A systematic review on the role of environmental toxicants in stem cells aging

Food and Chemical Toxicology 86 (2015) 298e308

Contents lists available at ScienceDirect

Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox

Invited review

A systematic review on the role of environmental toxicants in stem cells aging Mahshid Hodjat, Mohammad Amin Rezvanfar, Mohammad Abdollahi* Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center (PSRC), Endocrinology & Metabolism Research Center (EMRC), Toxicology & Poisoning Research Center (TPRC), Tehran University of Medical Sciences (TUMS), Tehran 1417614411, Iran

a r t i c l e i n f o

a b s t r a c t

Article history: Received 18 September 2015 Received in revised form 29 October 2015 Accepted 2 November 2015 Available online 12 November 2015

Stem cells are an important target for environmental toxicants. As they are the main source for replenishing of organs in the body, any changes in their normal function could affect the regenerative potential of organs, leading to the appearance of age-related disease and acceleration of the aging process. Environmental toxicants could exert their adverse effect on stem cell function via multiple cellular and molecular mechanisms, resulting in changes in the stem cell differentiation fate and cell transformation, and reduced self-renewal capacity, as well as induction of stress-induced cellular senescence. The present review focuses on the effect of environmental toxicants on stem cell function associated with the aging process. We categorized environmental toxicants according to their preferred molecular mechanism of action on stem cells, including changes in genomic, epigenomic, and proteomic levels and enhancing oxidative stress. Pesticides, tobacco smoke, radiation and heavy metals are wellstudied toxicants that cause stem cell dysfunction via induction of oxidative stress. Transgenerational epigenetic changes are the most important effects of a variety of toxicants on germ cells and embryos that are heritable and could affect health in the next several generations. A better understanding of the underlying mechanisms of toxicant-induced stem cell aging will help us to develop therapeutic intervention strategies against environmental aging. Meanwhile, more efforts are required to find the direct in vivo relationship between adverse effect of environmental toxicants and stem cell aging, leading to organismal aging. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Environmental toxicants Stem cells Systematic review Aging Age related disease

Contents 1. 2. 3.

4.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 Effect of oxidative stress induced by environmental toxicants on stem cells aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.1. Heavy metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 3.2. Tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.3. Ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 3.4. Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Epigenetic effects of environmental toxicants on stem cells aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 4.1. Metal compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 4.2. Plasticizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 4.3. Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 4.4. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 4.5. Other epigenetic inducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Genotoxic effects of environmental toxicants on stem cells aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Proteomics effects of environmental toxicants on stem cells aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

* Corresponding author. E-mail addresses: [email protected], Mohammad.Abdollahi@UToronto. Ca (M. Abdollahi). http://dx.doi.org/10.1016/j.fct.2015.11.002 0278-6915/© 2015 Elsevier Ltd. All rights reserved.

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

1. Introduction Aging is a complex physiological process accompanied by a progressive decrease in the organismal capacity to maintain homeostasis and regeneration. It involves accumulation of various types of damage in cellular compartments that lead to altered cell function and finally impairment of tissue and organ regeneration as a major manifestation of the aging process (Kirkwood, 2005). Many attempts have been made so far to find the underlying cause of aging and introducing the therapeutic targets to stop or at least defer this deterioration process, thereby potentially extending healthy life span, which is an old dream of mankind (Manayi et al., 2014; Ghanbari et al., 2012). Among diverse factors that affect the aging process, environmental exposure to toxicants is defined as one of the most important and strongest risk factors for aging. There are numerous environmental toxicants associated with aging and age-related disease, such as natural toxicants (e.g. aflatoxins, ochratoxin) (Eaton and Groopman, 2013; Sorrenti et al., 2013), metals (MonnetTschudi et al., 2006; Bahadar et al., 2014a), radiation (Rittie and Fisher, 2002; Sanches Silveira and Myaki Pedroso, 2014), sunlight (Lastowiecka-Moras et al., 2014) and pesticides (Zhang et al., 2012), etc. However, there is still no common mechanism to explain the effects of these factors on aging, which require fully understanding the detailed mechanism of action of each factor and gaining insight into the process of aging, particularly at the cellular level. Cellular aging was first described by Hayflick, who showed that somatic cells, after a definite number of cell replications in vitro, stop further divisions and permanently become arrested in cell cycle progression (Hayflick and Moorhead, 1961). Following genotoxic stress, the exhaustion of cell proliferation, namely senescence, is triggered by DNA damage response activation during telomere shortening. Further evidence suggested a role for cellular

Fig. 1. Environmental toxicants-induced stem cell aging through multiple molecular mechanisms.

senescence in organismal aging. Recently, the theory of stem cell aging has gained great attention in the field of gerontology and regenerative medicine. Stem cells are the foundation of embryonic generation and adult tissue regeneration that are divided into embryonic and adult stem cells. They have the capacity of selfrenewal and differentiation into different cell types. In the theory of stem cell aging, failure to replace the damaged cells as a result of the decrease in the regenerative potential of stem cells is the main concern associated with organisms aging (Mokarizadeh et al., 2013). Adult stem cells are found in most mammalian tissues where they are involved in tissue homeostasis and repair (Li and Clevers, 2010). As a repair system, stem cells act continually to replenish damaged tissues with healthy ones. Based on the reported evidence, in advancing aging these supportive sources of tissue regeneration undergo age-related changes in their replicative selfrenewal capacity and differentiation potential (Sudo et al., 2000; Rossi et al., 2005). The theory of stem cell aging is supported by the evidence that alteration in stem cell function is associated with pathophysiological attributes of aging including cancer, neurodegenerative disease, etc. (Torella et al., 2004). Another piece of evidence for implication of stem cells in organismal aging emerged from the potential usefulness of stem cell transplantation as a therapeutic strategy in the regeneration of aged organs such as brain (Limke and Rao, 2003) and heart (Segers and Lee, 2008). In this regard, bone marrow-bone marrow transplantation was shown as a promising strategy for treatment and prevention of age-related disease in experimental models of diabetes mellitus, osteoporosis, Alzheimer's disease, cancer, etc. (Taira et al., 2005; Takada et al., 2006; Amariglio et al., 2009; Ikehara and Li, 2014). The functional manifestation of stem cell aging might include changes in the differentiation fate, cell transformation, and exhaustion of the stem cell pool due to impairment in the selfrenewal capacity, and/or because of stress-induced cellular senescence (Fig. 1). Several intrinsic and extrinsic parameters have been investigated as possibilities to control stem cell aging. Stem cells, particularly those residing in tissues with higher turnover, experience multiple rounds of replication leading to replicative senescence as an intrinsic aging factor, attributed to chromosomal rearrangement, telomere shortening and genomic mutation. Extrinsic factors include all environmental influences from the stem cell surroundings that could directly affect cell functions and maintenance. Indeed, stem cell functions are dynamically regulated by their environmental area at multiple levels from their local micro-environment, namely niche, where stem cells dynamically interact with other cells, to the higher level of the surrounding tissue, the systemic milieu of the organism and the external environment that influence downstream levels (Scadden, 2006). The systemic micro-environment has an essential role in activation of stem cells in productive tissue regeneration, therefore any changes in the physiochemical properties of the surrounding environment could exert an important effect on stem cells' normal behavior related to aging (Conboy et al., 2005). Identification of extrinsic factors and their effects on stem cell survival and aging will help to identify therapeutic tools for controlling the aging process and age

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related disease. Furthermore, the knowledge on the factors influencing cellular aging has a significant implication for stem cellbased therapies (Stolzing et al., 2008; Han et al., 2012). It is noted that not only adult stem cells, but also embryonic stem cells could be affected by environmental factors during embryo development. There is considerable evidence available about prenatal exposure of environmental toxicants and their effects on the offspring (Tyl et al., 2002). During embryogenesis, which is a period of rapid cellular division, stem cells are highly susceptible to the toxicity of environmental chemicals, that could lead to an adverse effect on embryonic and fetal development (Perera and Herbstman, 2011). Although the link between environmental toxicants and embryonic stem cell aging has not been defined directly in humans, there are in vitro studies that confirm the deteriorating effect of these toxicants on embryonic stem cells and their contribution to an accelerated aging process. Oxidative stress is a major risk factor for development of several age-related diseases and has been implicated as an important molecular contributor to cellular damage following exposure to environmental agents (Fig. 1). In this review, we focus on the adverse effects of environmental toxicants on stem cells and the related mechanisms of cellular senescence. In order to fulfill this aim, a systematic literature review was carried out to find the potential underlying molecular mechanisms of genomic, proteomic and epigenomic alterations in environmental toxicant-induced stem cell aging and to identify the knowledge gaps in future stem cells-based toxicology studies to predict the possibility of accelerated aging due to exposure to environmental toxicants. 2. Methods In order to gather a comprehensive body of article, we searched PubMed, Google Scholar, MEDLINE and Science direct. The main keywords used in searching were “stem cells aging”, “germ cells”, “senescence” and “age related disease along with “environmental toxicants”, “pesticides”, “smoke”, “plasticizer”, “ionizing radiations”, “nanomaterials”, “heavy metals”, and “solvents”. Moreover, additional articles were extracted from the reference lists of the reviewed publications. Studies that used normal cell, cell lines, or whole embryos, as well as non-original articles were excluded from our research. The findings are summarized in four categories of toxicant and the results are presented in tables based on the mechanism of action of the toxicants that may contribute to stem cell aging. 3. Effect of oxidative stress induced by environmental toxicants on stem cells aging Reactive oxygen species (ROS) including free radicals such as superoxide, hydrogen peroxide, hydroxyl, and radical peroxide are essential for physiological cell function. However, their accumulation in cells could potentially induce oxidative stress leading to damage to all major classes of molecules in cellular compartments, including lipids, proteins, and nucleic acids. Oxidative stress has long been recognized as a major cause of aging and age related disease (Abdollahi et al., 2014; Saeidnia and Abdollahi, 2013; Rezvanfar et al., 2014). The link between oxidative stress and aging has been best shown in Drosophila. Overexpression of superoxide dismutase, a well-characterized antioxidant enzyme, extends life span in Drosophila (Parkes et al., 1998; Klichko et al., 1999). The implication of oxidative stress in stem cell aging was first shown in ataxia telangiectasia mutated (ATM) knock-out mice where isolated stem cells were highly susceptible to the ATM-mediated ROS generation resulted in the progressive decline in hematopoietic stem cells (HSC) function and

depletion of the HSC pool (Ito et al., 2007). In this experiment, antioxidant treatments restored HSC function and prevented HSC senescence. The same results were reported by Pan and his colleague (2007) on germline stem cells (GSC) in Drosophila ovary (Pan et al., 2007). It was shown that aging ovary is accompanied by gradual loss of GSCs and reduction of GSC proliferation. Superoxide dismutase (SOD) overexpression in GSC leads to the reduction of oxidative cellular damage and prevention of stem cell aging. This observation further demonstrates the causative link between oxidative stress and stem cell aging. Oxidative stress has the capacity to cause irreparable DNA damage in stem cells, which can lead to cell cycle arrest and oxidative-induced premature senescence (Burova et al., 2013). This type of cellular aging is related to DNA damage, particularly at the site of the telomere where the DNA repair mechanisms fail to remove injuries (Fumagalli et al., 2012). It is also notable that ROS could accelerate telomere loss during cell replication, and therefore is involved in induction of another type of cellular aging known as replicative senescence. These all imply that oxidative stress acts as a master driver of cellular senescence through targeting telomeres (von Zglinicki, 2002; Tchirkov and Lansdorp, 2003). A number of environmental toxicants have been shown to be involved in the generation of ROS and induction of oxidative stress. Heavy metals including arsenic, lead, beryllium, chromium, cobalt, cadmium, nickel and vanadium are known to damage cells via generation of oxidative stress (Burova et al., 2013). The same mechanism of cell toxicity was also reported for Ionizing radiation (Gerschman et al., 2005), air pollution (Chen et al., 2007), pesticides such as rotenone, paraquat, dieldrin, maneb, 1-methyl-4-phenyl
, 2009), 1,2,3,6-tetrahydropyridine (MPTP) (Migliore and Coppede and cigarette smoke (Catanzaro et al., 2007). The major intracellular source of ROS is mitochondrial respiration. A variety of alterations in mitochondrial function have been reported with aging, including accumulation of mitochondrial DNA (mtDNA) mutation, decline in oxidative phosphorylation function and an increase in oxidative stress, as a result of damage to the mitochondria (Lee and Wei, 2012). Indeed, recent studies suggest a main role for mitochondrial dysfunction and the generation of ROS in the aging process. Unlike the nuclear genome, mtDNA is very susceptible to the stress-induced mutations, which are related to the limited capacity of mitochondrial DNA repair mechanisms (Santos et al., 2013). Mitochondria are an important target for many environmental toxicants (Karami-Mohajeri and Abdollahi, 2013). Paraquat, rotenone, carbon monoxide and cyanide are examples of environmental toxicants that exert their effect largely via mitochondrial toxicity (Shokolenko et al., 2009; Martinez and Greenamyre, 2012). Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxic byproduct of desmethylprodine opioid synthesis, is a potent mitochondrial function inhibitor that is associated with age-related Parkinson disease. Although no direct evidence exists regarding the direct effect of MPTP on stem cell aging, it has been shown that transplantation of embryonic stem cells to MPTPexposed mice has a therapeutic effect that might reflect the impairment of stem cell normal function (Cui et al., 2010). The oxidative cytotoxicity of environmental toxicants has been widely studied in embryonic and adult stem cell (Table 1). In the following, we briefly review some studies on toxicants that induce oxidative stress in stem cells associated with aging and age-related disease. 3.1. Heavy metals Cadmium (Cd) is a toxic metal loaded into the environment mainly through agricultural and industrial activities. Cd-induced oxidative stress in pluripotent and adult stem cells resulted in

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Table 1 Environmental toxicants that induce oxidative stress in stem cells. Environmental toxicant

Species Stem cell type

Parameters

Reference

In vivo/ in vitro

M

Prostate stem cells/progenitor ES cell

(Jiang et al., 2011)

Cadmium

R

Bone marrow mesenchymal stem cell

In vitro In vivo In vitro

Methylmercury

R

Neural stem cell

YSphere-forming ability, YProliferation, YSelf renewal YViability, YMorphological changes, YNuclear breakage [Apoptosis

Lead, Arsenic

M

Mesenchymal stem cell

Arsenic

H

Mesenchymal stem cell

Cigarette smoke

M

Embryonic stem cell

Cigarette smoke

R

Cardiac stem cell

Cigarette smoke

H

Mesenchymal stem cell

M

Heavy metals Cadmium

Tobacco smoke

Ionizing radiation

Pesticides

Irradiation

M

Mesenchymal stem cell derived from exposed mice Bone marrow mesenchymal stem cell

Irradiation

H

Mesenchymal stem cell

YViability, Morphological changes, [DNA damage [DNA damage, [Apoptosis, Inhibit differentiation YTelomere length YBlastocyst rate YMembrane integrity, [Cytotoxicity, YProliferation YMigration YDifferentiation, [Apoptosis, YProliferation/Viability YBone marrow-derived cell migration, YDifferentiation Change differentiation, [senescence in BM MSC [Senescence

Paraquat Paraquat

M M

Mesenchymal stem cell Embryonic stem cell

[DNA damage foci, YDifferentiation potential [ROS, [Apoptosis, YProliferation

M R M

Embryonic stem cell Mesenchymal stem cell Spermatogonial stem cell

Chlorpyrifos Bisphenol Nanomaterials Silver nanoparticles

(Hussein and Hasan, 2010) (Ceccatelli et al., 2007) In In (Shakoori and Ahmad, In 2013) (Yadav et al., 2010) In (Yadav et al., 2013) (Huang et al., 2009) In In (Sumanasekera et al., In 2014) (Zhou et al., 2011) In

vitro vitro vitro vitro vivo vitro vitro vitro

In vivo (Ma et al., 2007)

In vivo

(Wang and Jang, 2009) (Hirabayashi, 2014) (Alves et al., 2010) (Perla et al., 2008)

In vitro

In In In YDifferentiation potential (Estevan et al., 2013) In Oxidative stress, alter cell morphology, Yviability (Lotfi et al., 2014) In YMitochondrial activity, YProliferation, (Braydich-Stolle et al., In [Cytotoxicity 2005)

vitro vitro vitro vitro vitro vitro

MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, M:Mouse; H:Human; R:Rat; TCDD:2, 3, 7, 8-Tetra chlorodibenzo-p-dioxin.

inhibition of self-renewal capacity, decreased proliferation and cell viability (Hussein and Hasan, 2010). Furthermore, it was found that Cd can disturb the redox balance and increase the number of quiescent cells, as observed in prostate stem progenitor cells (Jiang et al., 2011). Another environmental toxicant is methylmercury (MeHg), that has been well studied for its pro-oxidant capacity and related health concerns (Mostafalou and Abdollahi, 2013a; Maqbool et al., 2014). Mercury induces oxidative stress in rat neural stem cells leading to apoptotic changes and eventually cell death (Tamm et al., 2006; Ceccatelli et al., 2007). This neurotoxic metal has been associated with the development of age-related diseases such as Alzheimer's and Parkinson's diseases. Lead and arsenic are among the top environmental health threats, which exert their deleterious effects on human health at low doses. Shakoori and Ahmad (2013) reported the oxidative stress-mediated genotoxicity of lead and arsenic in mesenchymal stem cells (MSCs), accompanied by decreased cell viability and alterations in the cellular morphology (Shakoori and Ahmad, 2013). The same effects were detected by Yadav et al. (2010) on MSC exposed to sub-lethal doses of arsenite. It was shown that arsenic can inhibit adipogenic differentiation of MSCs by inducing apoptotic pathways in bone marrow-derived MSCs (Yadav et al., 2010, 2013). 3.2. Tobacco smoke Smoking and tobacco smoke are important risk factors for many age-related diseases in which oxidative stress has a pivotal role in their progression. Results of several studies confirm cigarette smoke-induced oxidative damage in stem cells. Huang et al. (2009) examined the in vivo effect of maternal cigarette smoking during pregnancy on embryo development. Their results showed that

smoke could affect embryo development by increasing oxidative stress and telomere shortening in mice exposed to continuous smoke (Huang et al., 2009). Further in vitro studies showed the inhibitory effect of cigarette smoke extracts on proliferation and migration of bone marrow-derived stem cells (F.C. Zhou et al., 2011). Modulation of ERK signaling is believed to be the main mechanism of oxidative-induced effects of cigarette smoke in cardiac stem cells (Sumanasekera et al., 2014). 3.3. Ionizing radiation Ionizing radiation is known to be a strong inducer of ROS as shown in different cell types. It causes deleterious DNA damage that could ultimately contribute to cellular senescence and apoptosis in cultured cells, including embryonic and adult stem cells (Wang and Jang, 2009; Burova et al., 2013; Hirabayashi, 2014). The implication of irradiation in stem cells aging was best shown during total body irradiation in a mouse model, leading to a reduction in the number of bone marrow MSCs, as well as alterations in differentiation capacity (Ma et al., 2007). 3.4. Pesticides For many years, toxicological research has focused on pesticideinduced oxidative stress as their possible mechanism of toxicity (Mostafalou and Abdollahi, 2013b). Studies on animal and human models suggested that pesticides could disrupt cellular homeostasis by different mechanisms, including generation of free radicals, induction of lipid peroxidation and decline in total antioxidant capability that lead to oxidative stress and subsequent cell damage (Abdollahi et al., 2004). Exposure of undifferentiated D3 mouse embryonic stem cells to paraquat resulted in increased ROS

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production and age-related decline in stem cells proliferation and differentiation capacity (Perla et al., 2008; Alves et al., 2010). Oxidative stress is the major underlying mechanism of chlorpyrifos neurotoxicity, associated with neurodevelopmental diseases. Stimulation of oxidative stress by chlorpyrifos inhibits cell proliferation and alters differentiation in stem cell culture and neonatal animal models (Dam et al., 1999; Estevan et al., 2013). Increased ROS generation was also reported after exposure of rat bone marrow MSCs to a high concentration of bisphenol A (Lotfi et al., 2014). 4. Epigenetic effects of environmental toxicants on stem cells aging Epigenetic changes represent an important mechanism through which environmental factors influence cell functions. Epigenetic change is a heritable process that alters gene activity without changing DNA sequences (Weinhold, 2006). A wide variety of epigenetic processes have been identified so far, among which DNA methylation and histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation, have been extensively studied. These modifications in genomic DNA and chromatin remodeling protein, lead to alterations in chromatin configuration and accessibility of chromosomal regions for transcriptional regulation and gene expression that ultimately affect the cell phenotype (Busuttil et al., 2007; Feser et al., 2010). Indeed, epigenetic modifications play a critical role in control of most cellular processes. The link between the epigenome and aging has been studied for a long time. Genomic hypomethylation and hypermethylation of specific genes have been reported in different aged tissues. Lee and Duerre evaluated the changes with age in histone methylation of rat brain and liver (Lee and Duerre, 1974). They observed a significant decrease in methylation of brain nuclei in aged mice compared to newborns. It is notable that the cellular senescence model of aging is commonly involved with accumulation of different epigenetic markers. Accordingly, senescence-associated heterochromatic foci (SAHF), the heterochromatin structure in senescent cells, was shown to be attributed to the epigenetic histone methylation upon methyltransferase activity (Narita et al., 2003). Epigenetic changes of cellular senescence were further observed in cultured fibroblasts after multiple cell passage that showed decreases in total DNA methylation and histone acetylation (Ryan and Cristofalo, 1972; Wilson and Jones, 1983). As was mentioned, age-associated dysfunction of stem cells and subsequent decline in tissue cell replenishing capacity is a critical driver for aging. Currently, many studies have focused on the role of epigenetic changes in stem cell aging (Li et al., 2011; Ratajczak et al., 2010). The study of global DNA methylation of isolated stem cells from old and young mice showed increased hypermethylation of HSCs related to the functional decline of cells during aging (Beerman et al., 2013). It is also suggested that age-associated changes in the differentiation fate of stem cell progeny might relate to dysregulation of DNA methylation (Beerman and Rossi, 2014). Histone modification is another epigenomic process involved in stem cell aging. Acetylation of H4K16ac and methylation of H3K4me3 were the main histone modifications detected in aged populations of adult stem cells (Florian et al., 2012; Liu et al., 2013; Sun et al., 2014). Using a computational model approach, it was shown that changes in trimethylation of histone H3 and DNA methylation could strongly affect stem cell heterogeneity and emergence of age-related phenotypes (Przybilla et al., 2014). This evidence further suggests that epigenomic dysregulation plays an important role in stem cell aging.

Environmental factors have long been recognized as a main driver of epigenomic aging, particularly in the context of stem cell aging. A wide range of environmental toxicants has been reported to induce epigenetic alterations associated with age-related disease. These include alcohol, nanomaterials, asbestos, benzene, endocrine disrupting chemicals (EDCs), metals, and ionizing radiation, etc. (Hou et al., 2011; Mogharabi et al., 2014). Indeed, the studies to monitor the regulatory effect of environmental factors in stem cell aging have been reported (Conboy et al., 2005; Dorshkind et al., 2009). By establishing a shared circulatory system between young and old mice, they exposed old mice to the factors present in young serum. The results showed that rejuvenation of aging stem cells occurs by exposure to factors present in young serum. Therefore, tissue regenerative potential can be reversed by modulation of systemic factors. Such rapid rejuvenation changes raised the possibility of involvement of an epigenetic phenomenon that is reversible and influenced by extrinsic factors. Although there are not many studies addressing the direct epigenetic effect of environmental toxicants on stem cell aging, we summarized here some findings related to environmental toxicant-induced DNA methylation as well as histone modification of stem cells, associated with aging and age-related diseases (Table 2). 4.1. Metal compounds Recent reports have shown that low concentrations of metals can promote epigenomic alteration and heritable changes in gene expression of stem cells (Martinez-Zamudio and Ha, 2011). Embryonic stem cell exposure to trace amounts of metals such as arsenic, cadmium, copper, lead, lithium, mercury, and nickel lead to change in gene expression of DNA repair genes, including Rad-18, Top-3a, and Ogg-1 that has been related to the decrease of H3K27 monomethylation (H3K27me) (Gadhia and others, 2012). Histone methylation and subsequent gene silencing is considered as a common mechanism of many metals. Various studies indicate the association of arsenic exposure with cancer disease. Accordingly, an in vitro study demonstrated that arsenic trioxide, at a low, non-cytotoxic concentration, induces stem cell transformation, due to activation of polycomb group (PcG) proteins and enhanced H3K27 trimethylation (Kim et al., 2012). Further studies showed that maternal exposure to lead acetate could cause epigenetic changes in offspring and increase susceptibility to age-related disorders, particularly, Alzheimer's disease (Basha et al., 2005). 4.2. Plasticizers Manikkam and his colleagues showed that a mixture of plastic compounds, including bis (2-ethylhexyl) phthalate (DEHP), bisphenol-A and dibutyl phthalate promoted epigenetic transgenerational inheritance of abnormalities associated with changes in sperm DNA methylation in the offspring (Manikkam et al., 2013). The same results were observed after bisphenol-A exposure that resulted in alteration of the epigenetic pattern during early stem cell development (Dolinoy et al., 2007; Aoki and Takada, 2012). 4.3. Pesticides Arai and his colleagues (2011) examined the effects of 25 environmental chemicals, including organophosphorus insecticides on DNA methylation status in mouse embryonic stem cells (mESCs). It was shown that among the examined pesticides, octachlorodipropyl ether and diethyl phosphate caused DNA methylation changes at specific loci in mESCs (Arai et al., 2011). Exposure

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303

Table 2 Environmental toxicants that induce epigenetic changes in stem cells. Group

Environmental toxicant

Species Stem cell type

Epigenetic hit

Metals

Lead

H

Lead

H

YGlobal DNA methylation Not defined

Lead

M

Mercury, Selenium Mercury

M N

Mercury, Nickel, M arsenic cadmium Arsenite M

Embryonic stem cell Amniotic fluid stem cells Gestating female

Parameters/Age related disease

YDifferentiation YViability, YNeural gene expression YProliferation (high concentration), apoptosis differentiation Methylation patterns of key Alzheimer genes Alzheimer's disease in offspring Change YEmbryoid body DNA methylation YGlobal DNA methylation [Senescence, YProliferation

Embryonic stem cell Embryonic cortical neural stem cell Embryonic stem YH3K27monomethylation cell Gestating female YH3K9 acetylation In offspring ES cell [H3K27me

Reference

In vivo/ in vitro

(Senut et al., 2014) (Gundacker et al., 2012) (Basha et al., 2005) (Arai et al., 2011) (Bose et al., 2012)

In vitro

YProliferation, Ygene expression of DNA repair Long-term memory impairment

Plasticizers Bisphenol A

R

Bisphenol-A Phthalate Bisphenol-A

R M

Embryonic stem cell

DEET

R

Gestating female Change in offspring sperm DNA methylation

DDT

R

TCDD

R

Gestating female Change in offspring sperm DNA methylation Gestating female Change in offspring sperm DNA methylation

Vinclozolin

R

Gestating female Change in offspring sperm DNA methylation

Methoxychlor

R

Gestating female Change in offspring Sperm DNA methylation

Diethyl phosphate, S-421 Ethanol

M

Embryonic stem cell

Change DNA methylation

(Gadhia et al., 2012) (Cronican et al., 2013) Cancer, [Proliferation (Kim et al., 2012) Change offspring phenotype (Dolinoy et al., 2007) Kidney, Testis disease, Obesity (Manikkam Ovarian disease in F1, F3 et al., 2013) [Ovarian markers (Foxl2 and Wnt4), (Aoki and Y testicular markers (Sox9 and Fgf9), Takada, 2012)
Differentiation Pubertal abnormalities, testis disease, (Manikkam and ovarian disease et al., 2012b) Testis disease, obesity, ovarian (Skinner et al., disease, In F1, F3 2013) Polycystic ovary diseaseF3 (Manikkam et al., 2012a) (GuerreroAffects sexual selection Gene expression in genes in olfactory Bosagna et al., 2010) transductionF3 Kidney disease, ovary disease, and (Manikkam obesity F1, F2, F3 et al., 2014) YEmbryoid body (Arai et al., 2011)

M

Neural stem cell Mesenchymal stem cell

YDNA methylation

YCell growth, Ydifferentiation

Not defined


Osteogenic differentiation, heart disease

Arsenic trioxide

Pesticides

Alcohol

M

H

Other

Genistein

M

Benzene

M

Quercetin

M

Jet fuel

Gestating female YDNA methylation in offspring Gestating female Change in offspring sperm DNA methylation Not defined

M

Embryonic stem Change in DNA methylation cell Bone marrow [DNA methylation stem cell Gestating female Offspring Hypomethylation SINEB1, [Expression of Phase I enzymes (Cyp1a1 and Cyp1b1) repetitive elements (SINEB1), [Phase II enzymes (Gstp1, Nqo1 and Ugt1a6) Gestating female Hypermethylation of repetitive elements,

R

Gestating female Change in offspring Sperm DNA methylation


Differentiation Hematotoxicity Liver disease, cancer risk

(Zhou et al., 2011a) (Gong and Wezeman, 2004) (Sato et al., 2011) (Zhang et al., 2010) (Vanhees et al., 2012)

In vitro In vivo In vitro In vitro

In vitro In vivo In vitro In vivo In vivo In vitro

In vivo In vivo In vivo In vivo

In vivo In vitro

In vitro In vitro

In vitro In vitro In vivo

Iron storage in the liver, Liver injury

(Vanhees et al., In vivo 2011) In vivo Primordial follicle loss and polycystic (Tracey et al., 2013) ovarian, Obesity inF3

DMR: DNA methylation regions; TCDD:2,3,7,8-tetrachlorodibenzo-p-dioxin; DEET N,N-diethyl-meta-toluamide; DDT: dichlorodiphenyltrichloroethane.

of mESCs to these toxicants impaired cell differentiation and embryoid body formation. Pesticides and fungicides have been shown to promote epigenetic transgenerational inheritance of developmental disorders of the nervous and reproductive system. Vinclozolin (Gerschman et al., 2005), dioxin (TCDD) (Manikkam et al., 2012a), N,N-diethylmeta-toluamide, methoxychlor (Manikkam et al., 2012b, 2014), dichlorodiphenyltrichloroethane (DDT) (Skinner et al., 2010) and chlorinated hydrocarbons (Tracey et al., 2013) are a number of environmental toxicants reported to be associated with epigenetic changes in stem cells (Table 2).

4.4. Alcohol Drinking alcohol is a well-studied risk factor in aging and several age-related diseases such as cancer. It has been speculated that epigenetic changes may be the underlying molecular mechanism of adverse effects of alcohol exposure. Indeed, alcohol modifies gene expression and epigenetic regulatory pathways through a variety of mechanisms, including histone modifications, DNA methylation and microRNAs. It has been reported that chronic alcohol exposure changes the DNA methylation pattern of cultured neural stem cells and retards cell differentiation (Y. Zhou et al., 2011). Moreover, it

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Table 3 Environmental toxicants that induce genotoxic effect in stem cells. Environmental toxicant

Species Stem cell type

Parameters

Reference

In vivo/ In vitro

Acetaldehyde

M

[Histone H2AX phosphorylation

(Garaycoechea et al., 2012)

In vitro

1,4-benzoquinone

M

Hematopoietic stem and progenitor cells Hematopoietic stem cell

(Faiola et al., 2004)

Benzene

M

Hematopoietic stem cell

In vivo In vitro In vitro

Genistein Quercetin, Kaempferol

H

Hematopoietic stem cell

DNA repair sys gene expression (changed) [Histone H2AX phosphorylation, [apoptosis Topoisomerase inhibitor, [DNA breaks

has been well documented that prenatal exposure to alcohol has marked destructive effects on the developing embryo and fetus, leading to a broad spectrum of structural and functional abnormalities, known as fetal alcohol spectrum disorders (FASD). There is accumulating evidence suggesting that DNA methylation and histone modification, as well as microRNAs are targets of alcohol's actions involved in FASD (Resendiz et al., 2013). 4.5. Other epigenetic inducers Benzene is well known for its carcinogenic and noncarcinogenic adverse effects (Bahadar et al., 2014b, 2015a, 2015b). It causes damage to HSCs via multiple mechanisms, among which induction of genetic, epigenetic abnormalities and genomic instability might be the relevant direct way to alter proliferation and differentiation capacity of HSCs (McHale et al., 2012). Sato and his colleagues reported changes in DNA methylation pattern of mESCs after exposure to genistein, the major soy phytoestrogen (Sato et al., 2011). They suggested that genistein could impair early embryo development by targeting DNA methylation and subsequent inhibition of embryonic stem cell differentiation. There is also evidence that exposure to hydrocarbons (Tracey et al., 2013) and quercetin (Vanhees et al., 2011) induce epigenomic transgenerational inheritance in the offspring of rodents. 5. Genotoxic effects of environmental toxicants on stem cells aging Genomic DNA is consistently exposed to extrinsic and intrinsic stress that could result in different types of damage to DNA, including single- and double-strand DNA breaks, single base mutations, translocations, telomere shortening, and so on. To combat such damaging effects, cells have evolved DNA repair mechanisms to maintain genomic integrity against DNA-damaging agents. It has been proposed that the activity and function of DNA repair systems are closely related to organismal aging and their life span (Hart and Setlow, 1974). In situations where it is not possible to repair the damaged lesion, the repair system shifts the cell fate towards senescence, apoptosis or necrosis that at higher levels could result in tissue and organ aging. As in most cells, accumulation of DNA damage in stem cells could diminish normal cell function and behavior. Using mouse models with deficiencies in the DNA repair system, Rossi and his colleagues demonstrated a marked premature decline in the proliferation capacity and function of HSC, accompanied by increased apoptosis and senescence (Rossi et al., 2007). They suggested that increased DNA damage is a principal mechanism of stem cell aging. Another evidence for a direct causative link between DNA susceptibility and stem cell aging was obtained by demonstrating the increased HSCs and MSCs senescence in progeroid syndromes, a group of disorders caused by genetic defects in DNA repair

(Zhu et al., 2013)

(Barjesteh van Waalwijk van Doorn-Khosrovani In vitro et al., 2007)

mechanism (Hirschfeld et al., 2007). Environmental agents as major extrinsic factors can cause damage to DNA. They could indirectly damage to DNA by raising the amount of cellular ROS, or impairment of mitochondrial function. A number of environmental toxicants such as Ionizing radiation, UV light and metals could directly interact with chromatin structure and produce irreparable changes to the DNA structure (Maqbool et al., 2015). Furthermore, it was shown that the genotoxic effect of environmental toxicants might be the consequence of inhibition of enzymes responsible for DNA replication and transcription (topoisomerase (topo) II alpha and beta), resulting in DNA damage breaks. Aldehydes and acetaldehydes are the byproducts of exogenous alcohol metabolism that cause DNA strand breakage. Garaycoechea et al. (2012) studied the genotoxic effect of acetaldehydes on HSCs and progenitor cells in mouse models (Table 3). Their results showed that only HSCs, and not mature blood precursors, are susceptible to the genotoxic effect of reactive aldehydes that leads to accumulation of DNA damage and depletion of HSCs pool. Formaldehyde is an air pollutant that causes DNA damage through induction of DNA-protein crosslinks. It was reported that formaldehyde at low concentrations induces DNA breakage in mouse bone marrow mesenchymal stem cells (MSCs), leading to a decrease cell survival (She et al., 2013). Moreover, it was shown that benzene metabolites, such as 1,4benzoquinone, could induce DNA breaks through inhibition of topoisomerase II alpha activity or disturbance of the mitotic apparatus (Hutt and Kalf, 1996). Damage to DNA resulting from benzene metabolites and misrepair of DNA lesions may lead to changes in HSCs and give rise to leukemia (Faiola et al., 2004; Zhu et al., 2013; Smith et al., 1996). Bioflavonoids are naturally occurring compounds that are found in plants, fruits, vegetables, soy, tea, coffee, etc. They are known as antioxidant agents and used largely to protect against cardiovascular diseases, cancer, and chronic inflammation. However, based on the reported evidence, they have a potent inhibitory effect on topoisomerase II (topo II) activity. Genistein was shown to be the most effective bioflavonoids inducing topoII-DNA cleavage complexes in both cultured mouse myeloid progenitor cells and embryonic fibroblasts (Azarova et al., 2010). Further studies showed that quercetin, genistein, and kaempferol at specific concentrations induce double strand DNA breaks in primary HSCs (Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2007).

6. Proteomics effects of environmental toxicants on stem cells aging Normal cell function depends on maintenance of entire intracellular proteins and requires timely removal of damaged or misfolded proteins. During aging, the level of damaged proteins increases due to a decrease in functional capacity of degradation systems such as autophagy and the ubiquitin proteasomal system

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(Tomaru et al., 2012). Many in vitro and in vivo studies have confirmed the association between autophagy and aging. Autophagy as an important selfdegradative process protects cells from stress by removing toxic proteins and disrupted organelles to the lysosome. It was shown that increased autophagy through genetic manipulation could delay aging and extend longevity (Rubinsztein et al., 2011). Autophagy dysfunction has also been associated with different agerelated diseases such as neurodegeneration, Huntington's, steatohepatitis etc. (Rubinsztein et al., 2011). As regards stem cell function, autophagy has been found to be an essential process for protection of HSCs from metabolic stress-induced aging (Warr et al., 2013). Accordingly, overexpression of heat shock protein 70 (HSP70), the main protein involved in chaperone-mediated autophagy, improves stem cell survival and functional behavior (Feng et al., 2014). Moreover, it was shown that activation of mammalian target of rapamycin (mTOR), the critical regulatory pathway in autophagy, contributes to premature aging of HSCs in mouse models (Chen et al., 2009). Therefore, based on increasing evidence, it is probable that the degradation system has an important role in stem cell aging and that manipulation and disruption of this system could lead to stem cell aging and aged-associated disease. A limited number of toxicology studies have examined the effect of environmental toxicants on stem cell autophagy. It was suggested that autophagy could be considered as a potential biomarker of metal toxicity in various cell types, particularly at non-cytotoxic doses. Cadmium and chromium are well-known carcinogenic heavy metals that induce autophagic activity in hematopoietic stem cells (Di Gioacchino et al., 2008). The ultrastructural analysis of surviving HSCs showed a prominent increase in autophagosomes. Liu et al. (2015) reported that tri-orthocresyl phosphate (TOCP), induces autophagic cell death in spermatogonial stem cells (Liu et al., 2015). Nonylphenol (p-NP) is used as a nonionic surfactant in many industries such as plastics. It was reported that cell death after exposure to specific concentrations of p-NP in rat MSCs is mediated by autophagic activity. The ubiquitin proteasomal system represents the main degradation machinery responsible for rapid removal of nonfunctional protein and organelles. The impairment of proteasome activity has been implicated in pathogenesis of age-related diseases such as Parkinson's and atherosclerosis. It is also known that proteasome activity changes during aging and senescence. The association between impairment of proteasome assembly and stress-induced cellular senescence has been confirmed by many experimental results (Chondrogianni et al., 2003; Hodjat et al., 2013; Narayanaswamy et al., 2014). Coming back to the context of stem cells aging, the proteasome is considered as one of the molecular targets of environmental toxicants affecting stem cells functions and finally contributes to impairment of differentiation and cell death (Rappolee et al., 2012). Organotins (e.g., triphenyltin) and pesticides are among chemicals that were studied for their inhibitory effects on proteasomal activity (Shi et al., 2009; Wang et al., 2006). 7. Conclusion The search for environmental toxicants that induce accelerated aging (gerontogenes) has gained more attention in recent years in the field of gerontology and age-related pathology. The most promising approach is to understand the molecular pathways and typical mechanism of action of toxicants on the aging process. Indeed, identifying the molecular drivers for the actions of chemical toxicants offers a valuable therapeutic approach to environmental aging and disease susceptibility. The present review focused on the published studies related to stem cell aging and exposure to

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environmental toxicants. According to the theory of aging, stem cells are key mediators in the aging process. Having the extensive proliferation capacity and potential to differentiate into various cell types, they play a critical role in replenishing of organs through the whole life span of organisms. Therefore, impairment of stem cell function could affect organs, maintenance and healing processes that gradually contribute to the occurrence of different pathological conditions and deterioration of body organs, leading to aging. Exposure to environmental chemicals affects human health at different developmental stages during the embryonic period and organ regeneration in adults. Transgenerational epigenetic changes are the most important effects of a variety of toxicants on germ cells and embryos. These changes are heritable and could transfer to the next generation. Therefore, the deleterious effects of environmental toxicants not only affect the exposed organisms, but can also continue to affect the health of next generation populations, manifested by increase rate of age-related disease and decline in life expectancy of unexposed individuals. As discussed in the present review, environmental toxicants cause damage to stem cells via multiple mechanisms, including genetic alterations, enhancing oxidative stress, epigenetic modifications and proteomic changes. Based on the available studies, the mechanism of stem cell toxicity of some toxicants is limited to specific pathways and cellular compartments. However, others could cause damage to stem cells via multiple mechanisms. Benzene, for example, in addition to its previously recognized role in chromosomal disruption, is involved in the alteration of gene expression, enhancement of oxidative stress and the induction of epigenetic changes. There are a variety of environmental toxicants that can perturb the cellular redox balance and enhance oxidative stress. Oxidative stress causes damage to all of the major classes of molecules and cellular compartments involved in aging and age-related diseases. In this regard, damage to mitochondria and mitochondrial DNA caused by reactive oxygen species appears to be one of the key players in the aging process. Many environmental toxicants have been investigated for their mitochondrial toxicity in different cell types. However, still more research is needed to assess the effect of these toxicants on stem cell mitochondrial toxicity related to the aging process. Nanoparticles are now increasingly used in various fields of applications, including medical interventions, food, clothing, cosmetic, etc. Although numerous studies have shown the potential cytotoxicity of nanomaterials, still there is a gap in knowledge about the mechanism of their toxicity. Even less is known about their toxic mechanism on stem cells. Our review showed that very few studies are available on the effect of these nanoscale compounds on stem cell aging and aging process. Therefore, considering the rapidly growing application of nanomaterials, future efforts are highly needed to reveal their adverse effect on human health (Pourmand and Abdollahi, 2012). In general, although many studies have been published regarding the age-associated changes in stem cells in response to chemical toxicants, more evidence is needed to support a direct causal link between organismal aging and exposure to environmental toxicants. Further in vivo studies are recommended to investigate the effect of systemic exposure to environmental toxicants on adult and embryonic stem cell populations. Defining the association between toxicants and stem cell aging might lead to the development of stem cell-based predictive models for examining the toxicity of gerontogenes in humans. Therefore, stem cells could offer new powerful diagnostic tools in toxicology and gerontology studies. In addition, understanding the underlying mechanisms of toxicant-induced stem cell aging will

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