PMID- 31733319 OWN - NLM STAT- MEDLINE DCOM- 20191230 LR - 20231213 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 319 DP - 2020 Feb 1 TI - Continuous gibberellin A3 exposure from weaning to sexual maturity induces ovarian granulosa cell apoptosis by activating Fas-mediated death receptor signaling pathways and changing methylation patterns on caspase-3 gene promoters. PG - 175-186 LID - S0378-4274(19)30369-8 [pii] LID - 10.1016/j.toxlet.2019.11.012 [doi] AB - Information on the effects of gibberellic acid (gibberellin A3, GA3) on ovarian follicle development is limited. In our present study, 21-day-old female Wistar rats were exposed to GA3 by gavage (25, 50, and 100 mg/kg body weight, once per day) for eight weeks to evaluate the influence of GA3 on ovarian follicle development. After treatment, significant (P < 0.05) increases (to 40.17 % and 44.5 %, respectively) in atretic follicle proportions and significant decreases (to 19.49 % and 17.86 %, respectively) in corpus luteum proportions were observed in the 50 and 100 mg/kg treatment groups compared to the control group. Significant (P < 0.05) increases (to 31.3 % and 42.0 %, respectively) in follicle apoptosis were observed in the 50 and 100 mg/kg treatment groups by transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Significantly increased expression of caspase-3, caspase-8, caspase-9 and Fas was observed by real-time PCR and Western blotting. Bisulfite sequencing PCR (BSP) revealed obviously decreased total methylation percentages of the caspase-3 promoter region in the two treatment groups. Real-time quantitative PCR also showed significantly decreased mRNA expression of DNA methyltransferase (Dnmt) 3a and Dnmt3b. Further in vitro studies showed that a DNA methylation inhibitor could enhance the GA3-induced increase in the mRNA expression of caspase-3. Overall, our present study indicates that GA3 administration from weaning until sexual maturity can affect ovarian follicle development by inducing apoptosis and suggests that signaling through the Fas-mediated apoptotic pathway may be an important underlying mechanism of this apoptosis. In addition, GA3-induced aberrant DNA methylation patterns might be partly responsible for upregulation of caspase-3 gene expression. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Guo, Yiwei AU - Guo Y AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Wang, Wenxiang AU - Wang W AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. Electronic address: wangwenxiang@fjmu.edu.cn. FAU - Chen, Yiqin AU - Chen Y AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Sun, Yan AU - Sun Y AD - Center for Reproductive Medicine, Teaching Hospital of Fujian Medical University, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China. FAU - Li, Yuchen AU - Li Y AD - Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Guan, Fangyuan AU - Guan F AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Shen, Qi AU - Shen Q AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Guo, Yiruo AU - Guo Y AD - Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. FAU - Zhang, Wenchang AU - Zhang W AD - Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China. LA - eng PT - Journal Article DEP - 20191113 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Fas-Associated Death Domain Protein) RN - 0 (Gibberellins) RN - BU0A7MWB6L (gibberellic acid) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) RN - EC 2.1.1.37 (DNA Methyltransferase 3A) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Caspase 3/*drug effects MH - DNA (Cytosine-5-)-Methyltransferases/biosynthesis/genetics MH - DNA Methylation/*drug effects MH - DNA Methyltransferase 3A MH - Fas-Associated Death Domain Protein/*biosynthesis/drug effects MH - Female MH - Gibberellins/*toxicity MH - Granulosa Cells/*drug effects MH - Ovarian Follicle/drug effects MH - Ovary/*cytology/drug effects MH - Promoter Regions, Genetic/drug effects MH - Rats MH - Rats, Wistar MH - Signal Transduction/*drug effects MH - Superovulation/drug effects MH - DNA Methyltransferase 3B OTO - NOTNLM OT - Apoptosis OT - DNA methylation OT - Follicle OT - Gibberellic acid OT - Ovary EDAT- 2019/11/17 06:00 MHDA- 2019/12/31 06:00 CRDT- 2019/11/17 06:00 PHST- 2019/08/25 00:00 [received] PHST- 2019/11/08 00:00 [revised] PHST- 2019/11/11 00:00 [accepted] PHST- 2019/11/17 06:00 [pubmed] PHST- 2019/12/31 06:00 [medline] PHST- 2019/11/17 06:00 [entrez] AID - S0378-4274(19)30369-8 [pii] AID - 10.1016/j.toxlet.2019.11.012 [doi] PST - ppublish SO - Toxicol Lett. 2020 Feb 1;319:175-186. doi: 10.1016/j.toxlet.2019.11.012. Epub 2019 Nov 13.