abstract - ACS Publications

Subscriber access provided by UNIV OF DURHAM

Critical 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, 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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 22

Environmental Science & Technology

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

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.

1

ACS Paragon Plus Environment


44 45

Table of Contents Art (TOC art)

46 47

2


Page 2 of 22

Page 3 of 22


48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

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.

3



92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135

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


Page 4 of 22

Page 5 of 22


136 137 138 139 140 141

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

142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179

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



180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210

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

211 212 213 214 215 216 217 218 219 220 221 222 223

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


Page 6 of 22

Page 7 of 22


224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246

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

247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264

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

265 266 267

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



268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311

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

8


Page 8 of 22

Page 9 of 22


312 313 314 315 316 317 318

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

319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336

3. ACTION MECHANISMS OF EMERGING ENVIRONMENTAL ACHE DISTRUPTORS

337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355

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

Reference 1.

Silbergeld, E. K.; Davis, D. L., Role of biomarkers in identifying and understanding

environmentally induced disease. Clin Chem 1994, 40, (7 Pt 2), 1363-7. 2.

Henderson, R. F.; Bechtold, W. E.; Bond, J. A.; Sun, J. D., The use of biological markers in

toxicology. Crit Rev Toxicol 1989, 20, (2), 65-82. 3.

Butcher, L. L., Cholinergic neurons and networks. In The Rat Nervous System: Forebrain (2nd

ed.). Paxinos, G., Ed.; Academic Press: Sydney 1995, pp. 1003–1015. 4.

Chatonnet, F.; Boudinot, E.; Chatonnet, A.; Taysse, L.; Daulon, S.; Champagnat, J.; Foutz, A. S.,

Respiratory survival mechanisms in acetylcholinesterase knockout mouse. Eur J Neurosci 2003, 18, (6), 1419-27. 5.

Cousin, X.; Strahle, U.; Chatonnet, A., Are there non-catalytic functions of acetylcholinesterases?

Lessons from mutant animal models. Bioessays 2005, 27, (2), 189-200. 6.

Woolf, N. J.; Butcher, L. L., Cholinergic systems mediate action from movement to higher

consciousness. Behav Brain Res 2011, 221, (2), 488-98. 7.

Abou-Donia, M. B.; Siracuse, B.; Gupta, N.; Sobel Sokol, A., Sarin (GB, O-isopropyl

methylphosphonofluoridate) neurotoxicity: critical review. Crit Rev Toxicol 2016, 46, (10), 845-875. 8.

Colovic, M. B.; Krstic, D. Z.; Lazarevic-Pasti, T. D.; Bondzic, A. M.; Vasic, V. M.,

Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013, 11, (3), 315-35. 9.

Cole, R. D.; Anderson, G. L.; Williams, P. L., The nematode Caenorhabditis elegans as a model

of organophosphate-induced mammalian neurotoxicity. Toxicol Appl Pharmacol 2004, 194, (3), 248-56. 10. Sultatos, L. G., Mammalian toxicology of organophosphorus pesticides. J Toxicol Environ Health 1994, 43, (3), 271-89. 11. Maroni, M.; Colosio, C.; Ferioli, A.; Fait, A., Biological Monitoring of Pesticide Exposure: a review. Introduction. Toxicology 2000, 143, (1), 1-118. 12. Lionetto, M. G.; Caricato, R.; Calisi, A.; Giordano, M. E.; Schettino, T., Acetylcholinesterase as a biomarker in environmental and occupational medicine: new insights and future perspectives. Biomed Res Int 2013, 2013, 321213. 13. Jalady, A. M.; Dorandeu, F., [Interest of the cholinesterase assay during organophosphate poisonings]. Ann Fr Anesth Reanim 2013, 32, (12), 856-62. 14. Zhao, F.; Wan, Y.; Zhao, H.; Hu, W.; Mu, D.; Webster, T. F.; Hu, J., Levels of Blood Organophosphorus Flame Retardants and Association with Changes in Human Sphingolipid Homeostasis. Environ Sci Technol 2016, 50, (16), 8896-903. 15. Sarkar, A.; Ray, D.; Shrivastava, A. N.; Sarker, S., Molecular Biomarkers: their significance and application in marine pollution monitoring. Ecotoxicology 2006, 15, (4), 333-40. 16. Marsillach, J.; Costa, L. G.; Furlong, C. E., Protein adducts as biomarkers of exposure to organophosphorus compounds. Toxicology 2013, 307, 46-54. 17. Hossain, S. M.; Luckham, R. E.; McFadden, M. J.; Brennan, J. D., Reagentless bidirectional lateral flow bioactive paper sensors for detection of pesticides in beverage and food samples. Anal Chem 2009, 81, (21), 9055-64. 18. Cajaraville, M. P.; Bebianno, M. J.; Blasco, J.; Porte, C.; Sarasquete, C.; Viarengo, A., The use of biomarkers to assess the impact of pollution in coastal environments of the Iberian Peninsula: a practical approach. Sci Total Environ 2000, 247, (2-3), 295-311.

15



468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511

Page 16 of 22

19. Van Dyk, J. S.; Pletschke, B., Review on the use of enzymes for the detection of organochlorine, organophosphate and carbamate pesticides in the environment. Chemosphere 2011, 82, (3), 291-307. 20. Barron, M. G.; Woodburn, K. B., Ecotoxicology of chlorpyrifos. Rev Environ Contam Toxicol 1995, 144, 1-93. 21. Xie, H. Q.; Xu, H. M.; Fu, H. L.; Hu, Q.; Tian, W. J.; Pei, X. H.; Zhao, B., AhR-mediated effects of dioxin on neuronal acetylcholinesterase expression in vitro. Environ Health Perspect 2013, 121, (5), 613-8. 22. Hanieh, H.; Alzahrani, A., MicroRNA-132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti-inflammation: a new Ahr-based exploration. Eur J Immunol 2013, 43, (10), 2771-82. 23. Xing, H.; Wu, H.; Sun, G.; Zhang, Z.; Xu, S.; Li, S., Alterations in activity and mRNA expression of acetylcholinesterase in the liver, kidney and gill of common carp exposed to atrazine and chlorpyrifos. Environ Toxicol Pharmacol 2013, 35, (1), 47-54. 24. Pohanka, M., Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011, 155, (3), 219-29. 25. Wang, X.; Li, J.; Xing, H.; Xu, S., Review of Toxicology of Atrazine and Chlorpyrifos on Fish. Journal of Northeast Agricultural University (English edition) 2011, 18, (4), 88-92. 26. Matozzo, V.; Binelli, A.; Parolini, M.; Previato, M.; Masiero, L.; Finos, L.; Bressan, M.; Marin, M. G., Biomarker responses in the clam Ruditapes philippinarum and contamination levels in sediments from seaward and landward sites in the Lagoon of Venice. Ecological Indicators 2012, 19, 191-205. 27. Vazquez-Boucard, C.; Anguiano-Vega, G.; Mercier, L.; Rojas del Castillo, E., Pesticide residues, heavy metals, and DNA damage in sentinel oysters Crassostrea gigas from Sinaloa and Sonora, Mexico. J Toxicol Environ Health A 2014, 77, (4), 169-76. 28. Barhoumi, B.; Le Menach, K.; Clerandeau, C.; Ameur, W. B.; Budzinski, H.; Driss, M. R.; Cachot, J., Assessment of pollution in the Bizerte lagoon (Tunisia) by the combined use of chemical and biochemical markers in mussels, Mytilus galloprovincialis. Mar Pollut Bull 2014, 84, (1-2), 379-90. 29. Barhoumi, B.; Clerandeau, C.; Gourves, P. Y.; Le Menach, K.; El Megdiche, Y.; Peluhet, L.; Budzinski, H.; Baudrimont, M.; Driss, M. R.; Cachot, J., Pollution biomonitoring in the Bizerte lagoon (Tunisia), using combined chemical and biomarker analyses in grass goby, Zosterisessor ophiocephalus (Teleostei, Gobiidae). Mar Environ Res 2014, 101, 184-195. 30. Buet, A.; Banas, D.; Vollaire, Y.; Coulet, E.; Roche, H., Biomarker responses in European eel (Anguilla anguilla) exposed to persistent organic pollutants. A field study in the Vaccares lagoon (Camargue, France). Chemosphere 2006, 65, (10), 1846-58. 31. Song, S. B.; Xu, Y.; Zhou, B. S., Effects of hexachlorobenzene on antioxidant status of liver and brain of common carp (Cyprinus carpio). Chemosphere 2006, 65, (4), 699-706. 32. Löf, M.; Sundelin, B.; Liewenborg, B.; Bandh, C.; Broeg, K.; Schatz, S.; Gorokhova, E., Biomarker-enhanced assessment of reproductive disorders in Monoporeia affinis exposed to contaminated sediment in the Baltic Sea. Ecological Indicators 2016, 63, 187-195. 33. Jung, J. H.; Hong, S. H.; Yim, U. H.; Ha, S. Y.; Shim, W. J.; Kannan, N., Multiple in vitro bioassay approach in sediment toxicity evaluation: Masan Bay, Korea. Bull Environ Contam Toxicol 2012, 89, (1), 32-7. 34. Matsumura,

H.;

Matsuoka,

M.;

Igisu,

H.;

Ikeda,

M.,

16


Cooperative

inhibition

of

Page 17 of 22


512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555

acetylcholinesterase activities by hexachlorophene in human erythrocytes. Arch Toxicol 1997, 71, (3), 151-6. 35. Tang, Y.; Donnelly, K. C.; Tiffany-Castiglioni, E.; Mumtaz, M. M., Neurotoxicity of polycyclic aromatic hydrocarbons and simple chemical mixtures. J Toxicol Environ Health A 2003, 66, (10), 919-40. 36. Goetz, C. G.; Bolla, K. I.; Rogers, S. M., Neurologic health outcomes and Agent Orange: Institute of Medicine report. Neurology 1994, 44, (5), 801-9. 37. Van den Berg, M.; Birnbaum, L.; Bosveld, A. T.; Brunstrom, B.; Cook, P.; Feeley, M.; Giesy, J. P.; Hanberg, A.; Hasegawa, R.; Kennedy, S. W.; Kubiak, T.; Larsen, J. C.; van Leeuwen, F. X.; Liem, A. K.; Nolt, C.; Peterson, R. E.; Poellinger, L.; Safe, S.; Schrenk, D.; Tillitt, D.; Tysklind, M.; Younes, M.; Waern, F.; Zacharewski, T., Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 1998, 106, (12), 775-92. 38. Nusair, S. D.; Abu Zarour, Y. S. i.; Altarifi, A. A., Effects of Dibenzo-p-Dioxins/Dibenzofurans on Acetylcholinesterase Activity and Histopathology of the Body Wall of Earthworm Eisenia andrei: a Potential Biomarker for Ecotoxicity Monitoring. Water, Air, & Soil Pollution 2017, 228, (7). 39. Ahmed, R. G., Perinatal TCDD exposure alters developmental neuroendocrine system. Food Chem Toxicol 2011, 49, (6), 1276-84. 40. Muthuvel, R.; Venkataraman, P.; Krishnamoorthy, G.; Gunadharini, D. N.; Kanagaraj, P.; Jone Stanley, A.; Srinivasan, N.; Balasubramanian, K.; Aruldhas, M. M.; Arunakaran, J., Antioxidant effect of ascorbic acid on PCB (Aroclor 1254) induced oxidative stress in hypothalamus of albino rats. Clin Chim Acta 2006, 365, (1-2), 297-303. 41. Xu, L.; Chen, Y.; Xie, H. Q. H.; Xu, T.; Fu, H.; Zhang, S.; Tsim, K. W. K.; Bi, C. W. C.; Zhao, B., 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppress AChE activity in NGF treated PC12 cells. Chem Biol Interact 2016, 259, (Pt B), 282-285. 42. Xie, H. Q.; Xia, Y.; Xu, T.; Chen, Y.; Fu, H.; Li, Y.; Luo, Y.; Xu, L.; Tsim, K. W. K.; Zhao, B., 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces alterations in myogenic differentiation of C2C12 cells. Environ Pollut 2018, 235, 965-973. 43. Xu, H. M.; Xie, H. Q.; Tao, W. Q.; Zhou, Z. G.; Li, S. Z.; Zhao, B., Dioxin and dioxin-like compounds suppress acetylcholinesterase activity via transcriptional downregulations in vitro. J Mol Neurosci 2014, 53, (3), 417-23. 44. Villeneuve, D. L.; Khim, J. S.; Kannan, K.; Giesy, J. P., Relative potencies of individual polycyclic aromatic hydrocarbons to induce dioxinlike and estrogenic responses in three cell lines. Environ Toxicol 2002, 17, (2), 128-37. 45. Nowak, E.; Wyrwicz, G.; Dabrowski, Z.; Smolenski, O.; Spodaryk, K., Rheological and biochemical examination of red blood cells after treatment with different pharmacological and toxic substances. Clin Hemorheol Microcirc 2002, 26, (2), 91-7. 46. Kang, J. J.; Fang, H. W., Polycyclic aromatic hydrocarbons inhibit the activity of acetylcholinesterase purified from electric eel. Biochem Biophys Res Commun 1997, 238, (2), 367-9. 47. Jett, D. A.; Navoa, R. V.; Lyons, M. A., Jr., Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons on acetylcholinesterase activity in vitro. Toxicol Lett 1999, 105, (3), 223-9. 48. Palanikumar, L.; Kumaraguru, A. K.; Ramakritinan, C. M.; Anand, M., Biochemical response of anthracene and benzo [a] pyrene in milkfish Chanos chanos. Ecotoxicol Environ Saf 2012, 75, (1), 187-97.

17



556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599

49. Oliveira, M.; Gravato, C.; Guilhermino, L., Acute toxic effects of pyrene on Pomatoschistus microps (Teleostei, Gobiidae): Mortality, biomarkers and swimming performance. Ecological Indicators 2012, 19, 206-214. 50. Rodrigues, A. P.; Lehtonen, K. K.; Guilhermino, L.; Guimaraes, L., Exposure of Carcinus maenas to waterborne fluoranthene: accumulation and multibiomarker responses. Sci Total Environ 2013, 443, 454-63. 51. Vicentini, M.; Morais, G. S.; Rebechi-Baggio, D.; Richardi, V. S.; Santos, G. S.; Cestari, M. M.; Navarro-Silva, M. A., Benzo(a)pyrene Exposure Causes Genotoxic and Biochemical Changes in the Midge Larvae of Chironomus sancticaroli Strixino & Strixino (Diptera: Chironomidae). Neotrop Entomol 2017, 46, (6), 658-665. 52. Mrdakovic, M.; Ilijin, L.; Vlahovic, M.; Matic, D.; Gavrilovic, A.; Mrkonja, A.; Peric-Mataruga, V., Acetylcholinesterase (AChE) and heat shock proteins (Hsp70) of gypsy moth (Lymantria dispar L.) larvae in response to long-term fluoranthene exposure. Chemosphere 2016, 159, 565-569. 53. Agrawal, D.; Sultana, P., Biochemical and structural alterations in rat erythrocytes due to hexachlorocyclohexane exposure. Food Chem Toxicol 1993, 31, (6), 443-8. 54. Santos, E. A.; Cruz, C.; Carraschi, S. P.; Marques Silva, J. R.; Grossi Botelho, R.; Velini, E. D.; Pitelli, R. A., Atrazine levels in the Jaboticabal water stream (Sao Paulo State, Brazil) and its toxicological effects on the pacu fish Piaractus mesopotamicus. Arh Hig Rada Toksikol 2015, 66, (1), 73-82. 55. Schmidel, A. J.; Assmann, K. L.; Werlang, C. C.; Bertoncello, K. T.; Francescon, F.; Rambo, C. L.; Beltrame, G. M.; Calegari, D.; Batista, C. B.; Blaser, R. E.; Roman Junior, W. A.; Conterato, G. M.; Piato, A. L.; Zanatta, L.; Magro, J. D.; Rosemberg, D. B., Subchronic atrazine exposure changes defensive behaviour profile and disrupts brain acetylcholinesterase activity of zebrafish. Neurotoxicol Teratol 2014, 44, 62-9. 56. Xing, H.; Wang, J.; Li, J.; Fan, Z.; Wang, M.; Xu, S., Effects of atrazine and chlorpyrifos on acetylcholinesterase and Carboxylesterase in brain and muscle of common carp. Environ Toxicol Pharmacol 2010, 30, (1), 26-30. 57. Gungordu, A., Comparative toxicity of methidathion and glyphosate on early life stages of three amphibian species: Pelophylax ridibundus, Pseudepidalea viridis, and Xenopus laevis. Aquat Toxicol 2013, 140-141, 220-8. 58. Gungordu, A.; Uckun, M.; Yologlu, E., Integrated assessment of biochemical markers in premetamorphic tadpoles of three amphibian species exposed to glyphosate- and methidathion-based pesticides in single and combination forms. Chemosphere 2016, 144, 2024-35. 59. Barky, F. A.; Abdelsalam, H. A.; Mahmoud, M. B.; Hamdi, S. A. H., Influence of Atrazine and Roundup pesticides on biochemical and molecular aspects of Biomphalaria alexandrina snails. Pesticide Biochemistry and Physiology 2012, 104, (1), 9-18. 60. de Melo Tarouco, F.; de Godoi, F. G. A.; Velasques, R. R.; da Silveira Guerreiro, A.; Geihs, M. A.; da Rosa, C. E., Effects of the herbicide Roundup on the polychaeta Laeonereis acuta: Cholinesterases and oxidative stress. Ecotoxicol Environ Saf 2017, 135, 259-266. 61. Matozzo, V.; Fabrello, J.; Masiero, L.; Ferraccioli, F.; Finos, L.; Pastore, P.; Di Gangi, I. M.; Bogialli, S., Ecotoxicological risk assessment for the herbicide glyphosate to non-target aquatic species: A case study with the mussel Mytilus galloprovincialis. Environ Pollut 2018, 233, 623-632. 62. Glusczak, L.; dos Santos Miron, D.; Crestani, M.; Braga da Fonseca, M.; de Araujo Pedron, F.; Duarte, M. F.; Vieira, V. L., Effect of glyphosate herbicide on acetylcholinesterase activity and

18


Page 18 of 22

Page 19 of 22


600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643

metabolic and hematological parameters in piava (Leporinus obtusidens). Ecotoxicol Environ Saf 2006, 65, (2), 237-41. 63. Gholami-Seyedkolaei, S. J.; Mirvaghefi, A.; Farahmand, H.; Kosari, A. A., Effect of a glyphosate-based herbicide in Cyprinus carpio: assessment of acetylcholinesterase activity, hematological responses and serum biochemical parameters. Ecotoxicol Environ Saf 2013, 98, 135-41. 64. Dey, S.; Samanta, P.; Pal, S.; Mukherjee, A. K.; Kole, D.; Ghosh, A. R., Integrative assessment of biomarker responses in teleostean fishes exposed to glyphosate-based herbicide (Excel Mera 71). Emerging Contaminants 2016, 2, (4), 191-203. 65. Samanta, P.; Pal, S.; Mukherjee, A. K.; Ghosh, A. R., Biochemical effects of glyphosate based herbicide, Excel Mera 71 on enzyme activities of acetylcholinesterase (AChE), lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST) and protein content on teleostean fishes. Ecotoxicol Environ Saf 2014, 107, 120-5. 66. Ikpesu, T. O., Therapeutic potential of Garcinia kola with reference to the restoration of inhibited acetylcholinesterase activities in induced Clarias gariepinus. Beni-Suef University Journal of Basic and Applied Sciences 2014, 3, (4), 293-300. 67. de Moura, F. R.; Brentegani, K. R.; Gemelli, A.; Sinhorin, A. P.; Sinhorin, V. D. G., Oxidative stress in the hybrid fish jundiara (Leiarius marmoratus x Pseudoplatystoma reticulatum) exposed to Roundup Original((R)). Chemosphere 2017, 185, 445-451. 68. Harayashiki, C. A.; Varela, A. S., Jr.; Machado, A. A.; Cabrera Lda, C.; Primel, E. G.; Bianchini, A.; Corcini, C. D., Toxic effects of the herbicide Roundup in the guppy Poecilia vivipara acclimated to fresh water. Aquat Toxicol 2013, 142-143, 176-84. 69. Modesto, K. A.; Martinez, C. B., Effects of Roundup Transorb on fish: hematology, antioxidant defenses and acetylcholinesterase activity. Chemosphere 2010, 81, (6), 781-7. 70. Qin, Y.; Li, X.; Xiang, Y.; Wu, D.; Bai, L.; Li, Z.; Liang, Y., Toxic effects of glyphosate on diploid and triploid fin cell lines from Misgurnus anguillicaudatus. Chemosphere 2017, 180, 356-364. 71. Larsen, K. E.; Lifschitz, A. L.; Lanusse, C. E.; Virkel, G. L., The herbicide glyphosate is a weak inhibitor of acetylcholinesterase in rats. Environ Toxicol Pharmacol 2016, 45, 41-4. 72. El-Demerdash, F. M.; Yousef, M. I.; Elagamy, E. I., Influence of Paraquat, Glyphosate, and Cadmium on the Activity of Some Serum Enzymes and Protein Electrophoretic Behavior (in Vitro). Journal of Environmental Science and Health, Part B 2006, 36, (1), 29-42. 73. Kwiatkowska, M.; Nowacka-Krukowska, H.; Bukowska, B., The effect of glyphosate, its metabolites and impurities on erythrocyte acetylcholinesterase activity. Environ Toxicol Pharmacol 2014, 37, (3), 1101-8. 74. Schantz, S. L.; Widholm, J. J., Cognitive Effects of Endocrine-Disrupting Chemicals in Animals. Environmental Health Perspectives 2001, 109, (12), 1197-1206. 75. Minier, C.; Forget-Leray, J.; Bjornstad, A.; Camus, L., Multixenobiotic resistance, acetyl-choline esterase activity and total oxyradical scavenging capacity of the Arctic spider crab, Hyasaraneus, following exposure to bisphenol A, tetra bromo diphenyl ether and diallyl phthalate. Mar Pollut Bull 2008, 56, (8), 1410-5. 76. Le, H. H.; Carlson, E. M.; Chua, J. P.; Belcher, S. M., Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett 2008, 176, (2), 149-56. 77. Chen, Q.; Yin, D.; Jia, Y.; Schiwy, S.; Legradi, J.; Yang, S.; Hollert, H., Enhanced uptake of BPA in the presence of nanoplastics can lead to neurotoxic effects in adult zebrafish. Sci Total Environ 2017,

19



644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687

609, 1312-1321. 78. Li, D.; Chen, Q.; Cao, J.; Chen, H.; Li, L.; Cedergreen, N.; Xie, H.; Xie, L., The chronic effects of lignin-derived bisphenol and bisphenol A in Japanese medaka Oryzias latipes. Aquat Toxicol 2016, 170, 199-207. 79. Luo, G.; Wei, R.; Niu, R.; Wang, C.; Wang, J., Pubertal exposure to Bisphenol A increases anxiety-like behavior and decreases acetylcholinesterase activity of hippocampus in adult male mice. Food Chem Toxicol 2013, 60, 177-80. 80. Fan, Y.; Ding, S.; Ye, X.; Manyande, A.; He, D.; Zhao, N.; Yang, H.; Jin, X.; Liu, J.; Tian, C.; Xu, S.; Ying, C., Does preconception paternal exposure to a physiologically relevant level of bisphenol A alter spatial memory in an adult rat? Horm Behav 2013, 64, (4), 598-604. 81. Macczak, A.; Duchnowicz, P.; Sicinska, P.; Koter-Michalak, M.; Bukowska, B.; Michalowicz, J., The in vitro comparative study of the effect of BPA, BPS, BPF and BPAF on human erythrocyte membrane; perturbations in membrane fluidity, alterations in conformational state and damage to proteins, changes in ATP level and Na(+)/K(+) ATPase and AChE activities. Food Chem Toxicol 2017, 110, 351-359. 82. Xu, H.; Shao, X.; Zhang, Z.; Zou, Y.; Chen, Y.; Han, S.; Wang, S.; Wu, X.; Yang, L.; Chen, Z., Effects of di-n-butyl phthalate and diethyl phthalate on acetylcholinesterase activity and neurotoxicity related gene expression in embryonic zebrafish. Bull Environ Contam Toxicol 2013, 91, (6), 635-9. 83. Jee, J. H.; Koo, J. G.; Keum, Y. H.; Park, K. H.; Choi, S. H.; Kang, J. C., Effects of dibutyl phthalate and di-ethylhexyl phthalate on acetylcholinesterase activity in bagrid catfish,Pseudobagrus fulvidraco(Richardson). Journal of Applied Ichthyology 2009, 25, (6), 771-775. 84. Ghorpade, N.; Mehta, V.; Khare, M.; Sinkar, P.; Krishnan, S.; Rao, C. V., Toxicity Study of Diethyl Phthalate on Freshwater Fish Cirrhina mrigala. Ecotoxicology and Environmental Safety 2002, 53, (2), 255-258. 85. Chen, L.; Huang, C.; Hu, C.; Yu, K.; Yang, L.; Zhou, B., Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae. Environ Toxicol Chem 2012, 31, (10), 2338-44. 86. Gill, S.; Hou, Y.; Li, N.; Pulido, O.; Bowers, W., Developmental neurotoxicity of polybrominated diphenyl ethers mixture de71 in Sprague-Dawley rats. J Toxicol Environ Health A 2016, 79, (12), 482-93. 87. Palacio-Cortes, A. M.; Signorini-Souza, I. L.; Yoshio Hara, E. L.; Disner, R. G.; Rebechi, D.; Grassi, M. T.; Cestari, M. M.; Navarro-Silva, M. A., Polybrominated diphenyl ethers (PBDEs) effects on Chironomus sancticaroli larvae after short-term exposure. Ecotoxicol Environ Saf 2017, 139, 308-315. 88. Vidal-Linan, L.; Bellas, J.; Fumega, J.; Beiras, R., Bioaccumulation of BDE-47 and effects on molecular biomarkers acetylcholinesterase, glutathione-S-transferase and glutathione peroxidase in Mytilus galloprovincialis mussels. Ecotoxicology 2015, 24, (2), 292-300. 89. Key, P. B.; Hoguet, J.; Chung, K. W.; Venturella, J. J.; Pennington, P. L.; Fulton, M. H., Lethal and sublethal effects of simvastatin, irgarol, and PBDE-47 on the estuarine fish, Fundulus heteroclitus. J Environ Sci Health B 2009, 44, (4), 379-82. 90. Slotkin, T. A.; Card, J.; Infante, A.; Seidler, F. J., BDE99 (2,2',4,4',5-pentabromodiphenyl ether) suppresses differentiation into neurotransmitter phenotypes in PC12 cells. Neurotoxicol Teratol 2013, 37, 13-7. 91. Lu, G.; Liu, J.; Zhang, F.; Nkoom, M.; Wu, D., Interactive Effects of BDE-153 and its

20


Page 20 of 22

Page 21 of 22


688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731

Metabolite 2,4-DBP on Biochemical Status in Crucian Carp (Carassius auratus). Polish Journal of Environmental Studies 2018, 27, (3), 1155-1163. 92. Liang, S. X.; Gao, H. X.; Zhao, Y. Y.; Ma, X. M.; Sun, H. W., Effects of repeated exposure to decabrominated diphenyl ether (BDE-209) on mice nervous system and its self repair. Environ Toxicol Pharmacol 2010, 29, (3), 297-301. 93. Garcia-Reyero, N.; Escalon, B. L.; Prats, E.; Stanley, J. K.; Thienpont, B.; Melby, N. L.; Baron, E.; Eljarrat, E.; Barcelo, D.; Mestres, J.; Babin, P. J.; Perkins, E. J.; Raldua, D., Effects of BDE-209 contaminated sediments on zebrafish development and potential implications to human health. Environ Int 2014, 63, 216-23. 94. Usenko, C. Y.; Abel, E. L.; Hopkins, A.; Martinez, G.; Tijerina, J.; Kudela, M.; Norris, N.; Joudeh, L.; Bruce, E. D., Evaluation of Common Use Brominated Flame Retardant (BFR) Toxicity Using a Zebrafish Embryo Model. Toxics 2016, 4, (3). 95. Liu, Q.; Ren, X.; Long, Y.; Hu, L.; Qu, G.; Zhou, Q.; Jiang, G., The potential neurotoxicity of emerging tetrabromobisphenol A derivatives based on rat pheochromocytoma cells. Chemosphere 2016, 154, 194-203. 96. Dong, H.; Lu, G.; Yan, Z.; Liu, J.; Yang, H.; Nkoom, M., Bioconcentration and effects of hexabromocyclododecane exposure in crucian carp (Carassius auratus). Ecotoxicology 2018, 27, (3), 313-324. 97. Rı́os, J. C.; Repetto, G.; Jos, A.; del Peso, A.; Salguero, M.; Cameán, A.; Repetto, M., Tribromophenol induces the differentiation of SH-SY5Y human neuroblastoma cells in vitro. Toxicology in Vitro 2003, 17, (5-6), 635-641. 98. Zhang, L.; Ji, F.; Li, M.; Cui, Y.; Wu, B., Short-term effects of Dechlorane Plus on the earthworm Eisenia fetida determined by a systems biology approach. J Hazard Mater 2014, 273, 239-46. 99. Sun, L.; Xu, W.; Peng, T.; Chen, H.; Ren, L.; Tan, H.; Xiao, D.; Qian, H.; Fu, Z., Developmental exposure of zebrafish larvae to organophosphate flame retardants causes neurotoxicity. Neurotoxicol Teratol 2016, 55, 16-22. 100. Sun, L.; Tan, H.; Peng, T.; Wang, S.; Xu, W.; Qian, H.; Jin, Y.; Fu, Z., Developmental neurotoxicity of organophosphate flame retardants in early life stages of Japanese medaka (Oryzias latipes). Environ Toxicol Chem 2016, 35, (12), 2931-2940. 101. Cheng, R.; Jia, Y.; Dai, L.; Liu, C.; Wang, J.; Li, G.; Yu, L., Tris(1,3-dichloro-2-propyl) phosphate disrupts axonal growth, cholinergic system and motor behavior in early life zebrafish. Aquat Toxicol 2017, 192, 7-15. 102. Abolaji, A. O.; Kamdem, J. P.; Lugokenski, T. H.; Nascimento, T. K.; Waczuk, E. P.; Farombi, E. O.; Loreto, E. L.; Rocha, J. B., Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster. Free Radic Biol Med 2014, 71, 99-108. 103. Hallgren, S.; Fredriksson, A.; Viberg, H., More signs of neurotoxicity of surfactants and flame retardants - Neonatal PFOS and PBDE 99 cause transcriptional alterations in cholinergic genes in the mouse CNS. Environ Toxicol Pharmacol 2015, 40, (2), 409-16. 104. Pretto, A.; Loro, V. L.; Silva, V. M.; Salbego, J.; de Menezes, C. C.; Souza Cde, F.; Gioda, C. R.; Baldisserotto, B., Exposure to sublethal concentrations of copper changes biochemistry parameters in silver catfish, Rhamdia quelen, Quoy & Gaimard. Bull Environ Contam Toxicol 2014, 92, (4), 399-403. 105. Xu, T.; Xie, H. Q.; Li, Y.; Xia, Y.; Chen, Y.; Xu, L.; Wang, L.; Zhao, B., CDC42 expression is altered by dioxin exposure and mediated by multilevel regulations via AhR in human neuroblastoma

21



732 733 734 735 736 737 738 739

cells. Sci Rep 2017, 7, (1), 10103. 106. Lin, T.; Simchovitz, A.; Shenhar-Tsarfaty, S.; Vaisvaser, S.; Admon, R.; Hanin, G.; Hanan, M.; Kliper, E.; Bar-Haim, Y.; Shomron, N.; Fernandez, G.; Lubin, G.; Fruchter, E.; Hendler, T.; Soreq, H., Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction. Transl Psychiatry 2016, 6, e801. 107. Xu, T.; Xie, H. Q.; Li, Y.; Xia, Y.; Sha, R.; Wang, L.; Chen, Y.; Xu, L.; Zhao, B., Dioxin induces expression of hsa-miR-146b-5p in human neuroblastoma cells. J Environ Sci (China) 2018, 63, 260-267.

740 741 742

22


Page 22 of 22

abstract - ACS Publications

Recommend Documents