Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101238455 Publication Model: Electronic Cited Medium: Internet ISSN: 1660-4601 (Electronic) Linking ISSN: 16604601 NLM ISO Abbreviation: Int J Environ Res Public Health Subsets: MEDLINE

Original Publication: Basel : MDPI, c2004-

Neurotoxicity Syndromes*/etiology ; Pharmaceutical Preparations* ; Water Pollutants, Chemical*; Animals ; Behavior Rating Scale ; Embryo, Nonmammalian ; Humans ; Zebrafish

Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish ( Danio rerio ) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans.

J Chromatogr B Analyt Technol Biomed Life Sci. 2015 May 15;990:23-30. (PMID: 25841203)
Neurotoxicol Teratol. 2019 Mar - Apr;72:39-48. (PMID: 30711622)
Hum Exp Toxicol. 2018 Sep;37(9):972-982. (PMID: 29239218)
Environ Pollut. 2019 Nov;254(Pt A):112999. (PMID: 31404734)
Autism Res. 2019 Nov;12(11):1693-1705. (PMID: 31317678)
PLoS One. 2012;7(6):e32917. (PMID: 22701549)
Environ Toxicol Chem. 2016 May;35(5):1297-309. (PMID: 26399705)
BMJ. 2010 Dec 02;341:c6581. (PMID: 21127116)
Prog Neuropsychopharmacol Biol Psychiatry. 2014 Dec 3;55:1-6. (PMID: 24593944)
Brain Dev. 2017 Sep;39(8):635-643. (PMID: 28450094)
BMC Med. 2017 May 5;15(1):95. (PMID: 28472982)
Chemosphere. 2020 Nov;259:127437. (PMID: 32593824)
Psychopharmacology (Berl). 2006 Jun;186(3):362-72. (PMID: 16432684)
N Engl J Med. 2014 Jun 19;370(25):2397-407. (PMID: 24941178)
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44. (PMID: 9501247)
Environ Sci Technol. 2016 Mar 15;50(6):3222-30. (PMID: 26866575)
Neurotoxicol Teratol. 2002 Nov-Dec;24(6):759-66. (PMID: 12460658)
Arch Toxicol. 2018 Dec;92(12):3549-3564. (PMID: 30288550)
Neurotoxicol Teratol. 2007 Nov-Dec;29(6):652-64. (PMID: 17761399)
ALTEX. 2010;27(1):17-42. (PMID: 20390237)
ALTEX. 2017;34(1):49-74. (PMID: 27452664)
Lancet. 2006 Dec 16;368(9553):2167-78. (PMID: 17174709)
Lancet Psychiatry. 2017 Apr;4(4):339-346. (PMID: 27979720)
Obstet Gynecol. 2011 Jul;118(1):111-120. (PMID: 21646927)
Epilepsia. 1997 Sep;38(9):981-90. (PMID: 9579936)
Sci Total Environ. 2012 Jun 15;427-428:70-7. (PMID: 22551934)
Brain Sci. 2020 May 01;10(5):. (PMID: 32370097)
Croat Med J. 2015 Apr;56(2):159-65. (PMID: 25891876)
Lancet Neurol. 2014 Mar;13(3):330-8. (PMID: 24556010)
Environ Pollut. 2021 Apr 1;274:116535. (PMID: 33524651)
BMC Genomics. 2016 Jun 29;17 Suppl 3:435. (PMID: 27356971)
Nat Protoc. 2008;3(6):1101-8. (PMID: 18546601)
Physiol Behav. 2016 May 1;158:68-75. (PMID: 26907956)
Environ Sci Technol. 2014 Nov 18;48(22):13434-42. (PMID: 25356744)
ALTEX. 2014;31(2):129-56. (PMID: 24687333)
Biomed Res Int. 2013;2013:726478. (PMID: 24324971)
Anal Chem. 2008 Mar 1;80(5):1756-62. (PMID: 18229944)
Environ Sci Technol. 2017 Nov 7;51(21):12889-12897. (PMID: 29019661)
Toxicol Sci. 2002 Apr;66(2):298-312. (PMID: 11896297)
Neurotoxicology. 2017 Mar;59:240-255. (PMID: 27212452)
Toxicol Appl Pharmacol. 2018 Sep 1;354:136-152. (PMID: 29544899)
Chemosphere. 2010 Aug;80(9):1095-100. (PMID: 20537681)
Reprod Toxicol. 2015 Aug 1;55:104-13. (PMID: 25461899)
Neurosci Lett. 2017 Nov 20;661:143-148. (PMID: 28965935)
Comp Biochem Physiol C Toxicol Pharmacol. 2019 Jan;215:1-8. (PMID: 30195060)
Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12435-E12442. (PMID: 30530669)
CNS Drugs. 2016 Jun;30(6):499-515. (PMID: 27138915)
BMC Genomics. 2013 May 24;14:348. (PMID: 23706039)
Comp Biochem Physiol C Toxicol Pharmacol. 2012 Jan;155(1):109-20. (PMID: 21684349)
Neurotoxicol Teratol. 2010 Jul-Aug;32(4):460-71. (PMID: 20211722)
Environ Pollut. 2021 Feb 1;270:116164. (PMID: 33341298)
Chem Cent J. 2013 Jan 25;7(1):15. (PMID: 23351428)
Reprod Toxicol. 2014 Nov;49:101-16. (PMID: 25111975)
PLoS One. 2018 Apr 27;13(4):e0196083. (PMID: 29702678)
Ecotoxicology. 2016 Sep;25(7):1426-37. (PMID: 27386877)
Mol Biol Cell. 2011 Mar 15;22(6):868-79. (PMID: 21270437)
Aquat Toxicol. 2014 Mar;148:130-8. (PMID: 24486880)
Environ Int. 2010 Jan;36(1):15-26. (PMID: 19819553)
Pharmacopsychiatry. 2009 May;42(3):95-100. (PMID: 19452377)
J Neurobiol. 2005 May;63(2):91-105. (PMID: 15660367)
Environ Sci Technol. 2020 Nov 17;54(22):14578-14588. (PMID: 33142061)
Environ Health Perspect. 2000 Jun;108 Suppl 3:511-33. (PMID: 10852851)
Environ Sci Pollut Res Int. 2019 Dec;26(34):34943-34952. (PMID: 31659707)
Chronobiol Int. 2019 Sep;36(9):1194-1207. (PMID: 31198056)
Toxicol In Vitro. 2011 Apr;25(3):745-53. (PMID: 21238576)
Environ Health Perspect. 2009 Jul;117(7):1162-7. (PMID: 19654928)
Toxicol Appl Pharmacol. 2018 Sep 1;354:7-18. (PMID: 29476865)
Toxics. 2016 Sep;4(3):. (PMID: 28730152)
Toxicology. 2013 Oct 4;312:158-65. (PMID: 23978457)
Sci Total Environ. 2016 Jan 15;541:1097-1105. (PMID: 26473711)
Environ Toxicol Chem. 2010 Jan;29(1):79-89. (PMID: 20821422)
BMJ Open. 2017 Jul 20;7(7):e017248. (PMID: 28729328)
Chemosphere. 2018 Jan;191:954-961. (PMID: 29145140)
Chemosphere. 2017 Nov;186:43-50. (PMID: 28772184)
Nat Neurosci. 2004 Mar;7(3):254-60. (PMID: 14758365)
Clin Pharmacokinet. 2015 Apr;54(4):359-70. (PMID: 25711391)
Clin Pharmacokinet. 1986 May-Jun;11(3):177-98. (PMID: 3524954)

Keywords: alternative to in vivo test; chemical mixtures; developmental neurotoxicity (DNT); environmental and human risk assessment; psychopharmaceuticals; zebrafish embryo behavioural test

0 (Pharmaceutical Preparations)
0 (Water Pollutants, Chemical)

Date Created: 20210702 Date Completed: 20210802 Latest Revision: 20210802

20231215

PMC8297305

10.3390/ijerph18136717

34206423