Casp8 hypomethylation and neural tube defects in association with polycyclic aromatic hydrocarbon exposure.
Animals
Case-Control Studies
Caspase 8
/ genetics
DNA Methylation
/ drug effects
Disease Models, Animal
Epigenesis, Genetic
/ drug effects
Female
Genetic Predisposition to Disease
Humans
Maternal Exposure
/ adverse effects
Maternal-Fetal Exchange
Mice
Neural Tube Defects
/ chemically induced
Oxidative Stress
Polycyclic Aromatic Hydrocarbons
/ adverse effects
Pregnancy
Promoter Regions, Genetic
Apoptosis
Caspase-8
Hypomethylation
Neural tube defects
Oxidative stress
Polycyclic aromatic hydrocarbons
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
07 05 2019
07 05 2019
Historique:
received:
13
01
2019
accepted:
26
04
2019
entrez:
9
5
2019
pubmed:
9
5
2019
medline:
19
3
2020
Statut:
epublish
Résumé
Epidemiological studies have found that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk for neural tube defects (NTDs). Aberrant DNA methylation, excessive apoptosis, and oxidative stress have been implied as the mechanism underlying the association between PAH exposure and NTDs, respectively. However, the role of DNA methylation aberration of apoptotic initiator CASP8 (caspase-8, apoptosis-related cysteine peptidase) in the formation of NTDs in association with PAH exposure is not known. By combining a case-control study and mouse model, we aimed to explore the full spectrum of the links from PAH exposure, oxidative stress, CASP8 methylation change, caspase-8 activation, apoptosis, to NTD formation. Hypomethylation of CASP8 promoter was noticed in the microarray profiled by Infinium HumanMethylation450 BeadChip using neural tissues from 10 terminated NTD fetuses and 8 terminated non-malformed fetuses (14 CpG sites, with β difference ranging between 8.8 and 26.3%), and was validated in a larger case-control sample performed with neural tissues from 80 NTD cases and 32 non-malformed fetuses, using the Sequenom MassARRAY system (7 CpG sites). Hypomethylation of CASP8 was a risk factor for NTDs (aOR = 1.11; 95% CI, 1.05-1.17) based on the logistic regression model. According to Pearson's correlation, methylation levels of CASP8 were inversely correlated with PAH concentrations in maternal serum and with oxidative stress markers in fetal neural tissues (p < 0.05). In the animal study, increased NTD rates (13.5% frequency), Casp8 hypomethylation, caspase-8 upregulation, increased caspase-8 cleavage, and excessive apoptosis were found in mouse embryos cultured with benz(a)pyrene (BaP) in vitro. Antioxidant N-acetyl-L-cysteine (NAC) and BaP co-treatment attenuated the changes found in BaP treatment group. Hypomethylation of Casp8 promoter is associated with the formation of NTDs, and Casp8 hypomethylation may be induced by oxidative stress that resulted from exposure to PAHs.
Sections du résumé
BACKGROUND
Epidemiological studies have found that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with increased risk for neural tube defects (NTDs). Aberrant DNA methylation, excessive apoptosis, and oxidative stress have been implied as the mechanism underlying the association between PAH exposure and NTDs, respectively. However, the role of DNA methylation aberration of apoptotic initiator CASP8 (caspase-8, apoptosis-related cysteine peptidase) in the formation of NTDs in association with PAH exposure is not known. By combining a case-control study and mouse model, we aimed to explore the full spectrum of the links from PAH exposure, oxidative stress, CASP8 methylation change, caspase-8 activation, apoptosis, to NTD formation.
RESULTS
Hypomethylation of CASP8 promoter was noticed in the microarray profiled by Infinium HumanMethylation450 BeadChip using neural tissues from 10 terminated NTD fetuses and 8 terminated non-malformed fetuses (14 CpG sites, with β difference ranging between 8.8 and 26.3%), and was validated in a larger case-control sample performed with neural tissues from 80 NTD cases and 32 non-malformed fetuses, using the Sequenom MassARRAY system (7 CpG sites). Hypomethylation of CASP8 was a risk factor for NTDs (aOR = 1.11; 95% CI, 1.05-1.17) based on the logistic regression model. According to Pearson's correlation, methylation levels of CASP8 were inversely correlated with PAH concentrations in maternal serum and with oxidative stress markers in fetal neural tissues (p < 0.05). In the animal study, increased NTD rates (13.5% frequency), Casp8 hypomethylation, caspase-8 upregulation, increased caspase-8 cleavage, and excessive apoptosis were found in mouse embryos cultured with benz(a)pyrene (BaP) in vitro. Antioxidant N-acetyl-L-cysteine (NAC) and BaP co-treatment attenuated the changes found in BaP treatment group.
CONCLUSIONS
Hypomethylation of Casp8 promoter is associated with the formation of NTDs, and Casp8 hypomethylation may be induced by oxidative stress that resulted from exposure to PAHs.
Identifiants
pubmed: 31064411
doi: 10.1186/s13148-019-0673-6
pii: 10.1186/s13148-019-0673-6
pmc: PMC6505285
doi:
Substances chimiques
Polycyclic Aromatic Hydrocarbons
0
CASP8 protein, human
EC 3.4.22.-
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
72Subventions
Organisme : NIEHS NIH HHS
ID : P30 ES009089
Pays : United States
Références
Environ Int. 2012 Jul;42:53-8
pubmed: 21511339
Sci Rep. 2017 Dec 4;7(1):16843
pubmed: 29203905
Genes Dev. 2011 May 15;25(10):1010-22
pubmed: 21576262
Int J Dev Neurosci. 2011 Nov;29(7):673-80
pubmed: 21723934
Epigenetics. 2017 Feb;12(2):157-165
pubmed: 28059605
Free Radic Biol Med. 2015 Mar;80:27-32
pubmed: 25542138
PLoS One. 2015 Mar 30;10(3):e0121869
pubmed: 25822193
Cell. 1983 Jan;32(1):239-46
pubmed: 6825170
FEBS J. 2012 Oct;279(20):3965-80
pubmed: 22913541
Free Radic Biol Med. 2007 Oct 1;43(7):1023-36
pubmed: 17761298
Clin Epigenetics. 2012 Oct 01;4(1):19
pubmed: 23025454
Oncotarget. 2017 Jan 3;8(1):1369-1391
pubmed: 27901495
Exp Suppl. 2012;101:107-31
pubmed: 22945568
Sci Signal. 2013 Aug 27;6(290):ra74
pubmed: 23982205
Chem Biol Interact. 2014 Feb 5;208:8-17
pubmed: 24239969
Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1261-4
pubmed: 8108398
Environ Pollut. 2018 Sep;240:403-411
pubmed: 29753248
World J Clin Pediatr. 2015 Aug 08;4(3):41-4
pubmed: 26261765
Birth Defects Res. 2017 Nov 15;109(19):1596-1604
pubmed: 28786179
Methods Mol Biol. 2012;887:15-22
pubmed: 22566042
Free Radic Biol Med. 2018 Feb 20;116:149-158
pubmed: 29309894
Environ Sci Technol. 2015 Jan 6;49(1):588-96
pubmed: 25488567
Transl Res. 2016 Mar;169:91-101.e1-3
pubmed: 26678678
Oncotarget. 2017 Mar 21;8(12):19814-19824
pubmed: 28177898
Free Radic Res. 2016 Aug;50(8):875-86
pubmed: 27367846
Lancet Neurol. 2013 Aug;12(8):799-810
pubmed: 23790957
Biol Rev Camb Philos Soc. 1978 Feb;53(1):81-122
pubmed: 352414
Environ Health Perspect. 2012 May;120(5):733-8
pubmed: 22256332
Arch Toxicol. 2013 Nov;87(11):2013-2022
pubmed: 23543013
Hum Mol Genet. 2009 Oct 15;18(R2):R113-29
pubmed: 19808787
Environ Health Perspect. 2012 Aug;120(8):1195-200
pubmed: 22562770
Mol Pharmacol. 2011 Dec;80(6):979-87
pubmed: 21868484
Science. 2013 Mar 1;339(6123):1222002
pubmed: 23449594
Epigenetics. 2011 Mar;6(3):355-67
pubmed: 21150308
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12770-5
pubmed: 21768370
Neurotoxicology. 2015 Jan;46:73-8
pubmed: 25522656
Reprod Sci. 2016 Aug;23(8):993-1000
pubmed: 26802109
Immunol Rev. 2017 May;277(1):76-89
pubmed: 28462525
Environ Pollut. 2018 Mar;234:396-405
pubmed: 29202418
Nat Rev Genet. 2012 May 29;13(7):484-92
pubmed: 22641018
Toxicol Mech Methods. 2017 Jan;27(1):1-17
pubmed: 27919191
Sci Rep. 2016 May 31;6:26969
pubmed: 27243754
Epigenetics. 2011 Jul;6(7):853-6
pubmed: 21617369
Reprod Toxicol. 2013 Jun;37:70-5
pubmed: 23416326
Birth Defects Res A Clin Mol Teratol. 2016 Apr;106(4):267-74
pubmed: 26879384