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Environmental concentration of carbamazepine accelerates fish embryonic development and disturbs larvae behavior

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Abstract

Environmental pollution caused by pharmaceuticals has been recognized as a major threat to the aquatic ecosystems. Carbamazepine, as the widely prescribed antiepileptic drug, has been frequently detected in the aquatic environment and has created concerns about its potential impacts in the aquatic organisms. The effects of carbamazepine on zebrafish embryos were studied by examining their phenotype, behavior and molecular responses. The results showed that carbamazepine disturbed the normal growth and development of exposed zebrafish embryos and larvae. Upon exposure to carbamazepine at 1 μg/L, the hatching rate, body length, swim bladder appearance and yolk sac absorption rate were significantly increased. Embryos in treatment groups were more sensitive to touch and light stimulation. At molecular level, exposure to an environmentally relevant concentration (1 μg/L) of carbamazepine disturbed the expression pattern of neural-related genes of zebrafish embryos and larvae. This study suggests that the exposure of fish embryo to antiepileptic drugs, at environmentally relevant concentrations, affects their early development and impairs their behavior. Such impacts may have future repercussions by affecting fish population structure.

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References

  • Ali S, Champagne DL, Alia A, Richardson MK (2011) Large-scale analysis of acute ethanol exposure in zebrafish development: a critical time window and resilience. PLoS One 6(5):e20037. doi:10.1371/journal.pone.0020037

    Article  CAS  Google Scholar 

  • Benotti MJ, Brownawell BJ (2007) Distributions of pharmaceuticals in an urban estuary during both dry-and wet-weather conditions. Environ Sci Technol 41(16):5795–5802

    Article  CAS  Google Scholar 

  • Brandão FP, Rodrigues S, Castro BB, Goncalves F, Antunes SC, Nunes B (2013) Short-term effects of neuroactive pharmaceutical drugs on a fish species: biochemical and behavioural effects. Aquat Toxicol 144–145:218–229

    Article  Google Scholar 

  • Bridges KN, Soulen BK, Overturf CL, Drevnick PE, Roberts AP (2015) Embryotoxicity of maternally-transferred methylmercury to fathead minnows (Pimephales promelas). Environ Toxicol Chem 9999(9999):1–6

    Google Scholar 

  • Brodin T, Fick J, Jonsson M, Klaminder J (2013) Dilute concentrations of a psychiatric drug alter behavior of fish from natural populations. Science 339(6121):814–815

    Article  CAS  Google Scholar 

  • Brun GL, Bernier M, Losier R, Doe K, Jackman P, Lee HB (2006) Pharmaceutically active compounds in Atlantic Canadian sewage treatment plant effluents and receiving waters, and potential for environmental effects as measured by acute and chronic aquatic toxicity. Environ Toxicol Chem 25(8):2163–2176

    Article  CAS  Google Scholar 

  • Calisto V, Domingues MRM, Erny GL, Esteves VI (2011) Direct photodegradation of carbamazepine followed by micellar electrokinetic chromatography and mass spectrometry. Water Res 45(3):1095–1104

    Article  CAS  Google Scholar 

  • CDC (Centers for Disease Control and Prevention) (2015) Chronic Disease Prevention and Health Promotion: targeting epilepsy. http://www.cdc.gov/chronicdisease/resources/publications/AAG/epilepsy.htm. Accessed 27 Feb 2016

  • Chen LG, Huang CJ, Hu CY, Yu K, Yang LH, Zhou BS (2012) Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae. Environ Toxicol Chem 31(10):2338–2344

    Article  CAS  Google Scholar 

  • Colwill RM, Creton R (2011) Locomotor behaviors in zebrafish (Danio rerio) larvae. Behav Process 86:222–229

    Article  Google Scholar 

  • Cornell RA, Eisen JS (2002) Delta/Notch signaling promotes formation of zebrafish neural crest by repressing Neurogenin 1 function. Development 129(11):2639–2648

    CAS  Google Scholar 

  • Cueva-Mestanza R, Torres-Padrón ME, Sosa-Ferrera Z, Santana-Rodríguez JJ (2008) Microwave-assisted micellar extraction coupled with solidphase extraction for preconcentration of pharmaceuticals in molluscs prior to determination by HPLC. Biomed Chromatogr 22(10):1115–1122

    Article  CAS  Google Scholar 

  • de Jongh CM, Kooij PJF, de Voogt P, ter Laak TL (2012) Screening and human health risk assessment of pharmaceuticals and their transformation products in Dutch surface waters and drinking water. Sci Total Environ 427–428(15):70–77

    Article  Google Scholar 

  • Delgado LF, Charles P, Glucina K, Morlay C (2012) QSAR-like models: a potential tool for the selection of PhACs and EDCs for monitoring purposes in drinking water treatment systems—A review. Water Res 46(19):6196–6209

    Article  CAS  Google Scholar 

  • Fent K, Weston AA, Caminada D (2006) Ecotoxicology of human pharmaceuticals. Aquat Toxicol 76(2):122–159

    Article  CAS  Google Scholar 

  • Galus M, Rangarajan S, Lai A, Shaya L, Balshine S, Wilson JY (2014) Effects of chronic, parental pharmaceutical exposure on zebrafish (Danio rerio) offspring. Aquat Toxicol 151:124–134

    Article  CAS  Google Scholar 

  • Greaney NE, Mannion KL, Dzieweczynski TL (2015) Signaling on Prozac: altered audience effects on male-male interactions after fluoxetine exposure in Siamese fighting fish. Behav Ecol Sociobiol 69(12):1925–1932

    Article  Google Scholar 

  • Gros M, Petrovi´c M, Barcel´o D (2006) Development of a multi-residue analytical methodology based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) for screening and trace level determination of pharmaceuticals in surface and wastewaters. Talanta 70(4):678–690

    Article  CAS  Google Scholar 

  • Grover DP, Zhou JL, Frickers PE, Readman JW (2011) Improved removal of estrogenic and pharmaceutical compounds in sewage effluent by full scale granular activated carbon: impact on receiving river water. J Hazard Mater 185(2–3):1005–1011

    Article  CAS  Google Scholar 

  • Hao C, Lissemore L, Nguyen B, Kleywegt S, Yang P, Solomon K (2006) Determination of pharmaceuticals in environmental waters by liquid chromatography/electrospray ionization/tandem mass spectrometry. Anal Bioanal Chem 384(2):505–513

    Article  CAS  Google Scholar 

  • Harkin G, Hopkinson H (2010) Carbamazepin Pract Diab Int 27(5):205–206

    Article  Google Scholar 

  • Huerta-Fontela M, Galceran MT, Ventura F (2011) Occurrence and removal of pharmaceuticals and hormones through drinking water treatment. Water Res 45(3):1432–1442

    Article  CAS  Google Scholar 

  • Jeong JY, Einhorn Z, Mercurio S, Lee S, Lau B, Mione M, Wilson SW, Guo S (2006) Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl. Proc Natl Acad Sci USA 103(13):5143–5148

    Article  CAS  Google Scholar 

  • Kleywegt S, Pileggi V, Yang P, Hao C, Zhao XM, Rocks C, Thach S, Cheung P, Whitehead B (2011) Pharmaceuticals, hormones and bisphenol A in untreated source and finished drinking water in Ontario, Canada—Occurrence and treatment efficiency. Sci Total Environ 409(8):1481–1488

    Article  CAS  Google Scholar 

  • Kokel D, Peterson RT (2011) Using the zebrafish photomotor response for psychotropic drug screening. Methods Cell Biol 105:517–524

    Article  CAS  Google Scholar 

  • Komesli OT, Muz M, Ak MS, Bakırdere S, Gokcay CF (2015) Occurrence, fate and removal of endocrine disrupting compounds (EDCs)in Turkish wastewater treatment plants. Chem Eng J 277:202–208

    Article  CAS  Google Scholar 

  • Kyzar EJ, Collins C, Gaikwad S, Green J, Roth A, Monnig L, El-Ounsi M, Davis A, Freeman A, Capezio N, Stewart AM, Kalueff AV (2012) Effects of hallucinogenic agents mescaline and phencyclidine on zebrafish behavior and physiology. Prog Neuro-Psychoph 37:194–202

    Article  CAS  Google Scholar 

  • Liu C, Wen XW, Ge Y, Chen N, Hu WH, Zhang T, Zhang JG, Meng FG (2013) Responsive neurostimulation for the treatment of medically intractable epilepsy. Brain Res Bull 97:39–47

    Article  Google Scholar 

  • Ma Q, Kintner C, Anderson DJ (1996) Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87(1):43–52

    Article  CAS  Google Scholar 

  • Mailler R, Gasperi J, Coquet Y, Deshayes S, Zedek S, Cren-Olive C, Cartiser N, Eudes V, Bressy A, Caupos E, Moilleron R, Chebbo G, Rocher V (2015) Study of a large scale powdered activated carbon pilot: removals of a wide range of emerging and priority micropollutants from wastewater treatment plant effluents. Water Res 72:315–330

    Article  CAS  Google Scholar 

  • Maximino C, Puty B, Benzecry R, Araújo J, Lima MG, Batista EDJO, Oliveira KRDM, Crespo-Lopez ME, Herculano AM (2013) Role of serotonin in zebrafish (Danio rerio) anxiety: relationship with serotonin levels and effect of buspirone, WAY 100635, SB 224289, fluoxetine and para-chlorophenylalanine (pCPA) in two behavioral models. Neuropharmacology 71:83–97

    Article  CAS  Google Scholar 

  • McCann SM, Rettori V (1986) Gamma amino butyric acid (GABA) controls anterior pituitary hormone secretion. Adv Biochem Psychopharmacol 42:173–189

    CAS  Google Scholar 

  • McEneff G, Barron L, Kelleher B, Paull B, Quinn B (2013) The determination of pharmaceutical residues in cooked and uncooked marine bivalves using pressurized liquid extraction, solid-phase extraction and liquid chromatography–tandem mass spectrometry. Anal Bioanal Chem 405(29):9509–9521

    Article  CAS  Google Scholar 

  • Miao XS, Yang JJ, Metcalfe CD (2005) Carbamazepine and its metabolites in wastewater and in biosolids in a municipal wastewater treatment plant. Environ Sci Technol 39(19):7469–7475

    Article  CAS  Google Scholar 

  • Mittelbach GG, Ballew NG, Kjelvik MK (2014) Fish behavioral types and their ecological consequences. Can J Fish Aquat Sci 71(6):927–944

    Article  Google Scholar 

  • Miyares RL, de Rezende VB, Farber SA (2004) Zebrafish yolk lipid processing: a tractable tool for the study of vertebrate lipid transport and metabolism. Dis Model Mech 7(7):915–927

    Article  Google Scholar 

  • Moshé SL, Perucca E, Ryvlin P, Tomson T (2015) Epilepsy: new advances. Lancet 385(9971):884–898

    Article  Google Scholar 

  • Nassef M, Matsumoto S, Seki M, Khalil F, Kang IJ, Shimasaki Y, Oshima Y, Honjo T (2010) Acute effects of triclosan, diclofenac and carbamazepine on feeding performance of Japanese medaka fish (Oryzias latipes). Chemosphere 80(9):1095–1100

    Article  CAS  Google Scholar 

  • Oertel WH, Mugnaini E, Tappaz ML, Weise VK, Dahl AL, Schmechel DE, Kopin AI (1982) Central GABAergic innervation of neurointermediate pituitary lobe: biochemical and immunocytochemical study in the rat. Proc Natl Acad Sci USA 79:675–679

    Article  CAS  Google Scholar 

  • Padhye LP, Yao H, Kung’u FT, Huang CH (2014) Year-long evaluation on the occurrence and fate of pharmaceuticals, personal care products, and endocrine disrupting chemicals in an urban drinking water treatment plant. Water Res 51:266–276

    Article  CAS  Google Scholar 

  • Palmer PM, Wilson LR, O’Keefe P, Sheridan R, King T, Chen CY (2008) Sources of pharmaceutical pollution in the New York City Watershed. Sci Total Environ 394(1):90–102

    Article  CAS  Google Scholar 

  • Pittman JT, Lott CS (2014) Startle response memory and hippocampal changes in adult zebrafish pharmacologically-induced to exhibit anxiety/depression-like behaviors. Physiol Behav 123:174–179

    Article  CAS  Google Scholar 

  • Rabiet M, Togola A, Brissaud F, Seidel JL, Budzinski H, Elbaz-Poulichet F (2006) Consequences of treated water recycling as regards pharmaceuticals and drugs in surface and ground waters of a medium-sized Mediterranean catchment. Environ Sci Technol 40(17):5282–5288

    Article  CAS  Google Scholar 

  • Ramirez AJ, Brain RA, Usenko S, Mottaleb MA, O’Donnell JG, Stahl LL, Wathen JB, Snyder BD, Pitt JL, Perez-Hurtado P, Dobbins LL, Brooks BW, Chambliss CK (2009) Occurrence of pharmaceutical and personal care products in fish: results of a national pilot study in the United States. Environ Toxicol Chem 28(12):2587–2597

    Article  CAS  Google Scholar 

  • Rinkwitz S, Mourrain P, Becker TS (2011) Zebrafish: an integrative system for neurogenomics and neurosciences. Prog Neurobiol 93(2):231–243

    Article  Google Scholar 

  • Shenker M, Harush D, Ben-Ari J, Chefetz B (2011) Uptake of carbamazepine by cucumber plants—a case study related to irrigation with reclaimed wastewater. Chemosphere 82(6):905–910

    Article  CAS  Google Scholar 

  • Smith BR, Blumstein DT (2008) Fitness consequences of personality: a meta-analysis. Behav Ecol 19(2):448–455

    Article  Google Scholar 

  • Strecker R. (2013) Toxicity and teratogenesis in zebrafish embryos (Danio rerio). Dissertation, Ruperto-Carola University of Heidelberg

  • Valcárcel Y, Alonso SG, Rodríguez-Gil JL, Castaño A, Montero JC, Criado-Alvarez JJ, Mirón IJ, Catalá M (2013) Seasonal variation of pharmaceutically active compounds in surface (Tagus River) and tap water (Central Spain). Environ Sci Pollut R 20(3):1396–1412

    Article  Google Scholar 

  • van den Brandhof EJ, Montforts M (2010) Fish embryo toxicity of carbamazepine, diclofenac and metoprolol. Ecotox Environ Safe 73(8):1862–1866

    Article  Google Scholar 

  • van Woudenberg AB, Snel C, Rijkmans E, de Groot D, Bouma M, Hermsen S, Piersma A, Menke A, Wolterbeek A (2014) Zebrafish embryotoxicity test for developmental (neuro) toxicity: demo case of an integrated screening approach system using anti-epileptic drugs. Reprod Toxicol 49:101–116

    Article  Google Scholar 

  • Vulliet E, Cren-Olive´ C, Grenier-Loustalot MF (2011) Occurrence of pharma-ceuticals and hormones in drinking water treated from surface waters. Environ Chem Lett 9(1):103–114

    Article  CAS  Google Scholar 

  • Wang SL, Zhou N (2016) Removal of carbamazepine from aqueous solution using sono-activated persulfate process. Ultrason Sonochem 29:156–162

    Article  Google Scholar 

  • Wang C, Shi HL, Adams CD, Gamagedara S, Stayton I, Timmons T, Ma YF (2011) Investigation of pharmaceuticals in Missouri natural and drinking water using high performance liquid chromatography-tandem mass spectrometry. Water Res 45(4):1818–1828

    Article  CAS  Google Scholar 

  • Westerfield M (2000) The zebrafish book: A guide for the laboratory use of zebrafish (Danio rerio). Eugene (Oregon)

  • WHO (World Health Organization) (2016) Media centre: epilepsy. http://www.who.int/mediacentre/factsheets/fs999/en/. Accessed 27 February 2016

  • Wiegel S, Aulinger A, Brockmeyer R, Harms H, Loffler J, Reincke H, Schmidt R, Stachel B, von Tumpling W, Wanke A (2004) Pharmaceuticals in the river Elbe and its tributaries. Chemosphere 57(2):107–126

    Article  CAS  Google Scholar 

  • Wille K, Kiebooms JAL, Claessens M, Rappé K, Bussche JV, Noppe H, Praet NV, Wulf ED, Caeter PV, Janssen CR, Brabander HFD, Vanhaecke L (2011) Development of analytical strategies using U-HPLC-MS/MS and LC-ToF-MS for the quantification of micropollutants in marine organisms. Anal Bioanal Chem 400(5):1459–1472

    Article  CAS  Google Scholar 

  • Xin Q, Rotchell JM, Cheng JP, Yi J, Zhang Q (2015) Silver nanoparticles affect the neural development of zebrafish embryos. J Appl Toxicol 35(12):1481–1492

    Article  CAS  Google Scholar 

  • Yan Q, Zhang YX, Kang J, Gan XM, Xu-Y P, Guo JS, Gao X (2015) A preliminary study on the occurrence of pharmaceutically active compounds in the river basins and their removal in two conventional drinking water treatment plants in Chongqing, China. CLEAN–Soil, Air. Water 43(6):794–803

    CAS  Google Scholar 

  • Zhang Y, Geißen SU, Gal C (2008) Carbamazepine and diclofenac: removal in wastewater treatment plants and occurrence in water bodies. Chemosphere 73(8):1151–1161

    Article  CAS  Google Scholar 

  • Zhang Q, Cheng JP, Xin Q (2015) Effects of tetracycline on developmental toxicity and molecular responses in zebrafish (Danio rerio) embryos. Ecotoxicology 24(4):707–719

    Article  CAS  Google Scholar 

  • Zhou XF, Dai CM, Zhang YL, Surampalli RY, Zhang TC (2011) A preliminary study on the occurrence and behavior of carbamazepine (CBZ) in aquatic environment of Yangtze River Delta. China Environ Monit Assess 173(1–4):45–53

    Article  CAS  Google Scholar 

  • Zuehlke S, Duennbier U, Heberer T (2004) Determination of polar drug residues in sewage and surface water applying liquid chromatography-tandem mass spectrometry. Anal Chem 76(22):6548–6554

    Article  CAS  Google Scholar 

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Funding

This study was supported by the Natural Science Foundation of Guangdong Province, China (No. s2012010010847), the New Century Excellent Researcher Award Program from Ministry of Education of China (No. NECT-12-0181), and the State Key Lab of Estuarine and Coastal Research (2012RCDW01).

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Authors and Affiliations

  1. State Key Laboratory of Estuarine and Coastal Research, East China Normal University, 200062, Shanghai, China

    Liyuan Qiang, Jinping Cheng, Jun Yi, Xiaotong Zhu & Junliang Zhou

  2. Environmental Science Programs, School of Science, Hong Kong University of Science and Technology, Clear Water bay, Kowloon, Hong Kong, China

    Jinping Cheng

  3. School of Biological, Biomedical & Environmental Sciences, University of Hull, Cottingham Road, Hull, HU67RX, UK

    Jeanette M. Rotchell

  4. School of Civil and Environmental Engineering, University of Technology Sydney, Broadway, NSW, 2007, Australia

    Junliang Zhou

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  1. Liyuan Qiang
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  2. Jinping Cheng
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  3. Jun Yi
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  4. Jeanette M. Rotchell
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  5. Xiaotong Zhu
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Correspondence to Jinping Cheng.

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Qiang, L., Cheng, J., Yi, J. et al. Environmental concentration of carbamazepine accelerates fish embryonic development and disturbs larvae behavior. Ecotoxicology 25, 1426–1437 (2016). https://doi.org/10.1007/s10646-016-1694-y

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