which specific environmental stressors mediate apoptosis and its relationship with oxidative stress (Fig. 1). 4.1. Metals Oxidant-mediated damage has been widely reported as the main mechanism of metal-induced cytotoxicity. Iron (Fe)-, copper (Cu)-, chromium (Cr)-, cobalt (Co)-, vanadium (Va)-, cadmium (Cd)-, arsenic (As)- and nickel (Ni)-mediated toxicity has been widely reported to involve oxidative DNA damage, lipid peroxidation and changes in calcium and sulfhydryls homeostasis [63–69]. We next summarize the molecular mechanisms and signaling cascades involve in metal-induced apoptosis. 4.1.1. Antimony (Sb) Sb exposure has been shown to induce DNA damage and apoptosis. Because Sb and arsenic belong to the same periodic group and have the same oxidation states, it is plausible that the DNA damage induced by Sb follows similar pathways as those for arsenic. Sb induces oxidative stress and generates ROS associated with MMP depolarization. However, whether ROS generation are a cause or consequence of MMP loss is still unclear [63]. Sb has been recently shown to induce ROS formation and activate JNK and its downstream target, AP-1 in a SEK1-dependent manner, an upstream regulator of JNK [70]. 4.1.2. Arsenic (As) Millions of people worldwide are exposed to As mainly through drinking water contaminated from natural mineral deposits. As exposure to humans results in degenerative, inflammatory and neoplastic changes of skin, respiratory system, lymphatic system, nervous system and reproductive system [71]. As-induced apoptosis is considered a potential therapeutic approach to distinct malignancies [72–77]. Apoptosis induced by As exposures has been demonstrated mediated by a wide variety of signaling cascades. As-induced oxidative stress has been largely proposed as a central player in the activation/regulation of these cell death pathways [78–85]. The sensitivity of different cell lines to undergo apoptosis is in general inversely proportional to GSH concentration [86–90]. As-induced GSH depletion has been clearly correlated to the progression of apoptosis [85,91–94]. Surprisingly alterations in GSH homeostasis independent from oxidative stress have also been suggested to regulate As-induced cell death [91]. Studies so far suggested three distinct mechanisms by which As depletes cellular GSH pools: (1) via GSH-mediated reduction of pentavalent to trivalent arsenicals where GSH acts as an electron donor; (2) direct interaction of GSH with As; and (3) by its oxidation through arsenic-induced generation of free radicals [71]. Accordingly, activation of distinct apoptotic cascades by As has been

demonstrated to correlate with alterations in GSH homeostasis [95,96]. Cell death mediated by oxidative stress from As exposure has been demonstrated to be largely prevented by GSH or NAC [97–104]. Interestingly, vitamin C (ascorbate or ascorbic acid) has been shown to potentiate As-induced apoptosis by induction of GSH depletion and oxidative stress. However, this effect has been reported to be mediated by the extracellular interaction of vitamin C with transition metals [89,105,106]. Accordingly, intracellular loading of dihydroascorbate (which is further reduced to ascorbate in the cytoplasm) prevents As-induced apoptosis [107,108]. Vitamin E analogues (␣-tocopherol) have also been shown to potentiate As-induced apoptotic cell death [109,110]. Interestingly, coadministration of vitamin C and E to As exposed rats in vivo seems to exert a protective effect against apoptosis and oxidative stress [111–113]. Overexpression of GST has also been shown to be protective against As-induced apoptosis and H2 O2 formation [104,114,115]. As is also known to interact with sulfhydryl (SH) groups (thiols) and thus interfering with the proteins’ enzymatic activity. For example, As has been recently demonstrated to induce apoptosis via inhibition of the thioredoxin system through a direct oxidation of the active cysteine thiol motif of thioredoxin reductase and thioredoxins [66,116]. As can either induce ROS that target the mitochondria or directly attack the mitochondria leading to the generation of ROS. The apoptotic effect of As has been directly ascribed to oxidative stress and the regulation of the mitochondrial pathway of apoptosis via the induction of proapoptotic Bcl-2 family members (Noxa, Bmf, Bax and Bim), the loss of the MMP, the release of cytochrome c and AIF [96,102,117–121]. Accordingly, overexpression of Bcl-2 prevents As-induced apoptosis [85,117,122]. Several reports also demonstrate that As-induced apoptosis is regulated/mediated via the activation of the death receptor pathway [123–129]. However, activation of caspase 8 and apoptosis by As exposure has also been shown to be independent of death receptor activation [127,130]. As-induced apoptosis has also been reported to be mediated via distinct signaling pathways such as those regulated by Rho kinase [131], SAPKs (JNK and p38) [132–139], as well as p53 [140–142]. SAPK activation has been observed to lead to induction of death receptors-mediated apoptosis [95,143]. As-induced apoptosis has been shown to induce cell cycle arrest via p21 and p53 signaling cascades [128,142,144–147]. However, a recent study has clearly separated the effects that As has on cell cycle arrest from its proapoptotic effects [115]. More recently As was shown to mediate apoptosis via inhibition of Bcr-Abl mRNA translation, which is known to induce the transcriptional regulation of antiapoptotic proteins [148]. In addition, phosphorylation of promyelocytic leukemia (PML) protein by MAPK has been shown to contribute to the proapoptotic effects of As [149]. As-induced apoptosis involves the activation of caspases including caspases 8, 9 and 3. Interestingly, caspase-independent apoptosis has also been reported upon exposure to As [63,67,103,117,118,150,151]. As has also been described as a trigger of ER-stress pathways for apoptosis [152,153]. In this regard, alterations in intracellular Ca2+ homeostasis have been demonstrated to participate in As-induced apoptosis [153–155]. As has been demonstrated to impair/downregulate the function of antiapoptotic signaling proteins such as Bcl-2, NF-kB and RIP [72,156–158]. On the other hand, resistance to As-induced apoptosis has been correlated to the up-regulation of MAPK-, PI3K (phosphoinositide 3-kinase)/Akt- and IkappaB kinase beta (IKKbeta)/NF-kB dependent signal transduction cascades [135,159–172]. Interestingly, the antiapoptotic role of distinct survival signaling cascades on As-induced cell death has been associated to the regulation of GSH homeostasis and oxidative stress [173,174]. As exposure has been recently shown to induce authophagic cell death [175–177].

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4.1.3. Beryllium (Be) Be-induced apoptosis has also been ascribed to the generation of ROS. Accordingly, Be-induced apoptosis is prevented by SOD mimics. Be-induced apoptosis has been shown to be caspase-dependent. Be also induces transcriptional activation of c-fos, c-jun and cmyc, together with PKC activation in a ROS-independent manner [63,178]. 4.1.4. Cadmium (Cd) Cd is an important toxic environmental heavy metal. Occupational and environmental pollution with Cd results mainly from mining, metallurgy industry and manufacture of nickel–cadmium batteries, pigments and plastic stabilizers. Cigarette smoke as well as food, water and air contamination are also important sources of human Cd intoxication. Cd induces apoptosis in a wide variety of cell lines and has toxic effects in several tissues [179–183]. Cd is a highly toxic metal that indirectly generates several RS such as H2 O2 , • O − , • OH− and NO by replacing Fe and Cu in various cytoplasmic 2 and membrane proteins such as ferritin and apoferritin and thus, increasing the amount of unbound free or chelated Cu and Fe ions which then participate in oxidative stress via Fenton reactions. High concentrations of Cd inhibit the activity of the antioxidant proteins catalase and GR. In this way, NAC and other non-thiol antioxidants have been shown to protect against Cd-induced apoptosis [184,185]. Cd also depletes GSH levels and increases protein-mixed disulfides and protein ubiquitination [186]. The susceptibility to Cdinduced apoptosis depends on metallothionein (MT), which binds to Cd to prevent toxic damage. Administration of exogenous metallothionein to rats exposed to Cd results in a decrease of oxidative stress and thus, a negative correlation exists between methallothionein levels and apoptosis after Cd exposure. Cd-induced apoptosis has been shown to be mediated by MAPK, SAPK, Ca2+ /calmodulindependent kinase II, mitochondrial damage (via Ca2+ overload or inhibition of the electron transport chain), caspase-dependent, caspase-independent, ceramide and ROS pathways [187–201]. All these pathways seem to converge at the level of the intrinsic mitochondrial pathway of apoptosis because Bcl-2 overexpression prevents cytochrome c release and caspase activation and consequently Cd-dependent apoptosis. Protein expression levels of other proapoptotic and antiapoptotic mediators such as Bax, Bcl-xl and Bad have also been shown to be regulated by Cd treatment [202]. Cd-induced apoptosis is also reported to be mediated by the extrinsic FasL-Fas-FADD caspase-8 pathway (including BID and execution caspase activation), as well as by DNA damage. The production of DNA DSB after Cd exposure is likely to be due to oxidative stress. Cd induces single strand breaks in DNA (SSB), chromosomal aberrations, sister chromatid exchanges and DNA–protein binding failures in several types of mammalian cells. More recently, Cd was reported to induce apoptosis by ER stress pathways via generation of ROS and activation of ATF6, CHOP, XBP1 and caspase 12 pathways [203–205]. Finally Cd has been shown to induce lipid peroxidation and membrane leakiness. Cd exposure also regulates redox-sensitive transcription factors such as p53 and NF-kB [63,65,206–208]. 4.1.5. Chromium (Cr) Once inside the cell, chromates Cr(VI) are reduced in the presence of cellular reductants, and cause a wide variety of DNA lesions including Cr–DNA adducts, DNA–protein crosslinks, DNA–Cr–DNA crosslinks and oxidative damage. Once formed, Cr(V) can react via Fenton reactions with H2 O2 forming • OH− which causes DNA damage. Reduction of Cr(VI) by GSH leads also to the generation of GS• (thyil) radical that can further lead to the formation of • O2 − , which further reduces Cr(VI) to Cr(V) catalyzing the decomposition of H2 O2 to • OH− . Cr(V) can also be reduced by ascorbate, GSH and to Cr(IV) participating in Fenton chemistry to generate • OH− [64].

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Because Cr(VI) is unable to react with macromolecules, Cr(V) and Cr(III), intermediates of Cr(VI) reduction, have been proposed to trigger the activation of DNA-dependent protein kinase (DNA-PK), p53 activation and cell apoptosis [209]. The DNA damaging effect of Cr(VI) has been proposed to involve ROS generated by Cr(VI) reduction. Cr has been largely shown to induce cell cycle arrest and apoptosis [210]. Cells exposed to Cr undergo p53-dependent apoptosis induced by DNA–Cr–DNA cross link. DNA-damage and p53 activation thus have been demonstrated to be important intermediators of Cr-induced apoptosis [211]. Activation of p53 by Cr(VI) has been reported to be mediated by DNA damage or ROS generated during Cr(VI) reduction which activates DNA-PK, ATM and ATR. Cr can also activate stress activated kinases such as JNK and p38, which in turn modulate p53 [212]. p53 also contains several redox-sensitive motifs which might mediate its direct regulation by Cr-induced oxidative stress through the mitochondrial pathway. H2 O2 and • OH− have been proposed to mediate p53 activation and cell death. p53-independent apoptosis has also been suggested to participate in Cr-induced apoptosis. The p53-independent pathway involves the mitochondria. Cr induction of ROS results in mitochondrial damage and down-regulation of Bcl-2 that leads to apoptosis by inducing the release of cytochrome c [213–215]. Antioxidants such as vitamin C and NAC have been reported to be protective against Cr-induced cell death [216]. However, both caspase-dependent and–independent apoptotic pathways have been observed to be induced by Cr exposure [63,67,217–220]. 4.1.6. Cobalt (Co) Co leads to oxidative DNA damage via • OH− formation through the Fenton reaction [64]. Co exposure has been reported to activate hypoxia-inducible factor-1 (HIF-1), MAPKs and accumulation of p53 [221,222]. Co has also been observed to induce ROS and apoptosis in different cell lines [223]. Co-induced apoptosis has been related to both extrinsic and intrinsic apoptotic pathways [224–226]. Co induces not only cytochrome c release, and caspase 9 and 3 activation, but also activation of p38 [63]. 4.1.7. Copper (Cu) Cu ions are prone to participate in the formation of ROS. Cu(II) is reduced in the presence of ascorbic acid and GSH to Cu(I), which catalyzes the formation of • OH− through the decomposition of H2 O2 via Fenton reactions leading finally to lipid peroxidation. Cu is also capable of inducing DNA strand breaks and oxidation of bases via ROS [65]. Cu-induced apoptosis has been demonstrated to involve the generation of ROS, induction of Bax and inactivation of NFkB [24]. In addition, two pathways for Cu-induced apoptosis have been described. The first one involves the activation of Bax and cytochrome c-mediated activation of caspase 9 and caspases 3. On the other hand, ROS-induced AIF release and caspase-independent pathway have also been described [227]. Cu has also been shown to activate p53-dependent and independent pathways of apoptosis [228]. Finally, it has recently been demonstrated that the X-linked inhibitor of apoptosis (XIAP) is involved in Cu homeostasis by promotion of the ubiquitination and degradation of COMMD1, a protein that promotes the efflux of Cu from the cell. XIAP was also shown to bind Cu directly and to undergo a conformational change that destabilizes XIAP. The Cu-bound XIAP is unable to inhibit caspases, and cells that express this form of the protein exhibit increased rates of cell death in response to apoptotic stimuli [229,230]. 4.1.8. Lead (Pb) Pb has been shown to induce the generation of ROS, including hydroperoxides, singlet oxygen, and H2 O2 . In addition, Pb induces the direct depletion of antioxidant molecules. Pb has in fact been shown to directly conjugate cytosolic GSH. Pb also binds to enzymes that have functional sulfhydryl groups, thus altering their enzy-

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matic activity and redox balance. Pb has been shown to inhibit aminolevulinic acid dehydrogenase (ALAD) and GR. Pb induces lipid peroxidation and accumulation of MDA (malondialdehyde) and also decreases membrane fluidity. Pb exposure triggers apoptosis in a wide variety of cell lines where it has been demonstrated that mitochondria play a critical role. Pb-induced apoptosis has been shown to be mediated by GSH depletion and generation of ROS [231,232]. Because Pb mimics Ca2+ , Ca2+ overload-related mechanisms are possible triggers for Pb-induced apoptosis via depolarization of MMP and opening of the MPTP, resulting in triggering of the mitochondrial intrinsic pathway of apoptosis. Bax translocation has been suggested to be involved in Pb-induced apoptosis and overexpression of Bcl-xl blocks its progression. Pb also induces Bcl-2 down-regulation and up-regulation of Bax. Recently, Pb has been shown to promote MMP loss, release of cytochrome c, and altered Bcl-2/Bax ratio, and these effects where shown to be associated with Ca2+ overload and ROS formation. In addition, Pb can induce activation of p53 by DNA damage resulting in caspase 3 dependent apoptosis. [63,233,234]. 4.1.9. Mercury (Hg) Hg is an ubiquitous environmental toxin that causes a wide range of adverse health effects in humans, and is found in different forms which have been observed to vary in the apoptotic pathways triggered [235,236]. Hg ions have a high affinity for reduced sulfur atoms of endogenous thiol-containing molecules, such as GSH, cysteine, metallothionein, homocysteine, NAC and albumin. Therefore the biological effects of inorganic or organic Hg are related to their interactions with sulfhydryl-containing residues. Indeed, binding to thiols mediates Hg-induced GSH depletion that causes oxidative stress (at the level of the mitochondria) and lipid peroxidation. Once absorbed in the cell, Hg forms covalent bonds with GSH and the cysteine residues of proteins. A single Hg ion can bind to and cause irreversible excretion of two GSH molecules. Released GSH-Hg conjugates result in greater activity of the free Hg ions disturbing GSH metabolism and damaging cells. Hg also depletes other antioxidant defenses in the cell such as vitamin C and E. Inorganic Hg is also suggested to increase H2 O2 production by impairing the efficiency of oxidative phosphorylation and the electron transport chain at the ubiquinone-cytochrome b5 step. Hg-induced apoptosis is indeed associated to ROS formation and GSH depletion [237]. Interestingly Hg also inhibits the antiapoptotic signaling cascade of NF-kB [238]. A link between Ca2+ homeostasis and Hg-induced cell death has been established, where Ca2+ regulates ROS production modulating downstream p38-dependent apoptotic signaling [239]. Finally, Hg has been shown to trigger apoptosis in cerebellar granule neurons by facilitating Ca2+ entry through membrane channels [240]. Algae and bacteria methylate Hg entering the waterways. Methylmercury (MeHg) makes its way through the food chain into fish and shellfish and ultimately into humans making it an important environmental concern. MeHg has been shown to induce apoptosis in several cell types. MeHg-induced apoptosis involves the activation of the mitochondrial pathway and Bcl-2 protects against cell death progression. In lymphocytes, MeHg induces GSH depletion which is followed by MMP loss, cytochrome c release, ROS generation, and cardiolipin oxidation [241–243]. MeHg is also known to be an uncoupling agent that stimulates state IV respiration and displaces Fe and Cu from their intracellular binding sites accelerating Fenton-mediated ROS formation [65,244]. Interestingly, a recent report shows that GSH depletion but not ROS is the primary step in the redox-regulation of MeHg-induced apoptosis [245]. In addition, MeHg increases intracellular Ca2+ by accelerating the influx of Ca2+ from the extracellular medium and also induces lysosomal damage [246]. MeHg-induced apoptosis has also been shown to activate both the intrinsic mitochondrial and ERstress pathways regulated by ASK/JNK activation [247]. In excitable

cells, MeHg-induced apoptosis is associated with cell cycle arrest, extracellular accumulation of glutamate by inhibition of its uptake, and activation of the mitochondrial pathway by Bax [248–251]. Thimerosal is an organic Hg compound that is widely used as a preservative in vaccines and other solution formulations. Its use has caused concern about its ability to cause neurological abnormalities due to Hg accumulation. Thimerosal-induced apoptosis is associated with cell cycle arrest, DNA damage by DSB and SSB formation, ROS, GSH depletion and the mitochondrial pathway of apoptosis [252–254]. Thimerosal also induces apoptosis by activation of JNK, p38, BIM and caspase 3 [255,256]. 4.1.10. Nickel (Ni) Ni produces ROS (• OH− ), lipid peroxidation, oxidative DNA damage and GSH depletion [65]. Little is known about the mechanisms for nickel-induced apoptosis. An increase in FasL protein and caspase 3 activation has been reported to be associated with Ni exposure. In addition, Ni has been shown to induce NO production [257]. Furthermore, Ni-resistant cells have a higher basal level of GSH and conversely, GSH depletion stimulates Ni-induced apoptosis. In addition, Ni activates NF-kB and decreases Bcl-2 expression [63,257,258]. 4.1.11. Vanadium (V) V(V), is a transition metal element which can be rapidly reduced to V(IV) by NADPH and ascorbic acid leading to formation of peroxovanadyl radicals, vanadyl hydroperoxide and • O2 − , that can be dismutated to H2 O2 that in turn leads to • OH− accumulation [64]. ROS induced by V have been reported to induce lipid peroxidation and oxidative DNA damage. V compounds activate several signaling proteins including AP-1, MEK-1, ERK, JNK, NF-kB and p53 by the formation of ROS and DNA damage [259]. The activation of several signaling pathways by V has been shown to be mediated by inhibition of protein tyrosine phosphates and the stimulation of tyrosine residue phosphorylation. V has also been shown to trigger or potentiate cell apoptosis [260–263]. V treatment induces activation of caspases 3, 8 and 9, induction of mitochondrial permeability transition, the release of cytochrome c and DNA fragmentation. In vivo studies have shown that V-induced apoptosis is associated with p53 and Bax overexpression as well as Bcl-2 down-regulation [264,265]. In addition, V has also been shown to activate the extrinsic pathway of apoptosis [266]. Pre-treatment with antioxidants, such as NAC and catalase, inhibits apoptosis induced by V suggesting a fundamental role for ROS in this process [67]. 4.2. Particulate matter and smoke Particulate matter (PM) is well known to induce oxidative stress and DNA damage leading to apoptosis through the activation of the intrinsic mitochondrial pathway [267]. Diesel exhaust particulate matter has been shown to induce apoptosis in human airway cells associated to an increase in the expression of SLC30A3 (zinc transporter-3 or ZnT3) [268]. PM (2.5) (i.e., fine particles 2.5 microns or smaller)-induced apoptosis has been shown to be related to Bim up-regulation and its subsequent translocation and activation of the mitochondrial pathway of apoptosis involving MMP loss and increased caspase-9, caspase-3 and PARP-1 activation [269]. Other reports show that PM is able to induce apoptosis by activating not only the extrinsic apoptotic (TNF-␣) pathway (TNF-alpha secretion, caspase-8 and -3 activation) [270], but also the mitochondrial pathway (cytochrome c, caspase 9 and 3 activation). Moreover, changes in the transcription levels of p53, Bcl-2, Bax genes and DNA fragmentation were also reported in human lung cells [271]. Urban PM has also been reported to mediate apoptosis via the intrinsic mitochondrial pathway in a p53-dependent manner [272]. Ca2+ overload induced by activation of transient receptor potential

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channels (TRPV) has been also recently demonstrated to mediate apoptosis induced by PM [273,274]. Cigarette (tobacco) smoke is well known to induce oxidative stress, DNA damage and apoptosis [275–279]. In human umbilicus venous endothelial cells, cigarette smoke induces apoptosis via activation of caspase 3 and increased p53 levels [280]. Recently, cigarette smoke has been shown to induce DISC formation differentially regulated by PKC␣ and PKC␨ via the PI3K/Akt pathway [281]. In addition, tobacco smoke has been observed to down-regulate NF-kB-dependent antiapoptotic genes, to induce the activation of caspases, cleavage of PARP and caspase-activated DNase, with the concomitant increase in the rate of apoptosis in the lung parenchyma [282]. In lung tissues, cigarette smoke-induced apoptosis was associated to both the activation of p38/JNK-JunFasL signaling, an increase in Bax-Bid/Bcl-2-Mcl1 ratio, induction of p53, and release of cytochrome c leading to the activation of caspases [283,284]. Furthermore, cigarette smoke extract has been observed to trigger apoptosis in human gastric epithelial cells through the inhibition of Bcl-2 and the activation of a mitochondria-related pathway. Smoke injury in human pulmonary epithelial cells has been shown to involve oxidative stress-mediated caspase-independent apoptosis via the induction of mitochondrialto-nuclear translocation of AIF and EndoG [285]. Other signaling cascades such as activation of phospholipases and ER stress have also been involved in cigarette smoke-induced apoptosis [279,286]. Finally, not only antioxidants and antioxidant-enzymes have been shown to protect against cigarette smoke-induced apoptosis [287,288], but also the redox-sensitive transcription factor Nrf2 was shown to exert antiapoptotic effects against cigarette smoke-induced cell death by regulation of antioxidant defenses [289]. 4.3. Carbon monoxide Carbon monoxide (CO) has been largely demonstrated to exert antiapoptotic effect in different cell types. However, carbon monoxide has also been shown to induce oxidative stress and cell death by apoptosis in brain cells and lymphocytes [290–294]. CO binds to iron or other transition metals promoting prooxidant activities of the more reactive gases, O2 and NO. CO has been shown to induce mitochondrial oxidative and nitrosative stress and decrease in the GSH/GSSG ratio [295]. In Jurkat cells CO stimulates Fas/CD95-induced apoptosis by up-regulation of FADD, caspase 8, 9, and 3 activation, and down-regulation of Bcl-2. Interestingly, this proapoptotic effect was independent of ROS production and involved the inhibition of the Fas/CD95-induced activation of the pro-survival signaling cascade of ERK1/2 [296]. 4.4. Asbestos Asbestos has been largely demonstrated to induce oxidative stress and DNA damage (DSBs) [297]. Several groups have shown that asbestos induces apoptosis in different cell types such as mesothelial and lung epithelial cells. It has been suggested that iron-derived ROS mediate asbestos-induced apoptosis. The iron in the core structure of asbestos can catalyze the formation of • OH− by the Fenton-catalyzed, Haber–Weiss reaction. The amphibole fibers have a higher iron content compared to chrysotile asbestos. Alveolar macrophage-derived • O2 − can mobilize redox-reactive iron from the surface of asbestos. Redox-reactive iron in asbestos also induces synthesis of apoferritin for iron storage. In addition, ROS (• OH, H2 O2 , and • O2 − ) can originate from the cells undergoing impaired phagocytosis of long asbestos resulting in mitochondrial dysfunction from NADPH oxidase activity or from impairment of the electron transport [298,299]. Crocidolite has also been shown to deplete intracellular GSH through its extrusion across the plasma

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membrane and by inhibition of the ␥-glutamyl cysteine synthetase (␥-GCS) [300]. Iron chelators and antioxidants prevent asbestosinduced DNA damage and apoptosis. Asbestos has been shown to release cytochrome c to the cytoplasm, resulting in activation of caspase 9, which suggests a role for the intrinsic mitochondrial pathway in apoptosis [301,302]. Accordingly, overexpression of Bcl-xl prevents MMP loss and apoptosis. Some reports have also shown that both Fas and TNF␣ receptors are increased after asbestos exposure. In addition, chrysotile asbestos activates the Fasmediated death receptor pathway, while TNF␣ levels are increased and released after asbestos exposure. Iron chelators and free radical scavengers prevent TNF␣ release. Asbestos also activates MAPK (ERK1/2) and PKC signaling cascades which have been correlated to apoptosis [298,303–305]. Several studies have also shown that p53dependent transcription has an important role in asbestos-induced DNA damage and apoptosis [306]. Finally, asbestos-induced PARP activation in lung epithelial cells and mesothelial cells leads to apoptosis [298,307]. 4.5. Pesticides Pesticides are widely used in agricultural and other settings, resulting in continuing human exposure. Pesticide toxicity has been clearly demonstrated to alter neurological and immunological functions. In addition, evidence suggests that pesticide exposure predisposes to cancer and neurodegenerative diseases. Pesticides consist of multiple classes and subclasses and exhibit a vast array of chemically diverse structures. Pesticides are commonly referred to by their functional class for the organisms designed to control (e.g., herbicides, insecticides, or fungicides) or by their chemical class (organophosphate, triazine) [308–310]. Pesticide-induced redox signaling has been demonstrated to mediate many of the toxicological effects of these chemicals. Exposure to a wide variety of pesticides induces oxidative stress reflected as accumulation of ROS, lipid peroxidation and DNA damage [311]. However, for certain pesticides, mechanism leading to alterations in cellular redox homeostasis are partially understood. In general pesticides have been shown to alter cellular redox balance by different mechanisms including: (1) by their enzymatic conversion to secondary reactive products and/or ROS; (2) by depletion of antioxidant defenses; and (3) by the impairment of antioxidant enzyme function [4,312]. Rotenone (rotenoid) is a broad-spectrum insecticide, and pesticide. It has been clearly demonstrated that rotenone induces apoptosis by inhibition the mitochondrial respiratory chain complex I. It inhibits the transfer of electrons from iron-sulfur centers in complex I to ubiquinone. This prevents NADH from being converted into usable cellular energy (ATP). Rotenone-induced apoptosis is considered to contribute to the etiology of Parkinson’s disease (PD) [313,314]. Rotenone enhances the amount of mitochondrial Reactive Oxygen Species production which mediate caspase-dependent apoptotic cell death. Accordingly, antioxidants such as GSH prevent rotenone-induced apoptosis [315–318]. Organophosphorus pesticides (OPs) are widely used throughout the world as insecticides in agriculture and as eradicating agents for termites around homes. Organophosphorus pesticides induce apoptosis in immune and neural cells via the mitochondrial pathway [319–322]. Chlorpyrifos and dichlorvos have been shown to induce caspase dependent apoptosis associated to oxidative stress [323–328]. Paraquat is a highly toxic quarternary nitrogen herbicide. Many cases of paraquat acute poisoning and death have been reported over the past few decades. The mechanisms of paraquat toxicity have been reported to involve the generation of superoxide anion (• O2 − ), which leads to the formation of more toxic ROS, such as hydrogen peroxide (H2 O2 ) and hydroxyl radical (• OH− ). Paraquat also induces the oxidation of NADPH, which impairs GSSG recycling to GSH and is also the major source of reducing equivalents for

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the intracellular reduction of paraquat [329]. Accordingly, GSH supplementation has been clearly shown to prevent paraquat-induced toxicity in animal models [329]. Paraquat-induced apoptosis has been demonstrated to involve the intrinsic mitochondrial pathway via activation of Bak [330,331] and activation of SAPK [332], consequently, overexpression of Bcl-2 protects against paraquat-induced cell death [333]. Interestingly, paraquat induced cytotoxicity has also been suggested to be mediated via the activation of the Fas extrinsic pathway of apoptosis [334]. The organochlorine pesticides dichlorodiphenyldichloroethane (DDT), endosulfan and dieldrin have been shown to induce apoptosis via GSH depletion and oxidative stress triggering the intrinsic mitochondrial apoptotic pathway [328,335–340]. Similarly, thiram chemicals have been reported to induce GSH depletion which is paralleled by protein carbonylation, lipid peroxidation and subsequent apoptotic cell death [341]. Carbamate derivatives such as mancozeb have also been shown to induce oxidative stress, DNA damage and activation of the mitochondrial pathway of apoptosis [342]. The organotins di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) have been demonstrated to induce ROS formation, SAPK activation and Ca2+ overload which precede cytochrome c release and apoptosis [343,344]. Finally, the diphenyl ether nitrofen has been reported to trigger caspase 3 activation in a redox-dependent manner [345]. 4.6. Dioxins, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and the role of the arylhydrocarbon receptor (Ahr) Dioxins are contaminants almost exclusively produced by industrial processes, including incineration, chlorine bleaching of paper and pulp, and the manufacture of some pesticides, herbicides, and fungicides. Dioxins and dioxin-like chemicals form a group of structurally related compounds which includes polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), biphenyls (PCBs), and related compounds. Dioxins consist of two benzene rings connected by two oxygen atoms and contain four to eight chlorines, for a total of up to 75 compounds or congeners. The commonly studied dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [346]. Apoptosis induced by TCDD exposure has been reported in different cell types and has been proposed to be largely ascribed to the activation of the Ahr receptor [347,348]. Ahr activation by TCDD has been shown to induce ROS but their role in apoptotic cell death is still considered controversial [349]. TCDD has been shown to induce apoptosis in pituitary cells [350] and in thymocytes via the activation of death receptors [351], TCDD also induces apoptotic cell death in activated T-cells via the extrinsic pathway of apoptosis and down-regulation oc c-FLIP [352–355]. TCDD has been shown to induce apoptosis via Ahr-dependent NFkB-induced FasL expression [356]. In addition, TCDD-induced cell death has also been shown to be induced by PKC and JNK activation in an Ahr-independent manner [357,358]. Polychloridated biphenyls (PCBs) are one of the most widely studied environmental contaminants, which are a mixture of manmade chemicals and range from oily liquids to waxy solids. PCBs were used in hundreds of industrial and commercial applications such as plasticizers in paints, plastics and rubber products, and also as pigment dyes and carbonless copy papers, being released form landfills and other areas to open air. PCBs have been shown to induce apoptosis in different cell types [359–363]. PCB 77 (3,3 ,4,4 tetrachlorobiphenyl), acting as an arylhydrocarbon receptor (AhR) agonist, can induce oxidative stress, activation of JNK, caspase 3 and apoptosis in endothelial cells which was shown to be regulated by the intracellular concentration of GSH [364]. On the other hand, Ahr-independent apoptosis has been reported for both 2,2 ,4,6,6 -PeCB-induced cell death in human monocytic cells [365]

and aroclor 1254-mediated toxicity in mouse spleen cells [366]. PCB-induced apoptosis of human microvascular endothelial cells involves caspase-dependent activation of the cAMP responsive element binding protein (CREB) [367]. Finally, PCBs induce apoptosis in primary renal tubular cells through a PKC␣, caspase-3 and Bcl2/Bax pathway [368]. Polycyclic aromatic hydrocarbons (PAHs) have been proposed to activate the Ahr receptor and induce apoptosis in a p53dependent manner [369]. They have been demonstrated to trigger a caspase-dependent apoptosis, through the mitochondrial pathway associated with the down-regulation of c-FLIP(L), Bcl-xl and up-regulation of p53 via metabolites generated via cytochrome P-450 [370]. PAHs and coal dust exposure also induce Bax overexpression/translocation and apoptosis [371–373]. PAHs have also been shown to alter ionic homeostasis inducing apoptosis via the modulation of Na+ /H+ exchanger [374] or via phospholipase activation [286]. Similarly, PAHs have been observed to induce cell death through the activation of MAPK in a p53-dependent manner [375]. 4.7. Radiation The mechanisms involved in radiation-induced apoptosis (IRA) have been studied with the aim of modulating the apoptotic response and thereby radiosensitivity of transformed cells. IRA can be in general classified as (1) premitotic (or rapid interphase apoptosis), which is induced by high dose radiation and depends on caspase activation but no gene transcription, and (2) postmitotic (including both postmitotic interphase apoptosis and delayed aberrant mitotic apoptosis), which is induced by low dose radiation, which is caspase-independent and requires gene transcription [376]. Ionizing radiation is well known to induce ROS, oxidative stress and depletion of intracellular GSH prior to the loss of plasma membrane integrity. ROS are well known to trigger the mitochondrial apoptosis pathway. Therefore, oxidative stress may play a direct role in radiation-induced apoptosis. More particularly, NADPH-dependent • O2 − generation, peroxidase release and the concomitant generation of • OH− and • ONOO− by low-radiation exposure have been related to the progression of IRA [377]. The mechanisms implicated in IRA involve unrepaired or misrepaired DNA damage. IRA signaling can be initiated in different cellular compartments including the nucleus, cytosol and plasma membrane. p53 plays a pivotal role in the cellular response to nuclear DNA damage. p53 activation causes a delay in cell cycle progression at the G1-S transition, allowing the damaged DNA to be repaired before replication and mitosis occur. If repair fails, p53 triggers the deletion of cells through apoptosis. p53 has been shown to regulate the expression of proapoptotic and antiapoptotic members of the Bcl-2 family such as Bcl-2 and Bax suggesting the involvement of the mitochondrial intrinsic pathway of apoptosis. Other studies suggest that activation of p53 regulates the expression of death receptors and/or their ligands, causing an autocrine or paracrine type of apoptosis. More recently, the ATM has been shown to act as a sensor for DNA damage upstream of p53. In addition, the DNAPK, which plays an essential role in the repair of DSB, has been shown to phosphorylate and activate p53. As mentioned above, transcription-mediated effects of p53 likely involve multiple target genes that act directly or indirectly on mitochondria. However, transcription-independent apoptosis mediated by p53 during IRA has also been reported, which involves the activation of caspase 8 by a FADD-independent mechanism [378]. Ionizing radiation has also been reported to activate acid and neutral sphingomyelinases, which have been reported to mediate IRA. In general, ceramide generation by radiation has been shown to be upstream of the activation of the mitochondrial pathway of apoptosis which involves translocation of Bax. Ionizing radiation also induces de novo synthesis of ceramide by activation of ceramide synthase. In addition,

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ionizing radiation-induced ceramide has been shown to inhibit the antiapoptotic signaling by PI3K. [379]. Several studies have also reported that PKC activation by ionizing radiation modulates apoptosis, but this effect seems to depend on the PKC isoform studied. For example, PKC␦, ␧, ␨ and ␪ have been shown to positively regulate IRA, while PKC␣ and ␩ seem to act as negative regulators [380]. On the other hand, IRA has been demonstrated to involve the activation of SAPKs such as JNK possibly by rapid sphingomyelin hydrolysis to ceramide. However, the mechanisms by which JNK regulates IRA remain inconclusive. It has been suggested that JNK regulates caspase activation and p53. IRA has been reported to be caspase-dependent and seems to involve the mitochondrial intrinsic pathway because Bcl-2 is able to block cytochrome c release and IRA. In addition, the CD95 binding protein Daxx has been shown to enhance CD95-induced apoptosis, and activate the JNK signaling when overexpressed during IRA [381]. Although it is well known that radiation induces apoptosis other types of cell death such as autophagy have been reported to occur in response to radiation exposure. Autophagy induced by ionizing radiation has been recently reported triggered by ER-stress and the unfolded protein response [382].

ever, the fact that overexpression of Bcl-2 and Bcl-xl protects against UVB-induced apoptosis suggests a central role of mitochondria in UVB-induced cell death [5]. UVB radiation has been shown to induce apoptosis via the mitochondrial pathway triggered by the proapoptotic Bcl-2 members Bid, Bad and Bax [403–405]. However, UVB-induced cell death has been also shown to occur in the absence of alterations in mitochondria [398]. ROS formation by UVB radiation has been largely proposed to mediate MAPK and SAPK activation [5]. Recently UVB-induced apoptosis was reported to be mediated via the activation of the ASK1-p38 signaling pathway by ROS that further trigger the mitochondrial pathway of apoptosis [404,406–408]. In melanocytes, activation of JNK by UVB radiation mediates apoptosis via lysosomal membrane permeabilization and Bim phosphorylation [409]. In contrast, several antiapoptotic signaling cascades triggered by UVB radiation have been shown mediated by surviving, galectins 3 and 7, NFAT, Gadd45, the small GTPase RhoE, Notch and cycloxygenase-2 [410–416]. In addition, the E2F1 transcription factor has been shown to mediate apoptotic resistance in response to UVB radiation by promoting DNA repair [417].

4.8. Ultraviolet radiation

5. Conclusions and perspectives

Of the three components of the solar ultraviolet (UV) radiation, only UVA (320–400 nm) and UVB (290–320 nm) can reach the surface of the earth, while UVC (200–290 nm) is completely blocked by the ozone layer. UV radiation induces a wide array of signal transduction pathways, leading to apoptotic cell death, which is considered to be a protective mechanism that removes damaged keratinocytes and avoids cellular transformation. Different pathways of apoptosis have been described to be induced by UV radiation which include activation of death receptors [383–386], DNA damage and the mitochondrial pathway of apoptosis [5,384,387–389]. At physiologically relevant doses, UV radiation primarily generates ROS that can cause lipid peroxidation in cellular membranes and induce oxidative damage to DNA and cellular proteins. UVA irradiation of macromolecules can cause the generation of H2 O2 and • O2 − . Iron-catalyzed reduction of H2 O2 by • O2 − can further generate the highly reactive • OH− . UVA has also been shown to induce singlet oxygen formation [390]. UVA and UVB radiation are proved to produce DNA damage directly and indirectly through oxidative stress. UVB radiation is the most cytotoxic and mutagenic waveband among the types of solar radiation. DNA bases directly absorb incident photons within the UVB narrow wavelength range leading to the formation of dimeric photoproducts between adjacent pyrimidine bases on the same strand. The phototoxic effect of UVA radiation is much lower than UVB radiation and DNA is not a chromophore for UVA radiation. However, DNA damage can potentially arise from photosensitization reactions initiated through absorption of UVA by other chromophores [391]. UV radiation also induces GSH depletion [392]. Accordingly, GSH supplementation with NAC also prevents apoptosis induced by UV radiation [393]. In addition, overexpression of peroxiredoxins protects against apoptosis-induced by UV radiation via detoxification of peroxides [394]. Recently, ROS formation by NADPH oxidase upon UVA radiation exposure was shown to be independent from the progression of apoptosis [395]. UVA-induced resistance to apoptosis have been shown mediated by PTEN/Akt, p38 signaling cascades [396,397]. ROS but not RNS have been shown to mediate UVB-induced apoptosis [398]. However, the role of ROS at lower doses of UVB radiation is still inconclusive [399]. Catalase but not SOD overexpression has been shown to protect against UVB-induced cell death suggesting a role for H2 O2 but not • O2 − [400]. UVB radiation induces both extrinsic and intrinsic pathways of apoptosis [401,402]. How-

Apoptosis is a basic homeostatic process involved in a wide variety of phenomena. During environmental toxicity induced by different pollutants or toxicants, apoptosis plays a transcendental role in both removing damaged cells and in the pathophysiology of distinct environment-associated disease conditions such as Alzheimer, Parkinson, chronic inflammatory lung diseases and cardiovascular diseases. In this review we have attempted to give an overview of the mechanisms involved in apoptosis triggered and regulated by distinct environmental stressors. When facing this challenge it is important to state that for many of the hazardous environmental contaminants or stressors reported (according to the Environmental Protection Agency EPA and Centers for Disease Control WebPages) there is a huge lack of research and information about the mechanistic events involved in the induction of cell death or apoptosis by these toxicants. We also recognize that many of these environmental stressors were left out of this review due to space restrictions. However, the data summarized above demonstrates that redox signaling is one of the central mechanisms by which many of these environmental stressors modulate/trigger apoptosis (Fig. 3). Redox signaling induced by environmental stressors involves both alterations in antioxidant defenses (such as decreases in GSH/GSSG ratio) and accumulation of ROS leading to oxidative stress. These biochemical events mediate a number of redoxdependent processes such as oxidative protein modifications, oxidative DNA damage and alterations in mitochondrial function which in turn trigger the activation of specific signaling cascades. Environmental stress or toxicity induces apoptosis mainly by the regulation of intrinsic pathways of apoptosis activated by mitochondria, ER-stress and DNA-damage with a high degree of crosstalk between their signaling elements. Activation of SAPKs such as JNK and of transcription-dependent p53 signaling cascades act as important sensors for environmental stress and the induction of apoptotic cell death. In certain circumstances environmental toxicants might trigger other types of cell death pathways such as necrosis and autophagy. Interestingly, environmental stressors also induce the activation of survival responses including, DNA repair mechanisms, MAPK/PI3K signaling cascades and up-regulation of antioxidant defenses in an attempt to counteract the deleterious effects of cell death pathways. In fact, in most cases both apoptotic and survival signaling cascades have been observed to be activated in parallel

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Fig. 3. Environmentally induced cell death and transformation. Redox signaling induced by environmental stressors involves both alterations in antioxidant defenses (including decreases in GSH/GSSG ratio) and oxidative stress (via accumulation of ROS) leading in turn to oxidative protein modifications, oxidative DNA damage, lipid oxidation and alterations in mitochondrial function. Redox signaling mediates the activation of both apoptotic pathways (to remove unwanted damaged cells) and survival signals (to counteract the progression of cell demise) in response to environmental exposures. Environmental toxicity-induced apoptosis is involved in the pathophysiology of distinct diseases such as neurodegeneration while deregulated activation of survival signals promotes cellular transformation aroused by the impairment of apoptotic signaling.

in response to environmental toxicity. Tipping the balance towards either cell death or survival depends in most cases on the intensity, length and type of exposure. Finally, deregulated activation of survival signals as a consequence of mutagenesis is well known to promote cellular transformation aroused by the impairment of apoptotic signaling. Thus, future research in the understanding of both environmentally induced cytotoxicity/apoptosis and environmentally induced cellular transformation is necessary for a complete understanding of the human health consequences to environmental exposures. Conflict of interest The authors declare that there are no conflict of interest. Acknowledgements This work was supported by the Intramural Research Program of the NIH, NIEHS (Franco R.); FOMIX project number FMSLP 2008C01-86772 (Sánchez-Olea R); funds provided by the School of Public Health of the University of Nevada at Reno (Panagiotidis MI). Due to space limitations we would like to apologize in advance to all our colleagues whose research was not cited in this review but whose work has certainly advanced our understanding of this complex field of research. References [1] D. Kultz, Molecular and evolutionary basis of the cellular stress response, Annu Rev Physiol 67 (2005) 225–257. [2] S.W. Ryter, H.P. Kim, A. Hoetzel, J.W. Park, K. Nakahira, X. Wang, A.M. Choi, Mechanisms of cell death in oxidative stress, Antioxid Redox Signal 9 (2007) 49–89. [3] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals and antioxidants in normal physiological functions and human disease, Int J Biochem Cell Biol 39 (2007) 44–84. [4] M. Abdollahi, A. Ranjbar, S. Shadnia, S. Nikfar, A. Rezaie, Pesticides and oxidative stress: a review, Med Sci Monit 10 (2004) RA141–147.

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