Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by nicotine administration and neural stem cell transplantation.
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.
Billauer-Haimovitch
Hana
H
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.
Slotkin
Theodore A
TA
Dotan
Sharon
S
Langford
Rachel
R
Pinkas
Adi
A
Yanai
Joseph
J
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
D007306:Insecticides; D018697:Nootropic Agents; D009538:Nicotine; D004390:Chlorpyrifos
Neurotoxicol Teratol. 2002 Nov-Dec;24(6):733-41
12460655
Nicotine Tob Res. 2003 Aug;5(4):515-26
12959789
Lancet. 2006 Dec 16;368(9553):2167-78
17174709
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2344-9
11782534
Mol Cell Neurosci. 2003 Dec;24(4):1074-82
14697670
Environ Health Perspect. 1976 Dec;18:79-83
71232
Int J Dev Neurosci. 1988;6(5):409-16
3202000
Pharmacol Biochem Behav. 1996 Dec;55(4):673-81
8981599
Nature. 1996 Oct 24;383(6602):713-6
8878480
J Pharmacol Exp Ther. 1996 Feb;276(2):482-9
8632313
Brain Res. 2004 Feb 27;999(1):142-7
14746932
Brain Res Dev Brain Res. 2000 Dec 29;125(1-2):9-19
11154756
Int J Dev Neurosci. 2004 Jun;22(4):175-83
15245752
J Neurochem. 2008 Jan;104(1):38-49
18004998
Neuropsychopharmacology. 2005 Jan;30(1):156-65
15496940
Neuroscience. 1998 Dec;87(3):659-73
9758232
Biol Psychiatry. 2001 Feb 1;49(3):258-67
11230877
Histochem Cell Biol. 2008 Aug;130(2):329-38
18425526
J Neurosci. 2005 Mar 9;25(10):2609-16
15758171
Neuropharmacology. 2000 Oct;39(13):2663-72
11044736
Mol Cell Neurosci. 2003 Nov;24(3):623-31
14664813
J Neurosci Methods. 1984 May;11(1):47-60
6471907
Exp Neurol. 2003 Dec;184(2):615-35
14769354
Toxicol Sci. 2006 Sep;93(1):105-13
16760416
Lab Invest. 2003 Jul;83(7):949-62
12861035
Exp Brain Res. 1987;67(1):195-215
3622677
Nat Biotechnol. 2007 Dec;25(12):1468-75
18037878
Mol Psychiatry. 2008 Feb;13(2):222-31
17876325
Neurotoxicol Teratol. 2002 May-Jun;24(3):369-84
12009492
J Pharmacol Exp Ther. 1998 Jun;285(3):931-45
9618392
Neurotoxicol Teratol. 2004 Jan-Feb;26(1):95-101
15001218
Glia. 2003 Jan;41(1):73-80
12465047
Pediatrics. 2006 Dec;118(6):e1845-59
17116700
J Anim Sci. 1999 Jul;77(7):1800-6
10438027
Neuroreport. 2001 May 8;12(6):1127-32
11338178
Chem Res Toxicol. 2004 Aug;17(8):983-98
15310231
Tissue Eng. 2003 Feb;9(1):105-15
12625959
Brain Res Dev Brain Res. 1992 Oct 23;69(2):207-14
1424097