Prenatal toxicity of the environmental pollutants on neuronal and cardiac development derived from embryonic stem cells

Reproductive Toxicology 90 (2019) 15–23

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Review

Prenatal toxicity of the environmental pollutants on neuronal and cardiac development derived from embryonic stem cells Eul-Bee Ko, Kyung-A Hwang, Kyung-Chul Choi

T

⁎

Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea

ARTICLE INFO

ABSTRACT

Keywords: Embryonic stem cells Cardiac development Neuronal development Pesticide Antibiotics Industrial excipient

Pesticides, antibiotics, and industrial excipients are widely used in agriculture, medicine, and chemical industry, respectively. They often end up in the environment, not only being not easily decomposed but also being accumulated. Moreover, they may cause serious toxic problems such as reproductive and developmental defects, immunological toxicity, and carcinogenesis. Hence, they are called environmental pollutants. It is known that the environmental pollutants easily enter the body through various channels such as respiration, ingestion of food, and skin contact etc. in everyday life. If they enter the mother through the placenta, they can cause the disturbance in embryo development as well as malfunction of organs after birth because early prenatal developmental process is highly sensitive to toxic chemicals and stress. Embryonic stem cells (ESCs) that consist of inner cell mass of blastocyst differentiate into distinct cell lineages via three germ layers such as the ectoderm, mesoderm, and endoderm due to their pluripotency. The differentiation process initiated from ESCs reflects dynamic nature of embryonic development. Therefore, ESCs have been used as a useful tool to investigate early developmental toxicities of a variety of stress. Based on relatively recent scientific results, this review would address toxicity of a few chemical substances that have been widely used as pesticide, antibiotics, and industrial excipient on ESCs based-prenatal developmental process. This review further suggests how they act on the viability of ESCs and/or early stages of cardiac and neuronal development derived from ESCs as well as on expression of pluripotency and/or differentiation markers through diverse mechanisms.

1. Introduction Environmental pollutants are defined as substances or energies that have ended up in the environment as a result of human uses. Chemical substances among the environmental pollutants include pesticides, antibiotics and industrial excipients such as phthalates, trichloroethylene and perfluorooctane sulfonate [1]. Generally, they have persistent properties that do not decompose well and accumulate in the environment. For instance, lipophilic organochlorine pesticides have been known to easily accumulate [2]. As well as persistence, they have various biological toxicities to ecosystem. Exposure to environmental pollutants via ingestion, oral uptake, inhalation, etc. elevates risks of infertility, early spontaneous abortion, developmental defects, reproductive toxicity or cancer [3,4]. For the pollutants that can penetrate from maternal blood into developing embryo or fetus via placenta, they can cause developmental toxicity [5,6]. According to Klaassen and Watkins III, developmental toxicity is broadly defined as the study of adverse effects on the

development of the organism resulting from exposure to toxic agents before conception, during prenatal, or post-natal development until puberty [7]. Among developmental periods, embryogenesis taking place during early stage of prenatal development is considered the most sensitive to exposure to toxicants [8]. In this period, zygote undergoes development to a multicellular embryo, and embryonic stem cells (ESCs) that consist of inner cell mass of blastocyst differentiate into distinct cell lineages via three germ layers such as the ectoderm, mesoderm, and endoderm. The ectoderm gives rise to epidermis and the nervous system. The endoderm gives rise to the epithelium of the respiratory system and digestive system such as liver and pancreas. The mesoderm gives rise to muscle, bone, and heart. Therefore, toxicant exposure during this stage can cause serious damage to the development of organs. It has been reported that chemical substances like phthalates, acrylamide, dioxins, cigarette smoke components and PCBs hinder the normal brain or heart development and induce disabilities of nervous or heart system. Disturbance of heart development can lead to congenital

⁎ Corresponding author at: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea. E-mail address: [email protected] (K.-C. Choi).

https://doi.org/10.1016/j.reprotox.2019.08.006 Received 1 June 2019; Received in revised form 31 July 2019; Accepted 9 August 2019 Available online 16 August 2019 0890-6238/ © 2019 Elsevier Inc. All rights reserved.

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heart defects (CHD) [9,10], cardiac hypertrophy, and myocardial infarction [11,12]. In addition, organophosphorus pesticides were revealed to increase the risk of neurodegenerative disease (Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD)) and neurodevelopmental diseases (autism, attention deficit hyperactivity disorder, developmental delay) [13,14]. This review focuses on the prenatal developmental toxicity of environmental pollutants such as pesticides, antibiotics, and industrial excipients that have been widely used in the field. Additionally, the developmental toxicity resulting from exposure to cigarette smoke is also included. To be more specific, their effects on cardiac and neural development from ESCs are introduced to verify their risk to early embryonic developmental process. Therefore, the importance of ESCs in the assessment of developmental toxicity is discussed first, and the ESCbased developmental toxicity for the substances of each pollutant group are presented hereafter.

cardiomyocytes themselves. 2.2. Neural development The nervous system is particularly sensitive to toxic insults during development and early childhood. Neural differentiation process is also sensitive to toxic chemicals, and exposure to environmental chemicals may be linked to the increasing incidence of neurodevelopmental disorders [26,27]. Neural differentiation consists of embryoid bodies (EB) formation and culturing ESCs in various media conditions to generate neurons or glial cells [28]. Since ESCs can differentiate into functional neurons or glial cells including oligodendrocytes under proper culture conditions, the differentiation process from ESCs and the ESCs-derived neural cells are used to test neuro-developmental toxicity [29]. Besides that, in vitro neuro-developmental toxicity may include neuronal cell death, abnormal differentiation, suppressed neurotransmission, and disruption of the blood–brain barrier [30]. Neuronal cells consisting of central nervous system such as oligodendrocytes and astrocytes are often used in the in vitro tests to evaluate neurotoxicity [31]. In central nerve system, oligodendrocytes are involved in myelination to wrap myelin sheaths which are around the axons of neurons, thereby increasing the speed of the propagation of action potentials along myelinated axons. Astrocytes help to regulate neurotransmitters and ion concentrations outside neurons. They can release neurotransmitters, even though they do not transmit action potentials. Astrocytes also play an important role in the formation of the blood-brain barrier that controls exchange of substances like oxygen and sugar from the bloodstream into the brain. They also provide structural support for neurons.

2. ESCs for assessment of developmental toxicity ESCs are pluripotent stem cells that can be isolated from inner cell mass of a blastocyst. They are self-renewal (the ability to unlimitedly divide without differentiation) and can be passaged indefinitely without genetic changes unlike cancer or immortalized cells. Also, they have pluripotency which is an ability to differentiate into any cell types derived from three germ layers (endoderm, mesoderm and ectoderm) [15]. For instance, ESCs differentiate into hepatocytes, cardiomyocytes, and neurons, which are the representative cell types of endoderm, mesoderm, and ectoderm and later form liver, heart, and brain, respectively. Differentiation process from ESCs into any cell type represents the dynamic nature of embryonic development. For such a reason, ESCs have been used as a model to investigate early developmental toxicities of potential teratogens in vitro [16,17]. Specifically, embryonic stem cell test (EST) which was established by European Centre for the Validation of Alternative Methods (ECVAM) is the most widely used as a substitute for animal testing [18,19]. In this test, mouse ESCs (mESCs) have been frequently used because they are more available and have a higher pluripotency level than human ESCs (hESCs) although hESCs may produce more reliable and appropriate results than mESCs for testing toxicity toward human. In addition, mESCs are considered more naïve than hESCs, indicating that the molecular characteristics of mESCs are more similar to those of pluripotent cells in the early embryo [18]. In the toxicological tests using ESCs, embryoid bodies (EB) formation from ESCs is also considered as an important process because EBs mimic the early stages of embryonic development which consists of any differentiating cell types of three germ cell layers [20]. The changes in EB size and quality can provide the information about the effect of chemicals on embryonic growth, differentiation, and morphogenesis [21,22].

3. ESC-based developmental toxicity of environmental pollutants 3.1. Pesticides Pesticides are chemicals that protect crops like cereals, vegetables and fruits from detrimental insects, weeds, or fungus and usually include insecticides, herbicides and fungicides. Pesticides are a group of a wide variety of chemical compounds including organophosphate, organochloride, and carbamate, etc. and act differently depending on the chemical classification. Pesticides are easily exposed to humans and animals, directly or indirectly. Direct exposure to pesticides is made by occupational, agricultural and household use, and indirect exposure through the ingestion of crops with pesticide residue [32]. In the past, some pesticides were prohibited due to their strong toxic effect but they are still detected in animals and humans. Thus, pesticides threaten humans and the environment not only because of their toxicity but also because of their ease of exposure and their persistence. Despite international efforts to reduce the pesticide usage in agriculture due to these reasons, a large amount of pesticide has been used in USA and Europe. Even in developing countries, old, non-patented, more toxic, environmentally persistent, and cheap chemicals are still used extensively, remaining harmful substances on the soil and underground water and causing acute health problems. Acute toxic symptoms derived from pesticides range from mild ones like skin irritation or other allergic symptoms to more severe ones like strong headache, dizziness, or nausea. Some pesticides such as organophosphates were reported to cause severe symptoms like convulsions, coma, and even death [33]. Long-term exposure to pesticides also impacts on infertility, immunotoxicity, neurotoxicity, spontaneous abortions, many kinds of cancers and neurodegenerative disorders [34]. Humans are exposed to pesticides intentionally (e.g. suicide) or unintentionally (e.g. occupational or residual exposure). Humans are also vulnerable to pesticides wherever agriculture has developed rather than limited area. The study in Columbia were conducted considering the size of the company, the amount of pesticides used, job types and period of exposure. Regardless of these considerations, the rate of spontaneous

2.1. Cardiac development Since ESCs can differentiate to various cell types in different developmental lineages as stated above, they are particularly useful to investigate toxicity of substances or stresses on specific differentiation process in embryogenesis. Cardiac differentiation from ESCs, which is one of the earliest events during embryogenesis, is considered extremely sensitive to environmental stress [19]. Any severe adverse effects during cardiac development could easily result in malformation of heart and embryo lethality [23]. Cardiac differentiation consists of various cell types in different differentiation stages such as undifferentiated ESCs, mesoderm, cardiac-mesoderm, cardiomyocyte progenitors and cardiomyocytes [24]. Among these, ESCs are first differentiated to cardiomyocytes [25], and this differentiation stage represents the early cardiac development [24]. Therefore, cardiac developmental toxicity mainly focuses on the effects of toxicants on differentiation of ESCs to cardiomyocytes or on the ESCs-derived 16

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abortion, prematurity and congenital malformations overall increased both in female workers and wives of male workers in floriculture [35]. A case-control study of non-Hodgkin lymphoma (NHL) in Sweden indicated that the pesticides increased the risk of NHL [36]. Lung cancer mortality in Florida increased by pesticide exposure [37]. It is wellknown that not only these cancers but other cancers such as leukemia, soft-tissue sarcoma, prostate cancer and ovarian cancer associated with pesticide exposure [38].

signaling pathways in different cells. HCB has been linked with neurological disorders which is related to GABAergic neurons’ function. The study was conducted to examine the effect of HCB on the mESCsderived GABAergic neurons, which produce γ-aminobutyric acid (GABA) that is the main inhibitory neurotransmitter in the brain. In this study, HCB did not affect cell viability but altered the expression of neuronal markers of mESCs such as GAD1 (catalyzing the production of gamma-aminobutyric acid from L-glutamic acid), GAT1 (GABA transporter) and TH (synthesizing of dopamine and norepinephrine). HCB inhibited neurite outgrowth via ROS production. N-acetylcysteine (NAC), a ROS scavenger, reversed the effect of HCB-derived ROS production. These results imply that HCB can disrupt the formation of GABAergic neurons and may increase the risk of the neurological disorders [61].

3.1.1. Chlorpyrifos Chlorpyrifos (CPF) which is the most commonly used organophosphorus insecticide is well known to cause neurodevelopmental toxicity [39]. Most organophosphorus pesticides (OPs) including CPF inhibit acetylcholinesterase (AChE). Inhibition of AChE by OPs induces accumulation of acetylcholine in synaptic cleft, leading to cholinergic symptoms and disruption of neurodevelopment [39,40]. The deletion of AChE gene in Drosophila and mice resulted in embryonic lethality [41,42]. Exposure to CPF and its metabolites (CPO and TCIP) during differentiation reduced the enzymatic activities of AChE and neuropathy target esterase (NTE) that regulates neurite outgrowth [43]. In relation with neurodevelopmental process, CPF particularly caused alteration of the neural cell proliferation and differentiation [43,44], neurite outgrowth [45], and DNA damage by oxidative stress [46]. In ESCs, CPF and its metabolites disrupt differentiation into neurons and expression of differentiation-related genes such as mesoderm markers (Flk1, Mhc and Pnpla6), ectoderm markers (Nefm, Nestin and Ache), endoderm marker (Afp) and pluripotency markers (Oct4 and Nanog) [43,44]. The alterations of these genes also potentially caused severe disturbances in differentiation, leading to fetal growth defects during pregnancy [47]. Likewise, the pregnant women’s offspring in agricultural regions have many chances to prenatal exposure to pesticides such as CPF, diazinon and bifenthrin, etc. Their offspring are linked to a greater risk of autism spectrum disorder according to the population based casecontrol study [48].

3.1.4. Arsenic (As) compounds Arsenic (As) compounds are used to produce the pesticides. It accumulates in soil and groundwater from taken up by grain, vegetables and marine organisms [62]. It has adverse effects on human health like cancers and cardiovascular and neurological diseases [63]. Previous study investigated the effects of arsenite exposure on early developing zebrafish embryos. It was revealed that exposure to arsenite caused changes in embryonic development, including morphological changes, reduced survival, and cardiac and neural defects [64]. Although the most of organs in the human body are affected by As, the heart was found to be most affected by it. Previous studies reported that the mechanism underlying As cardiotoxicity has included DNA fragmentation, apoptosis and alteration of cardiac ion channels due to As-derived oxidative stress [65,66]. In the experiment with mESCs treated with monomethylarsonic acid, a kind of As metabolites, mESCs formed clear EBs, but the expression of α-actinin (cardiac maturation marker) was significantly reduced and there were no beating cardiomyocytes. These results suggest that As has adverse effects on the differentiation of mESCs to cardiomyocytes [67]. 3.1.5. Triazoles Triazoles are widely used as antifungal agents in agriculture to treat fungal infections in humans and animals. The antifungal activity of triazoles is to interfere with steroid biosynthesis by inhibiting CYP51 (cytochrome P450 enzyme) that plays a role in the conversion of lanosterol to ergosterol in fungi and yeast. Triazole compounds include hexaconazole, flusilazole, myclobutanil, etc. in triazoles [68]. Exposure to Triazoles can cause skeletal defects, craniofacial malformation, maternal toxicity leading to intrauterine growth restriction [69,70]. In particularly, flusilazole was known to have the strongest effect on the mESCs-derived cardiomyocytes. Lower concentration of flusilazole could inhibit the differentiation of mESCs into cardiomyocytes than other triazoles [68]. In addition, flusilazole decreased the viability of mESCs by about 50 percent, and reduced cardiac differentiation rate of mESCs in a dose-dependent manner, causing the significant changes of cardiac differentiation-related gene expression. These results indicate that flusilazole adversely affects cardiac development of mESCs [71,72].

3.1.2. Paraquat (PQ) and maneb (MB) Paraquat (PQ) is widely used fast-acting and non-selective herbicide. Maneb (MB) is a fungicide. PQ and MB have been used in a mixture to treat various crop infections in agriculture. PQ inhibits mitochondria complex I and increases the production of ROS, which damages dopaminergic neurons [49]. PQ also has an adverse effect on the lungs, kidneys, liver and heart [50]. MB also causes oxidative stress through inhibition of mitochondria complex III and inhibits proteasomal activity in dopaminergic neurons [51]. The exposure to PQ and MB increases the risk of Parkinson’s disease (PD) [52], impairment of cognition, learning and memory [53]. In the experiment with ESCs, PQ and MB promoted the production of ROS by redox cycling, inhibition of mitochondrial electron transport chain and induction of ROS generating enzymes such as NADPH oxidases. Accumulation of ROS by PQ and MB was revealed to induce oxidative stress and apoptosis of ESCs [54,55]. This can affect cell viability, proliferation, and differentiation state [56]. In addition, oxidative stress induced by PD triggered cell death of dopaminergic neurons in the developing brain, which was considered to be the main cause of PD pathogenesis [57,58]. In PD, some possible pathways have been proposed: mitochondrial dysfunction, apoptosis, autophagy, accumulation of misfolded/aggregated proteins as well as oxidative stress [58,59].

3.2. Antibiotics Antibiotics are antimicrobial agents for preventing bacterial infections. They either inhibit the growth of bacteria or kill them. Some antibiotics also have antiprotozoal activity, but they are not effective against viruses. Antibiotics are also used as medications through suppressing growth and actions of bacteria in human bodies. Often, antibiotics with a broad spectrum have been administered in high doses for a long time, leading to problems like antibiotic resistance [73]. Besides that, it has been reported that antibiotics such as nitrofurans, macrolides, aminoglycosides, tetracyclines and sulfa drugs have an adverse effect on spermatogenesis or sperm function, leading to male infertility

3.1.3. Hexachlorobenzene (HCB) Hexachlorobenzene (HCB) is a fungicide belonging to organochlorine (OC) pesticides. It is known that HCB causes hepatic porphyria, thyroid dysfunctions and carcinogenesis, reproductive/developmental toxicity and carcinogenesis. HCB also adversely affects the endocrine system and exerts neurological toxicity and immunotoxicity [60]. Molecular mechanism of HCB toxicity has included numerous 17

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[74], and isoniazid, macrolides, penicillins, clavulanic acid, sulphonamides, nitrofurantoin and tetracycline have the potential to cause the hepatic dysfunction, such as hepatitis, intrahepatic cholestasis and fatty liver [75]. Rouveix, B. confirmed that fluoroquinolones antibiotics induce gastrointestinal intolerance or joint toxicity [76]. Another study revealed antibiotics, triclosan could induce cancer, cardiovascular malfunctions as well as developmental/reproductive toxicity [77].

were no changes in morphology and viability of undifferentiated ESCs, but MEHP reduced viability of ESCs-derived neurons. MEHP also induced apoptosis in both undifferentiated ESCs and ESCs-derived neurons. The differentiating neurons were more sensitive to MEHP than undifferentiated ESCs [90]. Nuoya Yin et al. addressed the neurotoxicity of DEP and DBP using ESCs. DEP and DBP showed different manners of cytotoxicity: DEP induced only oxidative stress, but DBP affected cell viability through cell membrane damage, apoptosis as well as oxidative stress. However, DEP and DBP could significantly alter the expression of neural-specific genes, suggesting their potential neurotoxicity [91]. Di-2-ethylhexyl phthalate (DEHP) and metabolites of phthalates (MEHP, MMP and MEP) may have cardiotoxic effects by inducing coronary heart disease [92], atherosclerosis [93] and increased blood pressure [94]. In the experiment using cardiomyocytes differentiated from ESCs, the beating of cardiomyocytes was reduced by monobutyl phthalates (MBP) exposure, and the expression of pluripotent and proliferation-related genes was still upregulated, implying that MBP inhibit cardiac maturation [95,96]. Cardiac beating and function are Ca2+-dependent. For DEHP, it was found to affect cardiomyocyte contraction by reducing calcium transient amplitude and shortening calcium transient duration. Therefore, DEHP was evaluated to potentially trigger arrhythmias [97].

3.2.1. Aminoglycosides Aminoglycoside antibiotics are commonly used antibiotics worldwide, which are broad-spectrum and effective to control Gram-negative bacterial infections [78]. In mammalian cells, aminoglycosides were found to induce cell death by generating ROS which activates Bax, a pro-apoptotic gene. Bax induces cytochrome c (cyt c) release from mitochondria to the cytosol. According to cyt c release, caspase-9 and caspase-3 are activated and apoptosis is induced [78]. Gentamicin, one of the aminoglycoside antibiotics, has been reported that it could cause nephrotoxicity and ototoxicity in neonates [79]. Gentamicin have no effect on the viability and pluripotency markers expression of hESCs. However, gentamicin decreased the viability of hESCs-derived neural differentiated cells in a dose-dependent manner. Decrease of cell viability accompanied the increase of capase-3 and cleaved PARP related to programmed cell death. In this study, the remarkable thing is that the expression of neural-specific genes like Pax6, Emx2, Pou3f2 and Otx2 was significantly decreased. These results support the hypothesis that aminoglycoside antibiotics could cause the neurodevelopmental disorders like autism [80,81].

3.3.2. Trichloroethylene Trichloroethylene (TCE) is widespread environmental contaminant that has been used in industry as an organic solvent for metal degreasing and in the production of chlorinated chemical compounds. It has been detected in air, soil, ground water and foods [98]. TCE metabolites occur through two major pathways, CYP51-dependent oxidation and glutathione (GSH) conjugation. The metabolites are formed in the liver, the lungs, kidneys, and male reproductive organs. They can generate acute organ-specific toxicity, mutagenesis, and carcinogenesis [99]. TCE metabolites play a critical role in developmental toxicity like fetal growth retardation, embryo lethality, ocular malformations, neurotoxicity and immunotoxicity [100]. There are many studies about the association between TCE and cardiac defects. Maternal drinking water contaminated by TCE might induce the increased incidence of congenital cardiac malformations in their fetuses [101]. Jiang Y et al. conducted the research to investigate the effect of TCE on developmental cardiotoxicity using human ESCs. In this study, the beating rate was slowed down, and cell area was increased by TCE. Pluripotency markers expression did not change, however, Nkx2.5 and Hand1, the cardiac progenitor markers, were up-regulated and cTnt and Myh-7, the cardiac maturation markers, were down-regulated. These results indicate that TCE may cause the adverse effects on transition from the cardiac progenitors to the cardiac maturation. Besides, TCE down-regulated the expression of Serca2 through up-regulation of phospholamban (a regulator of the Ca2+-ATPase inhibitor of cardiac sarcoplasmic reticulum). Serca2 transfers calcium from the cytosol to the lumen of the sarcoplasmic reticulum via ATP hydrolysis during cardiac muscle relaxation. The small change in Serca2 levels by TCE led to affect significantly the contractile ability in cardiomyocytes. Therefore, TCE was found to impair developmental cardiomyocytes by two routes such as a hindrance to transition of cardiac progenitors to maturated cardiomyocytes and a disturbance to Ca2+ dependent contractibility of cardiomyocytes [19]. In an animal study using maternal rat administered with the drinking water contaminated by TCE or dichloroethylene, they particularly caused atrial septal defects compared to control group [102]. In addition, TCE metabolites TCA and DCA as well as TCE caused the adverse effect such as CHD on the developing heart [98].

3.2.2. Danofloxacin (DF) Danofloxacin (DF), one of the fluoroquinolone antibiotics in the quinolones, is effective to control both Gram-negative and Gram-positive bacteria. It is used in veterinary medicine such as treatment of respiratory disease for chickens, cattle or pigs [82]. Kang et el. conducted the experiment about toxic effects of DF on the neural differentiation of mouse ES cells. Exposure to DF increased the expression of Pou5f1, self-renewal marker, during ESC neural differentiation. This indicate that DF may induce inhibition of neural differentiation. DF decreased the expression of all neural markers in dose-dependent manner. The blockage of ATP-dependent K+ channel might be a possible mechanism toward the inhibition of neural marker expression induced by DF because quinolone antibiotics have been known to act as GABA antagonist that blocks the ATP-dependent K+ channel [83,84]. 3.2.3. Sparfloxacin and levofloxacin Sparfloxacin and levofloxacin are fluoroquinolone antibiotics. Sparfloxacin is well known to cause cardiac disorders like prolongation of the QTc interval linked to cardiac arrhythmias [85]. Levofloxacin is safer and more well-tolerated than other fluoroquinolone antibiotics. Its toxicity is not well known [86]. Sparfloxacin and levofloxacin were used to assess the cardiotoxicity using ESCs. In ESCs-derived cardiomyocytes, the duration of cell beating markedly changed after sparfloxacin and levofloxacin treatment and the beating frequency and beating rate were reduced by only sparfloxacin. Under sparfloxacin stimulation, the beating frequency was the slowest, whereas the beating duration was the largest [87]. 3.3. Industrial excipients 3.3.1. Phthalates Phthalates are commonly used as plasticizers that make plastic flexible and additives in cosmetic products [88]. There are di-(2ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and diethyl phthalate (DEP), etc. It has been revealed that phthalates have an adverse effect on reproductive malformations, developmental abnormalities, and nervous and cardiovascular diseases [89]. In the study using mono-(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP, there

3.3.3. Perfluorooctane sulfonate Perfluorooctane sulfonate (PFOS), a representative of perfluoroalkyl 18

19 Human H9 Mouse D3 Mouse D3

Trichloroethylene

Perfluorooctane sulfonate

Perfluorooctane sulfonate

Diethyl phthalate (DEP) & Dibutyl phthalate (DBP)

Mouse ES cell lines derived from a single blastomere of early embryos (bm-ES cells) Mouse J1

Mouse D3

Sparfloxacin & levofloxacin

Di-(2-ethylhexyl)-phthalate (DEHP) & Mono(2-ethylhexyl) phthalate (MEHP)

Mouse NVRQS-11F

Arsenic compounds (iAsⅢ, MMAⅢ, DMAⅢ) Flusilazole

Danofloxacin (DF)

Mouse D3 Mouse D3

Hexachlorobenzene

Human H9

Primary cultures of Neural stem cells (NSCs) were prepared from rat embryonic cortices Mouse E1

Paraquat & Maneb

Gentamicin

Mouse D3

Chlorpyrifos and its metabolites (CPO, TCIP)

Cell line

×no change; ↑upregulated;↓downregulated; CMs: cardiomyocytes; NSCs: neural stem cells.

Industrial exipients

Antibiotics

Pesticides

Chemicals

Table 1 Toxicity of pesticides, antibiotics, industrial excipients on embryonic stem cells.

CMs

CMs

CMs

NPCs

Neurons

CMs

Neurons

Neurons

CMs CMs

Neurons

NSCs

Differentiated cells

Change of cell fate from neuronal to mesodermal cell lineages:↓GAD1, ↓GAT1, ↓TH, ↑Peg1 Inhibition of neurite outgrowth by oxidative stress in GABAergic neurons Interference with normal GABAergic neuronal functions in fetuses ↓EB formation ↓α-actinin MMAⅢ: disturbanc of differentiation ESCs to CMs ↓Viability of ESCs ↓ESC differentiation Toxicity: developmental-related > cell divisionrelated Alteration of the sterol synthesis pathway by differential gene expression ↓Pluripotency markers ↓Neural-specific markers ↑Apoptosis-related markers × Cell viability of undifferentiated ESCs ↓Cell viability of hESCs-derived neural cells ↓Early neurogenesis ↑POU5F1, ↓GABA-R, ↓GFAP, ↓Nestin, ↓TuJ1, ↓Map2 Inhibition of AChE activity Sensitivity to DF: Differentiating < Differentiated Cardiotoxicity was measured by LAPS biosensor Change in the duration of CMs beating ↓ Beating frequency Prolongation of QT interval ×DEHP MEHP: morphology change, ↓cell viability(ESCs: 1000μM, Neurons: over 50μM after 48 h), ↑active caspase-3, ↓TuJ1 → apoptosis Sensitivity to MEHP: ESCs-derived neurons > ESCs Cytotoxicity: ↑ROS, ↑LDH, ↑Caspase3/7 activity ↓Gata6, ↓Hand1, ↓T ↑Pax6, Nestin, Sox1, Sox3, Map2, Dcx Toxicity: DBP > DEP Abnormal alteration of neural ectoderm development Inhibition the transition of cardiac progenitors to cardiomyocytes: ↑Nkx2.5, ↑Hand1, ↓Mhc7, ↓cTnT Disturbance of Ca2+ turnover network: ↓Serca2, ↓Cav1.2 ↓Cardiac contractibility Disturbance of EB formation ↓MEF2C, ↓GATA4, ↓α-actinin, ↑TDH, ↑Xrcc5, ↑SOD2,↓Dnmt3b, ↓Dnmt3a ↑DNA damage Disturbance of differentiation into cardiomyocytes: ↓ROS, hidering of the OCT2 methylation Destruction of the MAM structure: ↑intracellular fatty acid, ↓PGC-1α ↓Mfn2, cytC release ↑ Mitochondria damage ↓ATP production Blocking Ca2+ transient of CMs: ↓IP3R, ↓LTCC

CPF: 117 μM, CPO: 212 μM, TCIP: 407 μM Inhibition of AChE activity Induction of the intrinsic neurodevelopmental toxicity by CPF and its metabolites ↓Cyclin D1, ↓Cyclin D2, ↓Rb1, ↓p19, ×p21, ↓Ki67, ×Nestin ↑ROS production Impairment of NSCs proliferation through the induction of oxidative stress by PQ + MB exposure

Results

[105]

[104]

[19]

[91]

[90]

[87]

[83]

[80]

[67] [71]

[61]

[56]

[43,44]

Reference

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defects [114].

substances (PFASs), is widely used as industrial and commercial surfactant [103]. PFOS can be accumulated in the body with the order of liver, heart, kidneys, lungs, brain [23]. The study about PFOS claimed that PFOS significantly altered the expression of cardiac-specific genes of mESCs. Moreover, PFOS could induce ROS generation, reduce ATP production, and cause apoptosis during the cardiogenesis [104]. Another study reported that PFOS up-regulates the expression of SOD2 (an antioxidant gene) and subsequently blocks ESCs differentiation into cardiomyocytes. PFOS significantly decreased EBs in size compared to control and also affected the expression of cardiac-specific genes. PFOS affected cardiac differentiation by regulating PPAR and MAPK signaling pathways [23]. The other study investigated the cardiac toxicity of PFOS related to mitochondria damage. PFOS damaged mitochondria of ESCs-derived cardiomyocytes and lowered ATP production. It blocked the calcium transient of cardiomyocytes, leading to a disturbance to cardiac contraction [105].

4. Conclusion Pesticides, antibiotics, and industrial excipients are constant in use to protect crops from harmful insects, to protect human and animals from microbial invasion, and to produce industrial products, respectively. They are essential to lead human life, but cause serious toxic problems to the environment where life lives. As a result of the exposure to pesticides, etc., a number of adverse effects on health such as infertility, spontaneous abortions, immunotoxicity, cardiotoxicity, neurotoxicity and cancer have been reported [34]. Therefore, it has become necessary to classify them into the environmental pollutants and manage regulations on their use. Based on the results of previous studies, this review suggested prenatal toxicity of a few chemical substances that have been used so far as pesticide, antibiotics and industrial excipient, respectively. Among various stages associated with prenatal development, the toxic effects of those chemicals were illuminated on ESCs based- early cardiac and neuro-developmental processes. As stated above, ESCs have been recognized as a useful tool to investigate early developmental toxicities of a variety of stress due to their pluripotency that instructs dynamic nature of embryonic development. Additionally, ESCs are regarded as an effective model to replace experimental animals in evaluation of developmental toxicity. in vivo toxicity tests using animal models have many problems such as enormous cost, high labor intensity, time required to obtain meaningful results, and ethical issues [115]. However, in vitro ESCs-based tests are evaluated to be able to overcome the disadvantages of animal experiments and have quite high reliability about 80 percent at the same time [116]. Nonetheless, using ESCs instead of animals is still controversial issue because it is difficult to predict the results of animal tests with in vitro data. Meanwhile, since most ESTs focus on mESCs, and there is no hESCs-based toxicity testing assay at present, the establishment of the standardized protocol using hESCs is required because hESCs can reflect human embryo development better than mESCs [117]. As summarized in Table 1, it was displayed that most chemical substances discussed in this article have prenatal developmental toxicity by affecting the viability of ESCs and/or early stages of cardiac and neuronal development derived from ESCs along with the induction of altered expression of pluripotency and/or differentiation markers through diverse mechanisms including mitochondrial dysfunction, oxidative stress and apoptosis. These results imply that if the environmental pollutants enter the mother through the placenta, they can cause the disturbance in cardiogenesis and neurogenesis of embryo as well as malfunction of heart and nerve system after birth (Fig. 1) as seen. Future studies are also needed to investigate their toxicity on

3.3.4. Cigarette smoke Cigarette smoke (CS) is an aerosol produced by combustion during smoking of cigarettes. It contains many toxic chemicals such as benzo (a)pyrene, formaldehyde, benzene, toluene, phenols, nicotine, etc. CS is comprised of mainstream smoke (MS) which is direct for smokers and sidestream smoke (SS) which damages to passive smokers, also called secondhand smoke. SS smoke is more toxic than MS smoke [106]. CS exposure leads to pulmonary inflammation, induction of lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease, developmental defects and immune system dysfunction [107]. Maternal smoking during pregnancy can adversely affect reproduction such as low birthweight, spontaneous abortions, perinatal mortality and congenital malformations [108,109]. It is also known that maternal smoking affects prenatal development [110]. According to population-based study, it is well-known that CS exposure affects heart development and function of offspring of smoking mother [111]. Cheng W et al. conducted the study regarding the effect of MS and SS on cardiac development in vitro. Exposure of MS and SS to ESC-derived cardiomyocytes interrupts cardiac-specific genes (Gata4, Nkx2.5, Mef2c, α-MHC and MLC1a) expression through the BMP-Smad4 signaling pathway. In particular, SS inhibits Gata4 expression even at noncytotoxic concentrations [112]. It is already known that apoptosis of cardiomyocytes increases in Gata4 knock-down mice model and it linked to the atrioventricular septal defects [113]. Taken together, dysregulation of Gata4 by MS and SS may suggest smoking and passive smoking during pregnancy can cause CHD [112]. These results are consistent with the population-based case-control study to investigate the parental cigarette exposure as risk factors for conotruncal heart defects. Parental smoking is associated with conotruncal heart defects in offspring and may increase the risk of offspring’s conotruncal heart

Fig. 1. Prenatal toxicity of the environmental pollutants on neuronal and cardiac development derived from ESCs. Exposure to the environmental pollutants may induce ESCs-derived developmental toxicity. As results of ESCs-based toxicological studies, pesticides, antibiotics, and industrial excipients exerted prenatal developmental toxicity by affecting the viability of ESCs, EB formation, and/or early stages of cardiac and neuronal differentiation derived from ESCs through diverse mechanisms including mitochondrial dysfunction, oxidative stress and apoptosis. The prenatal developmental toxicities of environmental pollutants can cause cardiac and neuronal diseases such as hypertrophy and autism after birth.

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further developmental processes in addition to ESCs-based development. Along with scientific testing, there will have to be regulations for use of these pesticides, antibiotics and industrial excipients.

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