title: Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by nicotine administration and neural stem cell transplantation.
abstract: Identifying the mechanisms underlying the adverse effects of developmental neurotoxicants enables the design of therapies that can potentially reverse neurobehavioral deficits in adulthood. We administered chlorpyrifos (CPF), a model organophosphate pesticide to pregnant mice and identified visuospatial deficits in adult offspring using performance in the Morris maze. We then evaluated two strategies to reverse the effects, nicotine administration and transplantation of neural stem cells. Daily administration of nicotine prior to behavioral testing did not alter maze performance by itself, but completely reversed the deficits evoked by prenatal CPF exposure. Similarly, control animals grafted with neural stem cells in adolescence did not show any alterations in behavioral performance as adults, but the grafts completely reversed the effects of prenatal CPF treatment. This study thus provides a model for the development and application of both pharmacologic and cell-based therapies to offset the effects of neurobehavioral teratogens.
authors.affiliation: The Ross Laboratory for Studies in Neural Birth Defects, Department of Medical Neurobiology, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, Box 12272, 91120 Jerusalem, Israel.
authors.forename: Hana
authors.initials: H
authors.lastname: Billauer-Haimovitch
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.forename: Sharon
authors.initials: S
authors.lastname: Dotan
authors.forename: Rachel
authors.initials: R
authors.lastname: Langford
authors.forename: Adi
authors.initials: A
authors.lastname: Pinkas
authors.forename: Joseph
authors.initials: J
authors.lastname: Yanai
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000473:pathology / Q000601:surgery; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy* / Q000628:therapy*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000637:transplantation*; D009538:Nicotine / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D033581:Stem Cell Transplantation
chemical_list: D007306:Insecticides; D018697:Nootropic Agents; D009538:Nicotine; D004390:Chlorpyrifos
references.citation: Neurotoxicol Teratol. 2002 Nov-Dec;24(6):733-41
references.pmid: 12460655
references.citation: Nicotine Tob Res. 2003 Aug;5(4):515-26
references.pmid: 12959789
references.citation: Lancet. 2006 Dec 16;368(9553):2167-78
references.pmid: 17174709
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2344-9
references.pmid: 11782534
references.citation: Mol Cell Neurosci. 2003 Dec;24(4):1074-82
references.pmid: 14697670
references.citation: Environ Health Perspect. 1976 Dec;18:79-83
references.pmid: 71232
references.citation: Int J Dev Neurosci. 1988;6(5):409-16
references.pmid: 3202000
references.citation: Pharmacol Biochem Behav. 1996 Dec;55(4):673-81
references.pmid: 8981599
references.citation: Nature. 1996 Oct 24;383(6602):713-6
references.pmid: 8878480
references.citation: J Pharmacol Exp Ther. 1996 Feb;276(2):482-9
references.pmid: 8632313
references.citation: Brain Res. 2004 Feb 27;999(1):142-7
references.pmid: 14746932
references.citation: Brain Res Dev Brain Res. 2000 Dec 29;125(1-2):9-19
references.pmid: 11154756
references.citation: Int J Dev Neurosci. 2004 Jun;22(4):175-83
references.pmid: 15245752
references.citation: J Neurochem. 2008 Jan;104(1):38-49
references.pmid: 18004998
references.citation: Neuropsychopharmacology. 2005 Jan;30(1):156-65
references.pmid: 15496940
references.citation: Neuroscience. 1998 Dec;87(3):659-73
references.pmid: 9758232
references.citation: Biol Psychiatry. 2001 Feb 1;49(3):258-67
references.pmid: 11230877
references.citation: Histochem Cell Biol. 2008 Aug;130(2):329-38
references.pmid: 18425526
references.citation: J Neurosci. 2005 Mar 9;25(10):2609-16
references.pmid: 15758171
references.citation: Neuropharmacology. 2000 Oct;39(13):2663-72
references.pmid: 11044736
references.citation: Mol Cell Neurosci. 2003 Nov;24(3):623-31
references.pmid: 14664813
references.citation: J Neurosci Methods. 1984 May;11(1):47-60
references.pmid: 6471907
references.citation: Exp Neurol. 2003 Dec;184(2):615-35
references.pmid: 14769354
references.citation: Toxicol Sci. 2006 Sep;93(1):105-13
references.pmid: 16760416
references.citation: Lab Invest. 2003 Jul;83(7):949-62
references.pmid: 12861035
references.citation: Exp Brain Res. 1987;67(1):195-215
references.pmid: 3622677
references.citation: Nat Biotechnol. 2007 Dec;25(12):1468-75
references.pmid: 18037878
references.citation: Mol Psychiatry. 2008 Feb;13(2):222-31
references.pmid: 17876325
references.citation: Neurotoxicol Teratol. 2002 May-Jun;24(3):369-84
references.pmid: 12009492
references.citation: J Pharmacol Exp Ther. 1998 Jun;285(3):931-45
references.pmid: 9618392
references.citation: Neurotoxicol Teratol. 2004 Jan-Feb;26(1):95-101
references.pmid: 15001218
references.citation: Glia. 2003 Jan;41(1):73-80
references.pmid: 12465047
references.citation: Pediatrics. 2006 Dec;118(6):e1845-59
references.pmid: 17116700
references.citation: J Anim Sci. 1999 Jul;77(7):1800-6
references.pmid: 10438027
references.citation: Neuroreport. 2001 May 8;12(6):1127-32
references.pmid: 11338178
references.citation: Chem Res Toxicol. 2004 Aug;17(8):983-98
references.pmid: 15310231
references.citation: Tissue Eng. 2003 Feb;9(1):105-15
references.pmid: 12625959
references.citation: Brain Res Dev Brain Res. 1992 Oct 23;69(2):207-14
references.pmid: 1424097