Acetylcholinesterase Is a Potential Biomarker for a Broad Spectrum of

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Acetylcholinesterase is a potential biomarker for a broad spectrum of organic environmental pollutants Hualing Fu, Yingjie Xia, Yangsheng Chen, Tuan Xu, Li Xu, Zhiling Guo, Haiming Xu, Heidi Qunhui Xie, and Bin Zhao Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b04004 • Publication Date (Web): 11 Jul 2018 Downloaded from http://pubs.acs.org on July 12, 2018

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Environmental Science & Technology

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Review Acetylcholinesterase is a potential biomarker for a broad spectrum of organic environmental pollutants Hualing Fu†,‡, Yingjie Xia†,‡, Yangsheng Chen†,‡, Tuan Xu†,‡, Li Xu†,‡, , Zhiling Guo†,‡ Haiming Xu§, Heidi Qunhui Xie*,†,‡, Bin Zhao*,†,‡ †

State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China ‡ University of Chinese Academy of Sciences, Beijing, China § School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China Address correspondence to Dr. Heidi Qunhui Xie, Research Center for Eco-Environmental Sciences (RCEES), Chinese Academy of Sciences, Beijing 100085, China; Telephone: (86) 010-62842865; Email: [email protected]; and Dr. Bin Zhao, Research Center for Eco-Environmental Sciences (RCEES), Chinese Academy of Sciences, Beijing 100085, China; Telephone: (86) 010-62842865; Email: [email protected]

ABSTRACT Acetylcholinesterase (AChE, EC 3.1.1.7) is a classical biomarker for monitoring contamination and intoxication of organophosphate (OP) and carbamate pesticides. In addition to these classical environmental AChE inhibitors, other organic toxic substances have been found to alter AChE activity in various species. These emerging organic AChE disruptors include certain persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and wildly used chemicals, most of which have received considerable public health concern in recent years. It’s necessary to reevaluate the environmental significances of AChE in terms of these toxic substances. Therefore the present review is aiming to summarize correlations of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE activity upon treatment with the emerging disruptors in vivo and in vitro and action mechanisms underlying the effects on AChE. Over 40 chemicals belonging to six main categories were reviewed, including 12 POPs listed in the Stockholm Convention. AChE activity in certain organisms has been found to be well correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. Moreover, it has been documented that most of the listed toxic chemicals could inhibit AChE activity in diverse species ranging from invertebrates to mammals. Besides directly inactivating AChE, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins. The collected evidence suggests that AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants.

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1. INTRODUCTION Biomarkers are widely used in environmental toxicology studies and pollution monitoring.1, 2 One of the most frequently used biomarkers for toxicity in nervous system is acetylcholinesterase (AChE, EC 3.1.1.7). It is an enzyme with potent catalytic activity of hydrolyzing acetylcholine, which is expressed in various organs and central and peripheral nervous systems.34 AChE plays a vital role in the cholinergic neurotransmission involved in motion and respiration in diverse species,4 and AChE is also crucial for advanced brain functions in mammals, such as learning and memory.5, 6 Chemicals such as the nerve gas sarin are designed to target AChE catalytic triad site, thereby inhibit the enzyme and cause permanent neurological damage and even death.7 Several environmental chemicals, such as organophosphate (OP) and carbamate pesticides, act similarly on AChE and irreversibly inhibit AChE enzymatic activity.8 Neuro-intoxication caused by these classical environmental AChE inhibitors can occur in various species ranging from Caenorhabditis elegan9 to mammals.10 Exposure to these environmental AChE inhibitors can lead to cholinergic crisis in humans even death from severe respiratory or cardiac failure.11 Therefore, AChE inhibition in human samples is conventionally used as a biomarker for occupational or accidental OP-exposure risk assessment.12-14 Moreover, AChE has been wildly used as a biomarker for monitoring environmental contamination by OP and carbamate pesticides.15-18 Reduction of AChE activity in certain species within particular habitats is well correlated with the level of OP and carbamate pesticides in there, in which the indicator organisms are mostly cold-blooded species such as bivalves, snails, fish and etc.15 Besides OP and carbamate pesticides, several emerging environmental AChE disruptors have been reported, including other types of pesticides and certain persistent organic pollutants (POPs).19, 20 Moreover, these emerging disruptors have been found affect AChE activity through previously unrecognized mechanisms. For example, dioxin, a typical POP, was shown to reduce human AChE activity by downregulating AChE mRNA expression through the aryl hydrocarbon receptor (AhR)-dependent signaling pathway,21 and AChE activity was reported to be decreased in dioxin-exposed mouse CD4+ T cells through the upregulation of an AChE-targeting microRNA, miRNA-132.22 Furthermore, AChE mRNA expression was found to be altered in the common carp after long-term exposure to the triazine-class herbicide atrazine (ATR).23 Thus, it is necessary and timely to review the effects on AChE activity and the action mechanisms of these organic emerging environmental AChE disruptors. Classical environmental AChE disruptors, such as OP and carbamate pesticides, have already been well reviewed.10, 20, 24 Reviews have also been published on emerging environmental AChE disruptors, such as organochlorinated pesticides and ATR herbicide.19, 25 These reviews are focused on the disruptors’ effects on AChE enzymatic activity, particularly in invertebrates and fish; however, few reviews have summarized the newly identified action mechanisms of the inhibitors, particularly for certain organic pollutants. Therefore, here, by searching literature in PubMed, Web of Science and ScienceDirect databases, we summarized effects of major classes of organic emerging AChE disruptors on the enzymatic activity, including correlation of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE enzymatic activity upon treatment with the emerging AChE disruptors in vivo or in vitro, as well as the action mechanisms underlying the disruption with an emphasis on previously unrecognized mechanisms related to AChE biosynthesis processes.

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2. EFFECTS OF EMERGING ENVIRONMENTAL ACHE DISTRUPTORS ON ACHE ENZYMATIC ACTIVITY By using “acetylcholinesterase” in combination with the names of chemical categories of interest as keywords, we collected 76 pieces of relevant literature published recently (TABLE 1). The emerging AChE disruptors reviewed here belong to diverse categories of well-known or emerging organic toxic substances that have attracted considerable public concern. We included other pesticides and herbicides than OP or carbamates pesticides, flame retardants and plasticizers that are wildly used currently or have been in the past, as well as pollutants intentionally or unintentionally produced from various industrial sources or daily human activity, including polycyclic aromatic hydrocarbons (PAHs) and certain POPs, such as dioxins, and dioxin-like polychlorinated biphenyls (DL-PCBs) (TABLE 2).

2.1 Organochlorinated pesticides Organochlorinated pesticides have attracted considerable research attention because of their persistence in the environment and marked endocrine-disrupting effects.19 Level of dichlorodiphenyltrichloroethane (DDT) and related organochlorinated pesticides have been found highly correlated with AChE activity of indicator organisms, such as bivalves, in certain habitats. Lower AChE activity in gill of clam (Ruditapes philippinarum) was found to associate with level of DDT in sediments at Lagoon of Venice.26 Moreover, in sentinel oysters (Crassostrea gigas), an increase in the level of dichlorodiphenyldichloroethylene (4,4-DDE), one of the metabolites of DDT, was detected in parallel with a decrease in AChE activity.27 Although the correlation between pesticide levels and AChE activity remains to be carefully analyzed, current evidence suggests that these pesticides can potentially inhibit AChE activity in these bivalve species. Body burden of DDT in mussels (Mytilus galloprovinciali) collected from Bizerte lagoon (Tunisia) was found to be negatively correlated with AChE activities in the gill (R2: 0.951),28 and total-body burden of DDT in grass goby fish collected in the same area was also reported to be negatively correlated with AChE activity in muscle samples (R2: 0.904).29 In European eels (Anguilla anguilla) collected from the Vaccare’s lagoon in southern France, AChE activity in the muscle was negatively correlated with 4,4-DDE levels in liver and muscle; while AChE activity in the brain was negatively correlated with dieldrin levels in the liver, which is a substitute of DDT.30 Besides, the AChE activity in the brain was positively correlated with level of ΣPCBs in the muscle, whereas negatively correlated with level of lindane (a new POP; gamma-hexachlorocyclohexane) in the liver of these European eels.30 Furthermore, total-body burden of hexachlorobenzene (HCB), another organochlorinated pesticide newly listed in the Stockholm Convention database, was also negatively correlated (R2: 0.963) with AChE activity in muscle samples of grass goby fish collected in Tunisia, with the correlation coeffecient again being the highest measured.29 In the sentinel oysters (Crassostrea gigas), the increment of endosulfan II level was in accordance with AChE inhibition.27 Apart from the correlation studies, the effects of treatments with HCB or PCBs on AChE activity have been examined in vivo or in vitro. After exposed to waterborne HCB at 2 to 200 µg/L for 10 days, AChE activity in the brain of juvenile common carps (Cyprinus carpio) was significantly inhibited.31 AChE activity of female amphipod (Monoporeia affinis) exposed to contaminated sediment in the Baltic Sea showed a negative correlation with level of PCBs contamination.32 By an in vitro AChE bioassay, extracts of 21 sediment samples collected from Masan Bay in Korea 4


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were found to inhibit fish AChE activity in vitro, which was correlated with the level of PCBs in the sediment.33 Pentachlorophenol (PCP) is another pesticide newly added to the Stockholm Convention database. Although there is a lack of correlation study on PCP, it has been reported to inhibit the activity of human erythrocyte membrane AChE in vitro with an ID50 of ~0.7 mM,34 and inhibit AChE activity in SY5Y human neuroblastoma cells following 1-day exposure to 3 µM PCP.35

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2.2 Dioxin and dioxin-like compounds Dioxins and PCBs are typical POPs that produce various toxic effects on different organs, including the nervous system,36 and among these compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic congener of the entire class.37 The effects of these POPs on AChE activity have been studied mainly in mammalian systems except for an in vivo study on earthworm (Eisenia Andrei). Acute filter paper toxicity test showed that AChE activity was significantly decreased in the earthworm (p < 0.001) after 48-hour exposure to 0.5, 1.0, and 1.5 ng/cm2 polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs), a mixture of 6 congeners of PCDD/Fs, compared to solvent control.38 Maternal exposure to TCDD (0.2 or 0.4 µg/kg body weight (bw)) from gestation day 1 to lactation day 30 of rats caused a drastic reduction in AChE activity (~50%) in the offspring cerebellum.39 Increase in hypothalamic AChE activity induced by vitamin C application was markedly diminished in rats intraperitoneally injected with Aroclor 1254 (2 mg/kg bw/day) for 30 days, which is a mixture of dioxin-like and non-dioxin-like PCBs.40 In nerve growth factor (NGF)-treated rat pheochromocytoma cells (PC12), AChE activity was decreased slightly, but in a statistically significant manner, after 3-day treatment with 1 nM TCDD, relative to DMSO (control) treatment.41 During myogenic differentiation of C2C12 cells, AChE activity was significantly reduced upon TCDD treatment. TCDD was effective in the 0.003– 0.1nM range and reduced AChE activity maximally by 60% relative to control, which was in parallel with the decrease in the mRNA level and the disturbances of the myogenesis.42 Apart from the effects on AChE in neuronal and muscular systems, TCDD exposure can lower AChE activity in CD4+ T cells in parallel with reducing the expression of IL-17, IL-6, IL-1β, IFN-γ, and TNF-α and suppressing T-cell proliferation in encephalitogenic mice.22 Moreover, AChE activity is decreased not only in mouse models, but also in TCDD-exposed human-derived systems: AChE activity in SK-N-SH human neuroblastoma cells was reported to be decreased slightly, but significantly, following administration of PCDD/Fs and polybrominated dibenzo-p-dioxins (PBDDs), including TCDD, 2,3,7,8-TCDF, 2,3,4,7,8-PentaCDF, 1,2,3,7,8-PentaCDD, and 2,3,7,8-TBDD.21, 43 The compounds were effective in the 0.1–10 nM range and reduced AChE activity maximally by 20%–30% relative to control. These distinct potencies might be related to the toxic equivalent factor of each compound.21, 43, 44 However, addition of these dioxins and dioxin-like compounds into SK-N-SH cell lysates in vitro did not directly affect AChE activity in the lysates.21, 43 Accordingly, in another in vitro study conducted using human red blood cells (RBCs) from healthy volunteers, the RBC membrane AChE activity was not altered after incubation with 32 ng/mL (100 nM) TCDD, but AChE activity was significantly affected when 32 µg/mL (100 µM) TCDD was used, which suggests very weak direct inhibition of AChE by TCDD.45 This effective dose of TCDD is approximately 105-fold higher than the average TCDD level in the serum collected from exposed populations after accidental contamination.21 However, there is a lack of field study showing the correlation between AChE activity of certain organisms and level of these chemicals in specific habitats. 5



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2.3 PAHs There is one field study reported a close correlation between AChE activity of indicator organism and level of PAHs in there. In the aforementioned field study carried out in the Vaccarès lagoon (Camargue, France), the levels of 16 priority PAHs (naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benzo(a)-anthracene, chrysene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, indeno(1,2,3-cd)pyrene, benzo(ghi)perylene, and dibenzo(ah)anthracene) and AChE activity were determined in parallel in different tissues of the European eels (Anguilla anguilla) living in the area. It was found that bile concentrations of PAHs containing 5 or less aromatic rings, except benzo(a)anthracene and benzo(a)pyrene showed strong positive relations with muscular AChE activity. Similar positive correlation was also found between the muscular AChE activity and PAH concentration in muscle, and few correlations were found with hepatic level of PAHs.30 However, the positive correlation obtained in the field study is not consistent with data from an in vitro study. The addition of certain PAHs in vitro was reported to dose-dependently inhibit the enzymatic activity of AChE purified from the electric eel,46 and PAHs containing ≥3 aromatic rings inhibited AChE most strongly (IC50: 2–6 ppm).46 Among the tested PAHs, chrysene and pyrene showed the highest and lowest potency (IC50: 2.40 ± 0.04 and 5.22 ± 0.38 ppm, respectively).46, 47 Inhibitions of AChE activity have been found in other fish species exposed to certain PAHs in vivo. AChE activity was significantly reduced in gill and head of milkfish (Chanos chanos) after acute exposure to anthracene (0.001–0.031 ppm) and benzo[a]pyrene (0.022–0.176 ppm).48 Moreover, short-term exposure to pyrene significantly inhibited the activity of head AChE at 0.5 ppm and muscle cholinesterases activity at 1 ppm in juveniles common goby (Pomatoschistus microps).49 Seven-day exposure of crab (Carcinus maenas) to waterborne fluoranthene at 0.04–0.1 ppm also caused significant decrease in the muscular AChE activity.50 However, exposure of fluoranthene or benzo(a)pyrene to certain insects caused elevations in AChE activity of the organisms, including midge larvae of the family Chironomidae51 and fifth instar gypsy moth (Lymantria dispar L.) larvae.52 In in vitro study using recombinant human AChE protein, benzo[a]pyrene was found to inhibit the enzymatic activity (IC50: 0.38 ± 0.13 ppm) showing a higher sensitivity to human AChE than that of electric eel.47

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2.4 Herbicides Several herbicides have been proposed as AChE disruptors in vivo and in vitro. In the sentinel oyster (Crassostrea gigas), the levels of herbicides such as γ-hexachlorocyclohexane (γ-HCH) was found to be elevated in accordance with AChE inhibition.27 Agrawal and Sultana (1993) reported that the AChE activity of rat erythrocytes was reduced by 50% 48 h after a single dose exposure (i.p.) to HCH at 300 mg/kg body weight (one-third of LD50 ).53 Several in vivo studies on the effects of ATR have been carried out in different fish species. AChE activity was significantly increased in the brain of pacu fish (Piaractus mesopotamicus) after 48-hour exposure to ATR at 15, 20, 25, 35, and 45 ppm.54 However, AChE activity was reduced in the brain of zebrafish after subchronic exposure to ATZ at 1 ppm in parallel with the occurrence of abnormal behavioral.55 Besides, 40-day exposure to ATR (4.28, 42.8, 428 ppb) was reported to cause reductions in AChE activity in the muscle and brain of common carp.56 Effects of glyphosate exposure on AChE activity have been extensively studied in polychaeta, 6


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snail, mussel, fish and tadpoles, particularly in diverse species of fish. In most of the cases, the AChE activity was reduced upon exposure to glyphosate at ppm level in vivo,57-59 except for that of polychaeta in which the AChE activity was increased.60 AChE activity could be increased or decreased in the gill of mussels upon glyphosate exposures that might likely depend on the duration of the exposure.61 Effects of glyphosate on AChE activity have been revealed in 9 fish species exposed to the chemical in vivo (TABLE 3).62-69 Among these species, brain and muscular AChE activity in Anabas testudineus and Heteropnestes fossilis as well as muscular AChE activity in Oreochromisniloticus were more sensitive to glyphosate exposure than those in other species (TABLE 3). Long-term treatment with glyphosate at 1.20 ppt could cause significant alterations in AChE activity including inhibition of brain and muscular AChE activity in Anabas testudineus and increases in the AChE activity in Heteropnestes fossilis and Oreochromisniloticus.64, 65 Interestingly, opposite effects on AChE activity were recognized in muscle, brain or spinal cord of Anabas testudineus exposed to higher level of glyphosate (17.20 ppm).64, 65 Apart from in vivo study in diverse fishes, significant reduction in the AChE activity were found in the primary cells derived from diploid and triploid of Misgurnus anguillicaudatus upon acute treatments with glyphosate at 80 ppm or above in vitro.70 Regarding mammals, mild inhibition of AChE activity has been found in tissue extracts of rat, human serum and human erythrocytes after incubated with glyphosate. AChE activity was inhibited most obviously in rat brain extract upon incubation with glyphosate, in which the maximum inhibition was around 80% and IC50 was 17.4 mM.71 While glyphosate inhibited the enzymatic activity of human serum AChE in vitro with an IC50 of 714.3 mM.72 But statistically significant decreases in AChE activity (about 20%) were found in human erythrocytes after 1 or 4-hour treatment with glyphosate at 0.25–5 mM.73

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2.5 Plasticizers Bisphenol A (BPA) has long been regarded as an endocrine disruptor that exhibits neurodevelopmental toxicities.74 In arctic spider crabs exposed to BPA at 50 ppb for 3 weeks, AChE activity was decreased by 52.4% relative to the activity in control crabs.75, 76 One to two-day exposure to BPA at 0.78–1 ppb could cause significant decreases in AChE activity from the head of zebrafish.77 Japanese medaka were exposed to BPA at 1.5 ppm for 60 days and significant decrease (around 25%) in AChE activity in fish liver was found.78 Furthermore, decrease of AChE activity have been found in hippocampus of adult female mice or offspring rat after sub-chronic or chronic maternal exposure to BPA.79, 80 Recently, an increase in AChE activity has been found in human red blood cells incubated with BPA at 5–100 ppm for 4–24 h.81 Identical exposure of the crabs to diallyl phthalate, a type of plasticizer, also suppressed AChE activity (by 63%).75 dibutyl phthalate (DBP), diethyl phthalate (DEP), and di-ethylhexyl phthalate (DEHP) are also widely used plasticizer that cause inhibition effect on fish AChE. DBP and DEP inhibit AChE (around 40% and 30%) of embryonic zebrafish at the exposure of 0.5mg/L from 2~96 hour post-fertilization (hpf).82 DBP and DEHP causes inhibition effect on liver, gill, kidney, heart, brain and muscle AChE of Pseudobagrus fulvidraco with 100–500 mg/kg diet exposure for 4–8 weeks.83 DEP inhibited brain AChE (by 50%) of Cirrhina mrigala after exposure at 25 ppm for 3 days.84

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2.6 Flame retardants Flame retardants form another group of chemicals that have raised considerable environmental concern, and brominate flame retardants (BFRs) have particularly attracted research attention. 7



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Polybrominated diphenyl ethers (PBDEs) cause different effects on AChE of multiple species. DE-71, a commercial PBDE mixture increased AChE activity of zebrafish larvae by 10.7% at 68.7 µg/L upon 2 to120 hpf exposure, while the AChE mRNA level was not changed.85 In another study, pregnant female rats were dosed with DE-71 from gestation day (GD)1 to postnatal day (PND) 21 from 0.3 mg/kg to 30 mg/kg. The PND21 female offspring with 30 mg/kg maternal exposure to DE-71 showed nearly 4-fold increase of midbrain AChE mRNA. The PND 250 offspring of both gender with 3.0 mg/kg maternal exposure showed 1.6–1.7 folds decrease of midbrain AChE mRNA.86 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), 2,2',4-tribromodiphenyl ether (BDE-17) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) inhibited AChE (ranging from 18% to 72%) of Chironomus sancticaroli larvae upon exposure at 0.5 ng/mL for 48 h.87 Exposure to BDE-47 at 50 µg/L for 3 weeks caused a similar reduction in AChE activity, by ~32.3%, as that observed with BPA treatment in the crab.75 BDE-47 inhibited gill AChE (about 40%) of mussels (Mytilus galloprovincialis) upon exposure at 2 µg/L for 30 days.88 While in fish (Fundulus heteroclitus), Four-day exposure to BDE-47 at 0.0125 mg/L led to an increase (~20%) in brain AChE activity .89 Six-day BDE-99 treatment inhibited AChE in rat PC12 by 10% at 20 µM and 25% at 50 µM.90 Four-day exposure to 0.2 mg/kg 2,2’,4,4’,5,5’-hexabromodiphenylether (BDE-153) in food caused a decrease of nearly 40% in brain AChE activity of crucian carp (Carassius auratus).91 BDE-209 has been reported to affect AChE in mammals. CD-1 Swiss mice were feeded with decabrominated diphenyl ether (BDE-209) at 0.1–160 mg/kg body weight per day (bw/d) for 15–60 days. The shorter exposure group (15 days) showed a nearly 3-fold increase in brain AChE activity at doses higher than 80 mg/kg bw/d. The longer exposure time (60 days) on the other hand caused a 50% decrease in brain AChE activity at 160 mg/kg bw/d.92 An in vitro binding and enzymatic assay showed a 40% inhibition at 10 µM and 62% inhibition at 20 µM of BDE-99 on human AChE.93 Zebrafish embryo exposed to 1.25 ppm tetrabromobisphenol A (TBBPA, another BFR) show an increase in AChE activity (about 1.6-fold) at 120 hpf.94 The TBBPA derivative, tetrabromobisphenol A bis(2-hydroxyethyl ether) (TBBPA-BHEE) can also increase AChE activity by nearly 40% in PC12 cells at 5 µM for 24 h.95 There are other BFRs that cause increase in AChE activity. AChE activity in the brain of fish (Carassius auratus) was increased by about 40% upon 7-day exposure to hexabromocyclododecane (HBCD) at a dose higher than 20 µg/L.96 AChE activity was increased upon the increase of exposure time in tribromophenol treated SH-SY5Y human neuroblastoma cells. Upon 72-hour exposure to HBCD, an EC50 at 7.5 µM was obtained in non-differentiated cells, and a lower EC50 (2.5 µM) in differentiated cells.97 Besides BFRs, chlorinated flame retardants, such as dechlorane plus (DP), an alternative polychlorinated flame retardant of Mirex, inhibited AChE activity in the earthworm Eisenia fetida; 14-day exposure to 10–50 mg/kg of soil containing DP decreased AChE activity by ~30% in the earthworms, whereas short-term exposure (7 days) to the soil at 0.1–50 mg/kg markedly elevated AChE activity in the earthworms.98 Organophosphorus flame retardants (OPFRs) are alternative flame retardants for BFRs, which have been found to cause neurotoxicity. Although OPFRs and OPs feature a similar chemical structure, exposure to tri-n-butyl phosphate (TNBP) at 625 and 3125 µg/L for 5 days lowered the AChE mRNA level by 50% in zebrafish larvae, but did not affect AChE activity, which differs from the effects of chlorpyrifos exposure.99 In another study, upon 96-hour exposure to triphenyl phosphate (TPHP) at 125 µg/L, AChE activity in Japanese medaka (Oryzias latipes) was decreased by about 40%, while exposure to TNBP at 3125 µg/L caused about 30% of increase.100

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Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) exposure at 900 µg/L from 2 to 120 hpf increased AChE activity in zebrafish (Danio rerio) larvae by about 25%.101 AChE activity was decreased by about 40% in flies (Drosophila melanogaster) upon 5-day exposure to 4-vinylcyclohexene at 100 µM.102 Upon a single oral dose exposure to perflourooctanosulphonate (PFOS) at 21 µmol/kg bw, AChE transcription level was decreased (nearly 50%) in cortex of the 10-day-old male mice 24 h after the exposure.103

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3. ACTION MECHANISMS OF EMERGING ENVIRONMENTAL ACHE DISTRUPTORS

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3.1 Direct inhibition of AChE enzymatic activity Certain emerging environmental AChE disruptors can directly inhibit AChE enzymatic activity in vitro, which suggests that their mechanism of action resembles that of OPs. For example, PCP inhibited human recombinant AChE in vitro.34 PAHs inhibited electric eel AChE (with IC50 at the ppm level).46 Among them, chrysene and pyrene showed the highest and lowest potency (IC50: 2.40 ± 0.04 and 5.22 ± 0.38 ppm, respectively).40, 47 Benzo[a]pyrene inhibited activity of recombinant human AChE protein in vitro (IC50: 0.38 ± 0.13 ppm), showing a higher sensitivity than that of electric eel.47 Besides, glyphosate also inhibited rat and human AChE activity in vitro (IC50: 17.4 mM for rat brain; IC50: 714.3 mM for human serum).71-73 Recently, BPA was found to enhance AChE of human red blood cells in vitro, with effective doses ranging 5–100 ppm.81 While BDE-99 was also able to inhibit human AChE in vitro with a 40% inhibition at 10 µM and 62% inhibition at 20 µM.93 However, the molecular mechanisms underlying the interaction between these chemicals and the AChE enzyme remain to be carefully analyzed. Moreover, certain chemicals had inhibitory effects on AChE from human erythrocyte membranes and serum with extremely low potency, such as TCDD and glyphosate.45, 71, 72 3.2 Newly recognized mechanisms in terms of interference with AChE biosynthesis Several signaling pathways have been proposed to be potentially involved in the effects of dioxins and DL-PCBs on AChE, such as the thyroid, antioxidant, and NGF-related signaling pathways,57, 67, 104 and these signaling mechanisms might participate in the transcriptional regulation of AChE. Accordingly, multilevel regulation of AChE biosynthesis has been documented. 3.2.1 AChE regulation at posttranscriptional or posttranslational level Dioxins have been suggested to suppress AChE expression through posttranscriptional regulation in human-derived models or in murine systems. TCDD exposure upregulated miRNA-132 through the AhR pathway, and caused AChE mRNA degradation and a subsequent reduction in AChE activity in encephalitogenic CD4+ T cells of mice.22 Recently, we demonstrated that in SK-N-SH neuroblastoma cells, dioxin treatment upregulated the expression of miRNA-608, a primate-specific miRNA, and of miRNA-146b-5p targeting AChE mRNA.105-107 Thus, miRNA-608, miRNA-146b-5p and other known AChE targeting microRNAs potentially being affected by dioxin treatment could represent another microRNA mediating posttranscriptional regulation of AChE by dioxin.41 Furthermore, in rat PC12 cells, Xu et al. demonstrated that dioxin treatment suppressed NGF-induced elevation of AChE activity; here, the AChE mRNA level was not affected but AChE subcellular distribution was slightly altered, which suggests a mechanism involving posttranslational modification for the effect on AChE activity.41, 45

9



356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381

3.2.2 AChE regulation at the transcriptional level In human neuroblastoma SK-N-SH cells, dioxins can decrease AChE activity by downregulating AChE mRNA expression through the AhR pathway, rather than by directly affecting AChE catalytic activity.21, 43 AhR is a nuclear receptor and transcription factor, and dioxins can activate AhR and trigger AhR translocation into nucleus, which is followed by AhR binding to dioxin-responsive elements (DREs) in the upstream region of responsive genes and modulation of gene expression. According to the DRE consensus sequence (5ʹ-GCGTG-3ʹ or 5ʹ-CACGC-3ʹ), Xie et al. have identified at least one DRE site in a reported human ACHE promoter region (~2.2‑kb region) that might function in mediating the suppressive effects of TCDD on ACHE promoter activity and AChE mRNA in SK-N-SH cells.21 Notably, mutation of the putative functional DRE site in the promoter reversed the effect of TCDD and other dioxin congeners on ACHE promoter activity.43 Thus, this AhR-DRE-mediated regulatory mechanism might be involved in the responses elicited by other AhR agonists, such as DL-PCBs and certain PAHs. Moreover, lacks of DRE consensus sequence within proximal region mouse and rat ACHE promoter (~2‑kb region) have been proposed as one of the explanations for the distinct response of mouse promoter activity and rat AChE activity to dioxin exposure from that of human AChE.43 Thus the interspecies difference in dioxin responsiveness of AChE is valuable for further investigations. Besides dioxin-treated organisms, zebrafish larvae exposed to OPFRs99 and common carp exposed to ATR35 exhibited marked alterations in AChE mRNA levels; this suggests the involvement of transcriptional regulation in mediating the effects produced by the compounds. Moreover, maternal DE-71 and PFOS exposure were foun to laed to decreases in AChE mRNA level in different parts of brain of the offspring in rat, suggesting these compounds may disturb the expression of AChE during brain development.86, 103 However, the precise mechanisms underlying these downregulation of AChE mRNA in fish and rat remain unknown.

382

4. CONCLUSION AND OUTLOOK

383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398

Chemicals belonging to six main categories were reviewed, including 12 POPs originally or newly being listed in the Stockholm Convention. AChE activity in certain organisms has been found to be highly correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. However, there is a lack of field study for other listed organic AChE disruptors, although most of the listed toxic chemicals have been documented to decrease AChE activity in diverse species from invertebrates to mammals. For most of the emerging AChE disruptors, research work was mostly conducted in lower species, including diverse invertebrate indicators, than that in mammals except for dioxins. However the mechanism study has not been sufficiently carried out on the emerging AChE disruptors. Based on limited information, some of the emerging AChE disruptors have been reported to act directly on AChE to inactivate the enzyme, but mostly with lower potency than that of OP pesticides. Besides, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins whose action mechanisms related to multiple biosynthesis processes of AChE. In conclusion, AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants for not only evaluating their potential ecological effects in indicator organisms but also for toxicological study in classical model system.

10


Page 10 of 22

Page 11 of 22


399

ASSOCIATED CONTENT:

400 401 402

None

403 404 405 406 407 408 409

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Nos. XDB14030401, XDB14030402) and the National Natural Science Foundation of China (Nos. 21377160, 21525730, 21527901). We thank Dr. Yvonne J. Rosenberg from PlantVax Inc. and Dr. Marjorie A. Philips from UC Davis for comments during manuscript preparation. All authors wrote and revised this paper. The authors declare no competing financial interests.

ACKNOWLEDGMENTS:

11



410 411

TABLES TABLE 1. Literature included in this reviewed

Number of reports Organo-chlorinated pesticides Dioxins and dioxin-like PCBs PAHs Herbicides Plasticizers Flame retardants 412 413

Page 12 of 22

a

12 9 9 23 11 21

Lower species refers to species lower than mammals

12


Study species Lower speciesa

Mammals

9 1 8 19 8 14

2 8 1 4 3 7

Page 13 of 22


TABLE 2. Reported persistent organic pollutants as environmental AChE disruptors

414 Type

Organochlorinated pesticides

Chemical

Organism/sample

Mode of study

Ref b

DDT DDT DDT DDT 4,4-DDE dieldrin lindane PCBs a PCBs a HCB HCB

correlation analysis correlation analysis correlation analysis in vitro exposure correlation analysis correlation analysis correlation analysis correlation analysis correlation analysis correlation analysis in vivo exposure

29 28 26 33 30 30 30 32 29 29 31

in vitro exposure

34

PCP endosulfan II

grass goby mussels clam sediment samples eel eel eel amphipod eel grass goby carp human erythrocyte membrane AChE human neuroblastoma cell (SY5Y) oyster

35 27

TCDD

rat

TCDD TCDD TCDD

rat pheochromocytoma cell (PC12) mouse mouse myoblast cell line(C2C12) human neuroblastoma cell (SK-N-SH) human neuroblastoma cell (SK-N-SH) human red blood cell worm rat carp

cellular exposure in vivo exposure in vivo exposure (maternal) cellular exposure in vivo exposure cellular exposure cellular exposure

21

cellular exposure

107

in vitro exposure in vivo exposure in vivo exposure in vivo exposure

45 38 40 96

PCP

Dioxins and DL-PCBs

TCDD TCDD TCDD PCDD/Fs a Aroclor 1254 HBCDD

415 416

Flame Retardants a Chemical mixture b Related reference

13


39 41 29 42


TABLE 3. Effects of glyphosate on AChE of different fishes

417 Species

Effect on AChE activitya

Dose

Time

Refb

N/A + N/A + N/A N/A

1.20 ppt 17.20 ppm 1.20 ppt 17.20 ppm 1.20 ppt 0.70 ppm

64 65 64 65 64 68

-

N/A

0.16 ppm

30 days 30 days 30 days 30 days 30 days 4 days 7, 14, 21, 28 days

N/A

N/A

N/A

1.36 ppm

4 days

67

-

N/A

N/A

N/A

-

-

N/A

N/A

4 days 5, 9, 16 days

69

-

N/A

N/A

N/A

N/A

1, 5 ppm 3.5, 7, 14 ppm 3, 6, 10, 20 ppm

4 days

62

Brain

Muscle

Liver

Serum

Spinal cord

Oreochromisniloticus Poecilia vivipara

+ + + NC NC

+ + + + NC

N/A N/A N/A N/A N/A N/A

N/A N/A N/A N/A N/A N/A

Clarias gariepinus

-

N/A

-

-

-

-

Cyprinus carpio Leporinus obtusidens

Anabas testudineus Heteropnestes fossilis

Leiariusmarmoratus × Pseudoplatystomareticulatum hybrid fish Prochiloduslineatus

418 419 420 421 422 423

Page 14 of 22

a

Increased: + ; decreased : Related reference c N/A: not analyzed d NC: no change

b

14


66

63

Page 15 of 22


424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467

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