PMID- 31064411 OWN - NLM STAT- MEDLINE DCOM- 20200318 LR - 20200318 IS - 1868-7083 (Electronic) IS - 1868-7075 (Print) IS - 1868-7075 (Linking) VI - 11 IP - 1 DP - 2019 May 7 TI - Casp8 hypomethylation and neural tube defects in association with polycyclic aromatic hydrocarbon exposure. PG - 72 LID - 10.1186/s13148-019-0673-6 [doi] LID - 72 AB - 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 beta 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. FAU - Huang, Yun AU - Huang Y AUID- ORCID: 0000-0001-9115-5638 AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China. FAU - Ren, Aiguo AU - Ren A AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. renag@bjmu.edu.cn. AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China. renag@bjmu.edu.cn. FAU - Wang, Linlin AU - Wang L AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. linlinwang@bjmu.edu.cn. AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China. linlinwang@bjmu.edu.cn. FAU - Jin, Lei AU - Jin L AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China. FAU - Lin, Shanshan AU - Lin S AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. AD - Division of Birth Cohort Study, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. FAU - Li, Zhiwen AU - Li Z AD - Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing, 100191, China. AD - Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China. FAU - McDonald, Jasmine A AU - McDonald JA AD - Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, 722 West 168th Street, New York, NY, 10032, USA. AD - Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA. LA - eng GR - P30 ES009089/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190507 PL - Germany TA - Clin Epigenetics JT - Clinical epigenetics JID - 101516977 RN - 0 (Polycyclic Aromatic Hydrocarbons) RN - EC 3.4.22.- (CASP8 protein, human) RN - EC 3.4.22.- (Caspase 8) SB - IM MH - Animals MH - Case-Control Studies MH - Caspase 8/*genetics MH - DNA Methylation/*drug effects MH - Disease Models, Animal MH - Epigenesis, Genetic/drug effects MH - Female MH - Genetic Predisposition to Disease MH - Humans MH - Maternal Exposure/*adverse effects MH - Maternal-Fetal Exchange MH - Mice MH - Neural Tube Defects/*chemically induced/genetics MH - Oxidative Stress MH - Polycyclic Aromatic Hydrocarbons/*adverse effects MH - Pregnancy MH - Promoter Regions, Genetic PMC - PMC6505285 OTO - NOTNLM OT - Apoptosis OT - Caspase-8 OT - Hypomethylation OT - Neural tube defects OT - Oxidative stress OT - Polycyclic aromatic hydrocarbons COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: For human subjects, the study protocol was approved by the Institutional Review Board of Peking University, and written informed consent was obtained from all participating women. All mice were maintained at the laboratory animal center at Peking University Health Science Center using standard techniques in accordance with protocols approved by the Institutional Animal Care and Use Committee of Peking University (certificate no. LA2013-36). CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/05/09 06:00 MHDA- 2020/03/19 06:00 PMCR- 2019/05/07 CRDT- 2019/05/09 06:00 PHST- 2019/01/13 00:00 [received] PHST- 2019/04/26 00:00 [accepted] PHST- 2019/05/09 06:00 [entrez] PHST- 2019/05/09 06:00 [pubmed] PHST- 2020/03/19 06:00 [medline] PHST- 2019/05/07 00:00 [pmc-release] AID - 10.1186/s13148-019-0673-6 [pii] AID - 673 [pii] AID - 10.1186/s13148-019-0673-6 [doi] PST - epublish SO - Clin Epigenetics. 2019 May 7;11(1):72. doi: 10.1186/s13148-019-0673-6.