国际妇产科学杂志

国际妇产科学杂志 ›› 2019, Vol. 46 ›› Issue (3): 310-315.

• 论著 • 上一篇    下一篇

孕期锌缺乏对大鼠胎心GATA4和Nkx2.5基因启动子区甲基化和组蛋白乙酰化水平的影响

刘超斌，洪新如，张群芳，谢熙，王勍，林顺和，王真红，孙庆华   

  1. 350001 福州，福建省妇幼保健院，福建医科大学附属医院妇四科（刘超斌，谢熙，林顺和，王真红）；国家环境影响早期个体发育国际科技合作基地，厦门大学附属东方医院，福建医科大学福总临床医学院，联勤保障部队第九〇〇医院妇产科（洪新如，张群芳）；福州市产品质量检验所（王勍）；美国俄亥俄州立大学公共健康学院环境健康科学系（孙庆华）
  • 收稿日期:2018-09-21 修回日期:2019-02-13 出版日期:2019-06-15 发布日期:2019-06-25
  • 通讯作者: 洪新如，E-mail：hxr0812@163.com E-mail:hxr0812@163.com
  • 基金资助:
    福建省自然科学基金（2015J01493）；国家自然科学基金（81172677，81773448）

Effects of Zinc Deficiency during Pregnancy on Methylation and Histone Acetylation of Fetal Cardiac GATA4 and Nkx2.5 Gene Promoters in Rats

LIU Chao-bin, HONG Xin-ru, ZHANG Qun-fang, XIE Xi, WANG Qing, LIN Shun-he, WANG Zhen-hong, SUN Qing-hua   

  1. Fourth Department of Gynecology, Fujian Maternity and Children Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China (LIU Chao-bin, XIE Xi, LIN Shun-he, WANG Zhen-hong); Department of Obstetrics and Gynecology, 900 Hospital of the Joint Logistics Team, Fuzhou Clinic Medical College, Fujian Medical University, Dongfang Affiliated Hospital of Xiamen University, China International Science & Technology Cooperation Base for Environmental Factors on Early Development, Fuzhou 350025, China (HONG Xin-ru, ZHANG Qun-fang); Fuzhou Institute of Product Quality Inspection, Fuzhou 350008, China (WANG Qing); Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus 43210-1240, OH, USA (SUN Qing-hua)
  • Received:2018-09-21 Revised:2019-02-13 Published:2019-06-15 Online:2019-06-25
  • Contact: HONG Xin-ru, E-mail: hxr0812@163.com E-mail:hxr0812@163.com

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摘要： 目的：观察大鼠孕期锌缺乏对胎鼠心脏特异性转录因子GATA结合因子4（GATA4）和Nk2型同源盒转录因子5（Nkx2.5）基因启动子区胞嘧啶-磷酸-鸟嘌呤（CpG）岛甲基化和组蛋白H3K9乙酰化水平的影响。方法：SD大鼠随机分为缺锌组、足锌组和配饲组（n=9），分别摄入含锌量为2.8、29.8、29.8 μg/g的饲料，配饲组日饲料摄取量接近缺锌组。锌耗竭性喂养14 d后受孕，同法饲养至孕19 d剖腹取胎。观察胎鼠血锌水平和胎心组织锌含量，检测胎心组织GATA4和Nkx2.5基因启动子区CpG岛甲基化和组蛋白H3K9乙酰化的水平。结果：①3组胎鼠血锌水平差异有统计学意义（P＜0.05），其中缺锌组显著低于足锌组（P＜0.001）和配饲组（P=0.014），配饲组与足锌组比较差异无统计学意义（P=0.109）。②3组胎鼠GATA4和Nkx2.5基因启动子CpG岛甲基化水平差异有统计学意义（均P＜0.05），其中缺锌组显著高于足锌组（P=0.005；P=0.024）和配饲组（P＜0.001；P=0.029），配饲组与足锌组比较差异无统计学意义（P=0.497；P=0.929）。③3组胎鼠GATA4和Nkx2.5基因启动子CpG岛乙酰化水平差异有统计学意义（均P＜0.05），其中缺锌组显著低于足锌组（P=0.018；P=0.033）和配饲组（P=0.007；P=0.007），配饲组与足锌组比较差异无统计学意义（P=0.701；P=0.512）。结论：大鼠孕期锌缺乏可导致胎心组织GATA4和Nkx2.5基因启动子区CpG岛甲基化和组蛋白H3K9乙酰化水平异常，提示心脏转录因子基因表观遗传学机制可能参与孕期锌缺乏对胎心发育异常的效应。

关键词: 锌缺乏, 心脏缺损, 先天性, 孕妇, GATA转录因子, Nkx2.5

Abstract: Objective：To investigate the changes of methylation and histone H3K9 acetylation in CpG sites of cardiac-specific transcriptor factors GATA binding protein 4 (GATA4) and NK2 homeobox 5 (Nkx2.5) gene promotors induced by zinc deficiency during pregnancy in rats. Methods: SD rats were randomized into either of the zinc deficient group, zinc sufficient group or paired feeding group (n=9 for each group). The rats in the three groups were fed by feedstuff which contains 2.8, 29.8 or 29.8 μg zinc element per gram, respectively. The quantity of feedstuff uptaken by the rats from the paired feeding group was comparable to that from the zinc deficient group. Copulation was performed 14 days after the zinc-deprived treatment began, and the same feedstuff feeding procedure was stretched till gestation day 19. The fetal hearts were then harvested. Zinc concentrations in the fetal blood and cardiac tissues were quantified. Levels of methylation and histone H3K9 acetylation in CpG sites of GATA4 and Nkx2.5 gene promotors were assayed. Results: ①The zinc levels in the blood were significantly different among the three groups. It was significantly lower in the zinc deficient group than in the zinc sufficient group (P＜0.001) and paired feeding group (P=0.014), and there was no significantly difference between the paired feeding group and zinc sufficient group (P=0.109). ②Levels of methylation in the promotor CpG sites for GATA4 and Nkx2.5 genes were significantly different among the three groups(P＜0.05). Level of methylation in the zinc deficient group was significantly higher than that in the zinc sufficient group (P=0.005; P=0.024) or paired feeding group (P＜0.001; P=0.029), whereas no significant difference was found between the paired feeding group and zinc sufficient group (P=0.497; P=0.929). ③Levels of histone H3K9 acetylation in the promotor CpG sites for GATA4 and Nkx2.5 genes were significantly different among the three groups, which were significantly lower in the zinc deficient group than those in the zinc sufficient group (P=0.018; P=0.033) or paired feeding group (P=0.007; P=0.007). No significant difference was found in these parameters between the paired feeding group and zinc sufficient group (P=0.701; P=0.512). Conclusions: The results indicate that zinc deficiency during pregnancy could induce alterations of methylation and histone H3K9 acetylation in CpG sites of GATA4 and Nkx2.5 gene promotors, which suggests a possible role of epigenetic mechanisms of cardiac transcription factors in the fetal heart maldevelopment induced by zinc deficiency during pregnancy.

Key words: Zinc deficiency, Heart defects, congenital, Pregnant women, GATA4 transcription factor, Nkx2.5