Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An
Journal
Environmental health perspectives
ISSN: 1552-9924
Titre abrégé: Environ Health Perspect
Pays: United States
ID NLM: 0330411
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
entrez:
24
10
2019
pubmed:
24
10
2019
medline:
25
3
2020
Statut:
ppublish
Résumé
Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene-environment interactions. The impact of PBO on Shh signaling The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO ( PBO attenuated Shh signaling These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene-environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https://doi.org/10.1289/EHP5260.
Sections du résumé
BACKGROUND
Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene-environment interactions.
OBJECTIVES
The impact of PBO on Shh signaling
METHODS
The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO (
RESULTS
PBO attenuated Shh signaling
DISCUSSION
These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene-environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https://doi.org/10.1289/EHP5260.
Identifiants
pubmed: 31642701
doi: 10.1289/EHP5260
pmc: PMC6867268
doi:
Substances chimiques
Hazardous Substances
0
Hedgehog Proteins
0
Piperonyl Butoxide
LWK91TU9AH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
107006Subventions
Organisme : NIEHS NIH HHS
ID : R01 ES026819
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES007015
Pays : United States
Références
Am J Trop Med Hyg. 1952 Sep;1(5):862-83
pubmed: 14952712
Toxicol Sci. 2007 Dec;100(2):456-63
pubmed: 17728282
Pediatrics. 1964 Aug;34:256-63
pubmed: 14211086
Nature. 2000 Aug 31;406(6799):1005-9
pubmed: 10984056
Teratology. 1970 May;3(2):175-80
pubmed: 4986632
Proc Soc Exp Biol Med. 1975 May;149(1):302-6
pubmed: 1144444
Birth Defects Res B Dev Reprod Toxicol. 2016 Aug;107(4-5):195-205
pubmed: 27643382
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13424-9
pubmed: 14581620
Exp Cell Res. 2006 Jul 1;312(11):1925-38
pubmed: 16571352
Mol Carcinog. 2010 Mar;49(3):302-14
pubmed: 20025076
Cereb Cortex. 2009 Sep;19(9):2196-207
pubmed: 19234067
Toxicol Lett. 1994 Apr;71(2):123-9
pubmed: 8171442
Birth Defects Res A Clin Mol Teratol. 2008 Aug;82(8):585-91
pubmed: 18566978
Cell. 1993 Dec 31;75(7):1401-16
pubmed: 8269518
Insect Biochem Mol Biol. 1996 Jul;26(7):645-9
pubmed: 8995787
Lipids. 1978 Oct;13(10):708-15
pubmed: 723484
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):122-127
pubmed: 30182446
Nat Rev Neurosci. 2012 Jan 18;13(2):107-20
pubmed: 22251963
Development. 1998 Dec;125(24):5079-89
pubmed: 9811591
Toxicol Sci. 2012 Aug;128(2):517-23
pubmed: 22552772
Dis Model Mech. 2016 Nov 1;9(11):1307-1315
pubmed: 27585885
Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):865-7
pubmed: 16265646
PLoS One. 2014 Feb 19;9(2):e89448
pubmed: 24586787
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):165-174
pubmed: 29770992
Transl Psychiatry. 2018 Jan 10;8(1):8
pubmed: 29317601
Genes Dev. 2002 Nov 1;16(21):2743-8
pubmed: 12414725
Environ Sci Technol. 2003 Oct 15;37(20):4543-53
pubmed: 14594359
Hum Mol Genet. 1999 Dec;8(13):2479-88
pubmed: 10556296
PLoS One. 2015 Mar 20;10(3):e0120517
pubmed: 25793997
Neuron. 2013 Feb 6;77(3):388-405
pubmed: 23395369
BMC Cell Biol. 2008 Sep 13;9:49
pubmed: 18789160
Wiley Interdiscip Rev Dev Biol. 2017 Jan;6(1):
pubmed: 27626243
Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):140-150
pubmed: 29749693
Toxicol In Vitro. 2010 Aug;24(5):1404-9
pubmed: 20434536
J Med Genet. 2012 Jul;49(7):473-9
pubmed: 22791840
Nat Prod Rep. 2016 May 4;33(5):595-601
pubmed: 26787175
Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):73-85
pubmed: 20104598
Food Cosmet Toxicol. 1977 Aug;15(4):337-9
pubmed: 590894
Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):52-61
pubmed: 20104595
Int J Pediatr Otorhinolaryngol. 2006 May;70(5):935-40
pubmed: 16280170
Development. 2005 Nov;132(22):4987-98
pubmed: 16221724
Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):29-42
pubmed: 20104601
Curr Top Dev Biol. 2016;116:569-80
pubmed: 26970642
Nat Genet. 1996 Nov;14(3):357-60
pubmed: 8896572
J Am Assoc Lab Anim Sci. 2015 Jul;54(4):368-71
pubmed: 26224435
J Vis Exp. 2011 Aug 19;(54):null
pubmed: 21876526
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5576-81
pubmed: 19716296
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14071-6
pubmed: 12391318
Teratology. 1977 Dec;16(3):261-72
pubmed: 594909
J Neuropathol Exp Neurol. 1985 Sep;44(5):472-85
pubmed: 2993532
Nature. 1996 Oct 3;383(6599):407-13
pubmed: 8837770
Nature. 2002 Aug 22;418(6900):892-7
pubmed: 12192414
PLoS One. 2012;7(8):e43067
pubmed: 22937012
Wiley Interdiscip Rev Dev Biol. 2015 Jan-Feb;4(1):17-32
pubmed: 25339593
Pediatrics. 2011 Mar;127(3):e699-706
pubmed: 21300677
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
PLoS One. 2017 Apr 25;12(4):e0176440
pubmed: 28441416
Toxicol Appl Pharmacol. 1979 Feb;47(2):353-8
pubmed: 452026
Birth Defects Orig Artic Ser. 1971 Feb;7(1):78-93
pubmed: 5173382
Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):183-90
pubmed: 20104615
Birth Defects Res B Dev Reprod Toxicol. 2015 Dec;104(6):227-37
pubmed: 26431353