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通讯作者:

王强(1978-),男,内蒙古呼和浩特人,教授,博士生导师,主要从事母源环境与生殖健康、卵母细胞发育的调控机理的研究。E-mail:qwang2012@njmu.edu.cn

中图分类号:R321.1

文献标识码:A

文章编号:2096-8965(2022)04-0051-07

DOI:10.12287/j.issn.2096-8965.20220407

参考文献 1
BROUGHTON D E,MOLEY K H.Obesity and female infertility:potential mediators of obesity's impact[J].Fertil Steril,2017,107(4):840-847.
参考文献 2
CATALANO P M,SHANKAR K.Obesity and pregnancy:mechanisms of short term and long term adverse consequences for mother and child[J].BMJ,2017,356:j1.
参考文献 3
OGUNWOLE S M,ZERA C A,STANFORD F C.Obesity management in women of reproductive age[J].JAMA,2021,325(5):433-434.
参考文献 4
WIMALAWANSA S J.Associations of vitamin D with insulin resistance,obesity,type 2 diabetes,and metabolic syndrome[J].J Steroid Biochem Mol Biol,2018,175:177-189.
参考文献 5
CUNNINGHAM T K,ALLGAR V,DARGHAM S R,et al.Association of vitamin D metabolites with embryo development and fertilization in women with and without PCOS undergoing subfertility treatment[J].Front Endocrinol(Lausanne),2019,10:13.
参考文献 6
LIU T,QU J,TIAN M,et al.Lipid metabolic process involved in oocyte maturation during folliculogenesis[J].Front Cell Dev Biol,2022,10:806890.
参考文献 7
GOMES R M,BUENO F G,SCHAMBER C R,et al.Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance[J].J Nutr Biochem,2018,61:24-32.
参考文献 8
TORTORIELLO D V,MCMINN J,CHUA S C.Dietaryinduced obesity and hypothalamic infertility in female DBA/2J mice[J].Endocrinology,2004,145(3):1238-1247.
参考文献 9
XU P,HUANG B Y,ZHAN J H,et al.Insulin reduces reaction of follicular granulosa cells to FSH stimulation in women with obesity-related infertility during IVF[J].J Clin Endocrinol Metab,2019,104(7):2547-2560.
参考文献 10
LAINEZ N M,COSS D.Obesity,neuroinflammation,and reproductive function[J].Endocrinology,2019,160(11):2719-2736.
参考文献 11
PINBORG A,GAARSLEV C,HOUGAARD C O,et al.Influence of female bodyweight on IVF outcome:a longitudinal multicentre cohort study of 487 infertile couples[J].Reprod Biomed Online,2011,23(4):490-499.
参考文献 12
HAN L S,WANG H,LI L,et al.Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway[J].J Pineal Res,2017,63(3):e12431.
参考文献 13
WANG H J,ZHU S,WU X H,et al.NAMPT reductioninduced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice[J].Aging Cell,2021,20(11):e13496.
参考文献 14
HAN L S,REN C,LI L,et al.Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes[J].Nat Genet,2018,50(3):432-442.
参考文献 15
LUZZO K M,WANG Q,PURCELL S H,et al.High fat diet induced developmental defects in the mouse:oocyte meiotic aneuploidy and fetal growth retardation/brain defects[J].PLoS One,2012,7(11):e49217.
参考文献 16
WANG D N,SUN H Z,ZHANG J Q,et al.FKBP25 regulates meiotic apparatus during mouse oocyte maturation[J].Front Cell Dev Biol,2021,9:625805.
参考文献 17
SMITS A,MAREI W F A,DE NEUBOURG D,et al.Diet normalization or caloric restriction as a preconception care strategy to improve metabolic health and oocyte quality in obese outbred mice[J].Reprod Biol Endocrinol,2021,19(1):166.
参考文献 18
STAROSTIK M R,SOSINA O A,MCCOY R C.Singlecell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism[J].Genome Res,2020,30(6):814-825.
参考文献 19
LAN M,HAN J,PAN M H,et al.Melatonin protects against defects induced by deoxynivalenol during mouse oocyte maturation[J].J Pineal Res,2018,65(1):e12477.
参考文献 20
RUSSO M,FORTE G,MONTANINO OLIVA M,et al.Melatonin and myo-inositol:supporting reproduction from the oocyte to birth[J].Int J Mol Sci,2021,22(16):8433.
参考文献 21
SABEN J L,BOUDOURES A L,ASGHAR Z,et al.Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations [J].Cell Rep,2016,16(1):1-8.
参考文献 22
ST JOHN J C,SRIRATTANA K,TSAI T S,et al.The mitochondrial genome:how it drives fertility[J].Reprod Fertil Dev,2017,30(1):118-139.
参考文献 23
VAN DEN AMEELE J,LI A Y Z,MA H,et al.Mitochondrial heteroplasmy beyond the oocyte bottleneck [J].Semin Cell Dev Biol,2020,97:156-166.
参考文献 24
HOU Y J,ZHU C C,DUAN X,et al.Both diet and gene mutation induced obesity affect oocyte quality in mice[J].Sci Rep,2016,6:18858.
参考文献 25
ALEXOPOULOS S J,CHEN S Y,BRANDON A E,et al.Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice[J].Nat Commun,2020,11(1):2397.
参考文献 26
PERKINS A T,DAS T M,PANZERA L C,et al.Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors[J].Proc Natl Acad Sci U S A,2016,113(44):E6823-E6830.
参考文献 27
ZHANG L,HAN L S,MA R J,et al.Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes[J].Cell Cycle,2015,14(18):2959-2968.
参考文献 28
GAO M,LI X Y,HE Y F,et al.SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation[J].FASEB J,2018,32(11):6228-6238.
参考文献 29
GRINDLER N M,MOLEY K H.Maternal obesity,infertility and mitochondrial dysfunction:potential mechanisms emerging from mouse model systems[J].Mol Hum Reprod,2013,19(8):486-494.
参考文献 30
WU L L,RUSSELL D L,WONG S L,et al.Mitochondrial dysfunction in oocytes of obese mothers:transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors[J].Development,2015,142(4):681-691.
参考文献 31
OZCAN L,TABAS I.Role of endoplasmic reticulum stress in metabolic disease and other disorders[J].Annu Rev Med,2012,63:317-328.
参考文献 32
ZHANG T,XI Q S,WANG D,et al.Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging:an analysis using single-cell RNAsequencing of mouse oocytes[J].J Ovarian Res,2019,12(1):53.
参考文献 33
ZHAO L,LU T,GAO L,et al.Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice[J].J Anim Sci Biotechnol,2017,8:62.
参考文献 34
DE CABO R,MATTSON M P.Effects of intermittent fasting on health,aging,and disease[J].N Engl J Med,2019,381(26):2541-2551.
参考文献 35
YU S C,GAO L P,ZHANG C,et al.Glycine ameliorates endoplasmic reticulum stress induced by thapsigargin in porcine oocytes[J].Front Cell Dev Biol,2021,9:733860.
参考文献 36
OAKES S A.Endoplasmic reticulum stress signaling in cancer cells[J].Am J Pathol,2020,190(5):934-946.
参考文献 37
SANTOS L E,FERREIRA S T.Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease[J].Neuropharmacology,2018,136(Pt B):350-360.
参考文献 38
YANG M Y,WANG Y B,HAN B,et al.Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells[J].Acta Pharmacol Sin,2018,39(1):48-58.
参考文献 39
SHIMOURA N,NAGAI H,FUJIWARA S,et al.Exacerbation and prolongation of psoriasiform inflammation in diabetic obese mice:a synergistic role of CXCL5 and endoplasmic reticulum stress[J].J Invest Dermatol,2018,138(4):854-863.
参考文献 40
SZPIGEL A,HAINAULT I,CARLIER A,et al.Lipid environment induces ER stress,TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes[J].Diabetologia,2018,61(2):399-412.
参考文献 41
VILLALOBOS-LABRA R,SUBIABRE M,TOLEDO F,et al.Endoplasmic reticulum stress and development of insulin resistance in adipose,skeletal,liver,and foetoplacental tissue in diabesity[J].Mol Aspects Med,2019,66:49-61.
参考文献 42
HSIEH C L,HUANG H S,CHEN K C,et al.A novel salicylanilide derivative induces autophagy cell death in castration-resistant prostate cancer via ER stress-activated PERK signaling pathway[J].Mol Cancer Ther,2020,19(1):101-111.
参考文献 43
SINGH A K,ZHAO B,LIU X,et al.Selective targeting of TET catalytic domain promotes somatic cell reprogramming[J].Proc Natl Acad Sci U S A,2020,117(7):3621-3626.
参考文献 44
MULHOLLAND C B,NISHIYAMA A,RYAN J,et al.Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals[J].Nat Commun,2020,11(1):5972.
参考文献 45
GU T P,GUO F,YANG H,et al.The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature,2011,477(7366):606-610.
参考文献 46
HUANG J L,RU G Z,SUN J J,et al.Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice[J].Mol Med,2022,28(1):17.
参考文献 47
DI FRANCESCO A,DI GERMANIO C,BERNIER M,et al.A time to fast[J].Science,2018,362(6416):770-775.
目录contents

    摘要

    随着肥胖的流行,育龄期女性中肥胖比例也在持续上升,并对女性生殖健康产生严重影响。其中,肥胖对卵母细胞质量的影响一直备受关注。近年来,关于肥胖导致卵母细胞减数分裂阻滞,线粒体、内质网功能丢失以及表观遗传修饰的异常变化等情况被报道,其相应的机制也逐渐被揭示。本文将对母源肥胖影响卵子质量的研究进展进行综述,并结合已报道的机制提出潜在的干预靶标,以期改善肥胖引起的卵子质量低下、促进优生优育。

    Abstract

    With an escalating global epidemic of obesity, the prevalence of obesity among reproductive women continues to rise. It has been widely reported that maternal obesity has profound effects on female reproduction. Of them, oocyte quality has been a major concern. In recent years, emerging evidence on maternal obesity has shown that meiosis damage, mitochondrial and endoplasmic reticulum dysfunction, and epigenetic modification changes occur in oocytes, and mechanisms are also being reported. Here we review the recent researches on the effects of maternal obesity on oocyte and embryo development, and propose the potential intervention targets and pathways to improve egg quality and reproductive outcome.

  • 1 母源肥胖与雌性生殖健康

  • 2021 年世界卫生组织公布全球人口健康报告,全球肥胖率较 1975 年增加了近 3 倍,超过 6.5 亿人[1]。1975年至2016年,18岁及以上的超重成年人超过19亿,占成年人群的39% (39%的男性和40% 的女性),其中超过 6.5 亿人肥胖,占成年人群的 13% (11% 的男性和 15% 的女性)。肥胖已成为一种全球范围内的流行病,逐渐损害人类健康,全球因超重和肥胖而死亡的人口远远多于体重不足而死亡的人口[2]

  • 育龄女性也未能避免这一巨大趋势,这一群体中有 23% 的女性肥胖[3]。肥胖女性常表现出月经不调,子宫内膜病变和不孕,这大大降低了生育能力。妊娠期肥胖往往伴随多种并发症囊卵巢综合征[4],包括高血压疾病、妊娠期糖尿病、早产和剖宫产率[2]。卵巢是雌性生殖系统的关键部分,是产生卵母细胞的器官,其组织细胞结构完整性、原始卵泡的数量、原始卵泡发育和排卵是决定女性生殖的重要因素。肥胖女性 (包括年轻适龄且具有正常月经周期) 不易受孕可能与卵巢功能紊乱有关。 Cunningham 等[5] 检查了肥胖患者卵泡液内的激素和代谢物后发现,卵泡液中胰岛素、甘油三酯和乳酸盐的水平随着体重指数 (Body Mass Index,BMI) 的增加而显著性升高。卵泡微环境的改变影响了卵巢对促性腺激素的反应,阻碍了卵泡的发育和排卵,最终导致肥胖患者生育力下降[6]。另外,在肥胖小鼠模型中,小鼠卵巢存在大量凋亡的卵泡,卵母细胞体积更小,具有更低的成熟率[7]。肥胖可能影响了下丘脑-垂体-卵巢轴[1]。Tortoriello 等[8] 发现饮食诱导的肥胖 (Diet-Induced Obesity,DIO) 小鼠自然妊娠率下降了60%,通过补充外源促性腺激素可恢复正常。分析发现,DIO 小鼠体内瘦素水平显著高于正常饮食小鼠,并且DIO小鼠下丘脑拥有更少的瘦素受体。而在女性生育率研究中发现,随着BMI值的增长,瘦素浓度升高,体外受精之后成功妊娠率显著下降[9]。Lainez等[10] 研究了痛经型肥胖女性,发现黄体生成素 (Luteinizing Hormone,LH) 显著降低,再次指出了这种疾病所导致的中枢缺陷。临床胚胎移植实验提示,肥胖是导致卵母细胞质量受损、女性生育力低下的关键因素。BMI与获得的卵母细胞数量、胚胎发育率呈负相关,肥胖女性的妊娠率(正常体重女性的28.3%比20.8%)和活产率均降低(正常体重女性的21.5%比15.2%)[11]

  • 大量的人类与动物临床试验证实,肥胖影响卵母细胞多个层面,包括减数分裂装置组装[12],线粒体动力学[13],表观遗传修饰[14] 等。这些可能与非整倍体率增加、早期胚胎发育率显著性降低以及胎儿出现发育滞缓有关[121315]。因此,本文将对母源肥胖对于卵母细胞的减数分裂、卵母细胞内线粒体和内质网的功能以及卵母细胞表观遗传重塑这些方面的研究进展进行综述。

  • 1.1 肥胖与卵母细胞减数分裂

  • 减数分裂是指进行有性生殖的生物性母细胞成熟、形成配子的过程中出现的一种特殊分裂方式。正确的减数分裂不仅是保持物种遗传物质稳定传递的手段,同时也是物种适应环境变化不断进化的机制。在卵母细胞发育过程中,随着染色质的凝聚和微管结构的组装,卵母细胞逐渐成熟,排出第一极体,并阻滞在第二次减数分裂中期,等待受精[16]。减数分裂成熟包括两个重要事件,纺锤体组装和染色体排列,这一过程中的任何错误都可能导致异常卵母细胞的产生,如非整倍体卵母细胞的产生[10]。研究人员发现高脂饮食 (High-Fat Diet,HFD) 诱导的肥胖小鼠卵母细胞纺锤体异常率显著性升高,纺锤体轴结构散乱,染色体并未在中期赤道板上正确排列,染色体非整倍率显著增加[1215]。Smits 等[17] 对来自于体外受精中未能成功受精的卵母细胞进行了检查,也发现了来自肥胖女性患者的卵母细胞与小鼠类似的现象,减数分裂中期的卵母细胞拥有高比率异常纺锤体,并且染色体并未正确排列在赤道板上。卵母细胞如果出现染色体非整倍性,那么在受精之后往往会引起自然流产、妊娠缺陷和发育障碍。人类非整倍体卵子的受精是导致妊娠丢失的主要原因,即使胚胎存活到足月,这种缺陷也会导致子代发育障碍[18]。研究人员发现肥胖小鼠的卵母细胞内活性氧 (Reactive Oxygen Species,ROS) 水平显著升高,而褪黑素可以有效的降低细胞内ROS水平,减缓氧化应激对于卵母细胞的损伤[121920]。有趣的是,无论是口服褪黑素还是在卵母细胞体外成熟培养体系中加入褪黑素,在降低肥胖小鼠卵母细胞内ROS水平的同时,发现纺锤体、染色体异常率也显著性降低;显著提高了肥胖小鼠卵母细胞成熟率和胚胎发育率[12]

  • 1.2 肥胖与卵母细胞线粒体功能

  • 线粒体作为细胞的动力车间,最重要的功能是通过氧化磷酸化产生三磷酸腺苷 (Adenosine Triphosphate,ATP),为细胞的代谢、物质运输等活动提供能量。线粒体拥有双膜结构,有属于自己的 DNA,能编码 13 种呼吸链相关的蛋白,参与调节代谢、凋亡、细胞氧化还原状态等多种生物学过程[2122]。线粒体为卵母细胞的成熟、受精、以及早期胚胎发育提供充足的能量[23]

  • 后代组织的线粒体均来源于卵母细胞,所以线粒体数量和功能的异常,不仅影响卵母细胞本身,也对后代的健康有着长远的影响。研究人员发现母源肥胖引起的代谢综合征诱导卵母细胞线粒体在结构、空间和代谢方面发生改变[12]。卵母细胞拥有数以百万的线粒体,在卵母细胞成熟过程中其分布以及数量呈现动态变化。然而母源肥胖似乎并没有影响卵母细胞内线粒体数量,但是其线粒体分布却受到了显著性的影响。相比于在正常卵母细胞中线粒体均匀分布于核周围,而在肥胖小鼠卵母细胞整个卵胞质中或呈散乱分布或聚集成团[2425]。肥胖对于卵母细胞结果的影响主要表现在线粒体结构紊乱,线粒体嵴减少,腔泡增多,并有肿胀的迹象[25]

  • 线粒体内发生着复杂的氧化磷酸化反应,在产生ATP的同时,氧化磷酸化的天然副产物ROS也同时在线粒体中产生,过度的ROS破坏细胞的多种成分,从而扰乱多种生物过程,如细胞代谢的异常,导致卵母细胞过早老化[25]。产生的氧化应激对于卵子质量和受精具有毒害作用,甚至影响早期胚胎发育[26]。肥胖女性以及肥胖小鼠的卵母细胞中 ROS水平均显著升高[27]。因此,调节细胞内氧化和抗氧化之间的稳态对于保证卵母细胞的质量显得极为重要。肥胖小鼠卵母细胞中 SIRT3 蛋白表达显著降低,ROS水平异常升高,而过表达sirt3基因可以显著性的降低卵母细胞中ROS的水平。线粒体内超氧化物歧化酶 2 (Superoxide Dismutase2,SOD2) 被认为是清除细胞 ROS 的主要抗氧化酶。研究发现 SIRT3蛋白依赖SOD2去乙酰化在卵母细胞氧化应激和减数分裂缺陷中发挥保护作用,确定了 SIRT3以及SOD2在调节ROS稳态中起着重要作用[1227]。通过补充褪黑素,可以诱导小鼠卵母细胞内 SIRT3蛋白的表达,提高 SOD2 的抗氧化活性,进而减少 ROS 水平,提高线粒体抗氧化能力[12] (见图1)。

  • 图1 褪黑素改善肥胖小鼠卵母细胞质量的分子基础

  • 2018年,Gao 等[28] 在小鼠卵母细胞中敲降Sirt7,减数分裂成熟同样也会受到损伤,尤其是扰乱了纺锤体的组装、染色体的排列、微丝帽的丢失等等,最终导致非整倍体卵的产生。此外,报道称,敲降 Sirt7 可以导致小鼠卵母细胞内 ROS 水平显著性提高,从而增加受精后胚胎DNA损伤和细胞凋亡,损害了早期胚胎的发育。在肥胖小鼠卵母细胞中, SIRT7 蛋白水平显著性降低,在肥胖小鼠卵母细胞中过表达外源性 SIRT7不仅可以改善由于母源肥胖引起的减数分裂损伤,并且可以大大降低卵母细胞内的ROS水平[28]

  • 线粒体受到了损伤,三羧酸循环产生的柠檬酸量大大减少,ATP水平降低,肥胖小鼠线粒体拷贝数异常增加,这可能是作为一种代偿效应发挥作用[1529]。另外,Wu等[30] 还发现肥胖小鼠卵母细胞线粒体膜电位降低,自噬水平高。肥胖小鼠的卵母细胞经过体外受精后,早期胚胎发育力降低,检测发现囊胚中线粒体脱氧核糖核酸 (mitochondrial Deoxyribonucleic Acid,mtDNA) 水平降低。Saben 等[21] 证实,肥胖小鼠卵母细胞中的异常线粒体通过雌性生殖系持续存在,即使子代小鼠饮食正常,雌性后代外周胰岛信号通路仍然受损,这与线粒体功能障碍有关,母亲紊乱的线粒体动态由卵母细胞传递到胚胎,并遗传到第二代和第三代。

  • 1.3 肥胖与卵母细胞内质网功能

  • 内质网为细胞内网状膜结构,参与蛋白质合成和加工。Wu等[30] 发现在肥胖小鼠卵丘-卵母细胞复合体中表现出内质网应激、细胞内脂质水平高、纺锤体异常和细胞外基质蛋白 PTX3 减少,这提示肥胖引起了内质网脂毒性和功能异常。

  • 胞内脂毒性是细胞对细胞外高脂质环境的一种反应,包括高水平的甘油三酯、胆固醇和游离脂肪酸,这些脂类增加了细胞内脂质积累并损害细胞器,特别是内质网。大量人类研究和动物模型的研究表明,在心脏、骨骼肌、胰腺、肝脏和肾脏中积累了过量脂质,由此导致的脂毒性引起细胞功能障碍和死亡,可能是心力衰竭、肥胖和糖尿病的发病机制之一[3132]。内质网正常功能的紊乱,触发一系列协调适应和凋亡反应的信号网络 (见图2)。过量的游离脂肪酸可能损害正常的细胞信号传导,导致细胞功能障碍,甚至可诱导细胞凋亡[303334]。Yu等[35] 发现甘氨酸可以显著性改善猪卵母细胞内质网应激相关基因,如 UprXbp1Chop 等的表达进而提高了内质网功能,提高了卵子发育以及早期胚胎发育。

  • 内质网功能的异常会破坏蛋白分泌通路和蛋白折叠反应。同时,内质网 Ca2+ 离子外泄会破坏线粒体的膜电势,进而导致细胞内ROS水平增加,引起氧化应激[36]。外源性补充内质网压力抑制剂,能显著改善肥胖引起的卵母细胞线粒体相关蛋白表达和线粒体DNA拷贝数异常,同时对其胎儿的生长发育也具有改善作用[30]。越来越多的证据表明,长期的内质网应激与许多疾病的发展和进展有关,包括神经退行性病变[37]、动脉粥样硬化[38]、肥胖症[39]、Ⅱ型糖尿病[40]、肝病[41] 和癌症[42]。随着对潜在分子机制的进一步理解,针对内质网应激反应的治疗干预将成为治疗由长期内质网应激引起的各种疾病的潜在策略。

  • 图2 肥胖引起卵母细胞内质网脂毒性和功能异常

  • 1.4 肥胖与卵母细胞表观遗传重塑

  • 在配子发生以及胚胎着床前发育过程中,表观修饰状态发生显著变化,并对环境变化敏感。当精子与成熟的卵母细胞结合后,形成雌雄原核,此时,原核开始发生全面的表观遗传重塑过程。表观遗传的重塑作为早期胚胎发生的先决条件,其中最主要的事件是合子中伴随 5-甲基胞嘧啶 (5-Methylcytosine,5mC) 氧化为 5-羟甲基胞嘧啶 (5-Hydroxymethyl cytosine,5hmC) 的全基因组 DNA 去甲基化的擦除[43],即在受精后不久发生全面去甲基化,但这种去甲基化模式并不均匀地分布在整个基因组中。父系基因组在合子形成后不久就完全去甲基化,而母系基因组则依赖于DNA复制稀释的方式进行逐步去甲基化,因此在合子中,雌雄原核之间建立了明显的表观遗传不对称性[14]。值得注意的是,雌原核中5mC的维持很大程度上依赖于去甲基保护因子Stella[44]。而此前研究人员发现肥胖小鼠卵母细胞内Stella水平显著性的降低[14],肥胖小鼠受精卵的去甲基化模式也因为卵母细胞中 Stella 水平的降低而遭到破坏。

  • 对常规饮食 (Normal Diet,ND) 和 HFD 小鼠中晚期受精卵中雌雄原核内 5mC 和 5hmC 的分布和表达情况进行了检查。通过免疫荧光染色发现,在 ND小鼠受精卵中,5hmC染色在雄原核中富集,整体缺失5mC,而雌原核显示出强烈的5mC染色和较弱的 5hmC 信号。HFD 小鼠受精卵的雌原核中 5mC 染色显著减少,5hmC 染色显著增加。同样,科研人员也观察到,在来自 ob/ob 肥胖小鼠的合子中,雌雄原核都失去了 5mC 信号,获得了 5hmC 信号。因此可以推测肥胖小鼠受精卵中雌原核发生了过早的去甲基化[14]。并且通过体外受精和胚胎移植证实了肥胖小鼠雌原核中5mC的快速丢失与子宫环境无关,而是源于卵母细胞本身。

  • TET3 作为一种关键的双加氧酶,在合子发育期间,将雄原核基因组中 5mC 转化成 5hmC 的[45],因此TET3仅在雌原核中被观察到,而Stella可以阻断 TET3 活性进而起到维持雌性原核基因组的 DNA 甲基化的目的,但是HFD合子的雌雄原核中均可检测到 TET3。因此,HFD 卵母细胞 TET3 进入雌原核,Stella 不足无法维持 5mC,从而促进 5mC 氧化为5hmC[14] (见图3)。

  • 图3 母源肥胖引起早期胚胎发育缺陷的潜在机制

  • 组蛋白修饰在稳定染色体高级结构以及调控基因的表达和抑制方面发挥着重要作用。研究表明,高脂饮食和基因突变引起的小鼠肥胖症不仅仅使小鼠卵母细胞DNA甲基化水平异常降低,其组蛋白甲基化也同样出现异常,如 H3K27me2 异常降低, H3K9me2异常升高[24]。基因组甲基化和组蛋白甲基化修饰的异常干扰了基因的正常表达,但这些并不是受到遗传基因的调控,而仅仅是受到环境饮食的调控。这些潜在的可逆与非可逆修饰可能比基因改变影响更为深远。

  • 2 总结与展望

  • 肥胖引起的各种疾病严重影响着人们的健康,而育龄女性也面临来自肥胖的挑战。由于在妊娠前和妊娠期间过量高热量食物的摄入,也包括婴幼儿生长环境等诸多因素的影响,育龄女性需要考虑更多的健康问题和潜在风险。肥胖所带来的不仅仅是各类妊娠并发症,更多的是包括哮喘、心血管疾病,糖尿病等在内的代谢性遗传病在代际之间的直接传播[46]。科研人员对高脂饮食小鼠的代谢情况做了细致的检查,高脂饮食在导致小鼠患有肥胖症的同时,其血糖代谢也遭到损伤[1214]。高脂饮食显著降低了小鼠的糖耐受,增加了代谢紊乱的风险,并且F1代小鼠也未能幸免[46]。同时肥胖小鼠卵母细胞 ROS 和磷酸化的组蛋白 H2AX(Phosphorylated Histone H2AX,γ. H2AX)水平异常升高,并降低了卵母细胞内的线粒体膜电位,导致了高水平的氧化应激损伤和DNA损伤。此外,肥胖导致卵母细胞纺锤体异常率增加,非整倍体率升高,并最终降低了早期胚胎的发育潜力,影响了子代的出生[14]。而通过补充褪黑素不仅可以提高卵母细胞内 SIRT3的表达,增强 SOD2 的去乙酰化能力,进而减少 ROS 水平,提高线粒体抗氧化能力,而且在一定程度上改善了纺锤体组装和染色体排列,降低了非整倍体卵率,促进了卵母细胞减数分裂进程。在辅助生殖技术中,对来自肥胖患者卵母细胞进行体外受精/卵母细胞单精子注射治疗时,较高的BMI往往引起较低的胚胎发育率、种植率、妊娠率以及活产率,而这种效应在年轻的女性群体中尤为显著[1]

  • 最近,热量限制作为肥胖预防以及减肥策略逐渐进入大众视野。葡萄糖和脂肪酸是细胞的主要能量来源。进食后,葡萄糖被用作直接的能量来源,脂肪以甘油三酯的形式储存在脂肪组织中。在禁食期间,甘油三酯转化为成脂肪酸和甘油,脂肪酸进一步转化为酮类,可以作为许多组织细胞能量的主要来源,尤其是大脑[47]。人类通过饮食摄取身体生存所需的能量,摄入过少的食物不足以为身体的生理活动提供足够的能量,而摄入过多的食物则会导致营养过剩或者脂肪堆积。适时适量的从食物中摄取热量才能保持身体能量稳态。肥胖导致细胞内存在大量的活性氧,对细胞造成损伤。而热量限制可以引发细胞适应性反应,减少活性氧的产生和累积,减少细胞受到的损伤,增强细胞防御以及抗应激能力。女性在怀孕之前减少热量的摄入,不仅可以改善机体的糖脂代谢,而且还可以改善卵母细胞线粒体,降低细胞内脂质含量,进而提高卵母细胞质量[17]

  • 大量临床研究证实了肥胖影响女性生育能力,探讨了肥胖对于卵母细胞和着床前胚胎影响的机制,并提出减重、饮食调整在内的干预措施,这对肥胖患者生育力的提高具有重要的指导作用。然而,这些研究数据大都是对于局部领域的整合,其相应机制还鲜有报道,具体应用措施更为匮乏。为了更好地理解肥胖和生殖之间的关系,建立健康的家庭,还需要发现更多的有效预防与治疗策略。

  • 参考文献

    • [1] BROUGHTON D E,MOLEY K H.Obesity and female infertility:potential mediators of obesity's impact[J].Fertil Steril,2017,107(4):840-847.

    • [2] CATALANO P M,SHANKAR K.Obesity and pregnancy:mechanisms of short term and long term adverse consequences for mother and child[J].BMJ,2017,356:j1.

    • [3] OGUNWOLE S M,ZERA C A,STANFORD F C.Obesity management in women of reproductive age[J].JAMA,2021,325(5):433-434.

    • [4] WIMALAWANSA S J.Associations of vitamin D with insulin resistance,obesity,type 2 diabetes,and metabolic syndrome[J].J Steroid Biochem Mol Biol,2018,175:177-189.

    • [5] CUNNINGHAM T K,ALLGAR V,DARGHAM S R,et al.Association of vitamin D metabolites with embryo development and fertilization in women with and without PCOS undergoing subfertility treatment[J].Front Endocrinol(Lausanne),2019,10:13.

    • [6] LIU T,QU J,TIAN M,et al.Lipid metabolic process involved in oocyte maturation during folliculogenesis[J].Front Cell Dev Biol,2022,10:806890.

    • [7] GOMES R M,BUENO F G,SCHAMBER C R,et al.Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance[J].J Nutr Biochem,2018,61:24-32.

    • [8] TORTORIELLO D V,MCMINN J,CHUA S C.Dietaryinduced obesity and hypothalamic infertility in female DBA/2J mice[J].Endocrinology,2004,145(3):1238-1247.

    • [9] XU P,HUANG B Y,ZHAN J H,et al.Insulin reduces reaction of follicular granulosa cells to FSH stimulation in women with obesity-related infertility during IVF[J].J Clin Endocrinol Metab,2019,104(7):2547-2560.

    • [10] LAINEZ N M,COSS D.Obesity,neuroinflammation,and reproductive function[J].Endocrinology,2019,160(11):2719-2736.

    • [11] PINBORG A,GAARSLEV C,HOUGAARD C O,et al.Influence of female bodyweight on IVF outcome:a longitudinal multicentre cohort study of 487 infertile couples[J].Reprod Biomed Online,2011,23(4):490-499.

    • [12] HAN L S,WANG H,LI L,et al.Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway[J].J Pineal Res,2017,63(3):e12431.

    • [13] WANG H J,ZHU S,WU X H,et al.NAMPT reductioninduced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice[J].Aging Cell,2021,20(11):e13496.

    • [14] HAN L S,REN C,LI L,et al.Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes[J].Nat Genet,2018,50(3):432-442.

    • [15] LUZZO K M,WANG Q,PURCELL S H,et al.High fat diet induced developmental defects in the mouse:oocyte meiotic aneuploidy and fetal growth retardation/brain defects[J].PLoS One,2012,7(11):e49217.

    • [16] WANG D N,SUN H Z,ZHANG J Q,et al.FKBP25 regulates meiotic apparatus during mouse oocyte maturation[J].Front Cell Dev Biol,2021,9:625805.

    • [17] SMITS A,MAREI W F A,DE NEUBOURG D,et al.Diet normalization or caloric restriction as a preconception care strategy to improve metabolic health and oocyte quality in obese outbred mice[J].Reprod Biol Endocrinol,2021,19(1):166.

    • [18] STAROSTIK M R,SOSINA O A,MCCOY R C.Singlecell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism[J].Genome Res,2020,30(6):814-825.

    • [19] LAN M,HAN J,PAN M H,et al.Melatonin protects against defects induced by deoxynivalenol during mouse oocyte maturation[J].J Pineal Res,2018,65(1):e12477.

    • [20] RUSSO M,FORTE G,MONTANINO OLIVA M,et al.Melatonin and myo-inositol:supporting reproduction from the oocyte to birth[J].Int J Mol Sci,2021,22(16):8433.

    • [21] SABEN J L,BOUDOURES A L,ASGHAR Z,et al.Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations [J].Cell Rep,2016,16(1):1-8.

    • [22] ST JOHN J C,SRIRATTANA K,TSAI T S,et al.The mitochondrial genome:how it drives fertility[J].Reprod Fertil Dev,2017,30(1):118-139.

    • [23] VAN DEN AMEELE J,LI A Y Z,MA H,et al.Mitochondrial heteroplasmy beyond the oocyte bottleneck [J].Semin Cell Dev Biol,2020,97:156-166.

    • [24] HOU Y J,ZHU C C,DUAN X,et al.Both diet and gene mutation induced obesity affect oocyte quality in mice[J].Sci Rep,2016,6:18858.

    • [25] ALEXOPOULOS S J,CHEN S Y,BRANDON A E,et al.Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice[J].Nat Commun,2020,11(1):2397.

    • [26] PERKINS A T,DAS T M,PANZERA L C,et al.Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors[J].Proc Natl Acad Sci U S A,2016,113(44):E6823-E6830.

    • [27] ZHANG L,HAN L S,MA R J,et al.Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes[J].Cell Cycle,2015,14(18):2959-2968.

    • [28] GAO M,LI X Y,HE Y F,et al.SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation[J].FASEB J,2018,32(11):6228-6238.

    • [29] GRINDLER N M,MOLEY K H.Maternal obesity,infertility and mitochondrial dysfunction:potential mechanisms emerging from mouse model systems[J].Mol Hum Reprod,2013,19(8):486-494.

    • [30] WU L L,RUSSELL D L,WONG S L,et al.Mitochondrial dysfunction in oocytes of obese mothers:transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors[J].Development,2015,142(4):681-691.

    • [31] OZCAN L,TABAS I.Role of endoplasmic reticulum stress in metabolic disease and other disorders[J].Annu Rev Med,2012,63:317-328.

    • [32] ZHANG T,XI Q S,WANG D,et al.Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging:an analysis using single-cell RNAsequencing of mouse oocytes[J].J Ovarian Res,2019,12(1):53.

    • [33] ZHAO L,LU T,GAO L,et al.Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice[J].J Anim Sci Biotechnol,2017,8:62.

    • [34] DE CABO R,MATTSON M P.Effects of intermittent fasting on health,aging,and disease[J].N Engl J Med,2019,381(26):2541-2551.

    • [35] YU S C,GAO L P,ZHANG C,et al.Glycine ameliorates endoplasmic reticulum stress induced by thapsigargin in porcine oocytes[J].Front Cell Dev Biol,2021,9:733860.

    • [36] OAKES S A.Endoplasmic reticulum stress signaling in cancer cells[J].Am J Pathol,2020,190(5):934-946.

    • [37] SANTOS L E,FERREIRA S T.Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease[J].Neuropharmacology,2018,136(Pt B):350-360.

    • [38] YANG M Y,WANG Y B,HAN B,et al.Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells[J].Acta Pharmacol Sin,2018,39(1):48-58.

    • [39] SHIMOURA N,NAGAI H,FUJIWARA S,et al.Exacerbation and prolongation of psoriasiform inflammation in diabetic obese mice:a synergistic role of CXCL5 and endoplasmic reticulum stress[J].J Invest Dermatol,2018,138(4):854-863.

    • [40] SZPIGEL A,HAINAULT I,CARLIER A,et al.Lipid environment induces ER stress,TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes[J].Diabetologia,2018,61(2):399-412.

    • [41] VILLALOBOS-LABRA R,SUBIABRE M,TOLEDO F,et al.Endoplasmic reticulum stress and development of insulin resistance in adipose,skeletal,liver,and foetoplacental tissue in diabesity[J].Mol Aspects Med,2019,66:49-61.

    • [42] HSIEH C L,HUANG H S,CHEN K C,et al.A novel salicylanilide derivative induces autophagy cell death in castration-resistant prostate cancer via ER stress-activated PERK signaling pathway[J].Mol Cancer Ther,2020,19(1):101-111.

    • [43] SINGH A K,ZHAO B,LIU X,et al.Selective targeting of TET catalytic domain promotes somatic cell reprogramming[J].Proc Natl Acad Sci U S A,2020,117(7):3621-3626.

    • [44] MULHOLLAND C B,NISHIYAMA A,RYAN J,et al.Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals[J].Nat Commun,2020,11(1):5972.

    • [45] GU T P,GUO F,YANG H,et al.The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature,2011,477(7366):606-610.

    • [46] HUANG J L,RU G Z,SUN J J,et al.Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice[J].Mol Med,2022,28(1):17.

    • [47] DI FRANCESCO A,DI GERMANIO C,BERNIER M,et al.A time to fast[J].Science,2018,362(6416):770-775.

  • 参考文献

    • [1] BROUGHTON D E,MOLEY K H.Obesity and female infertility:potential mediators of obesity's impact[J].Fertil Steril,2017,107(4):840-847.

    • [2] CATALANO P M,SHANKAR K.Obesity and pregnancy:mechanisms of short term and long term adverse consequences for mother and child[J].BMJ,2017,356:j1.

    • [3] OGUNWOLE S M,ZERA C A,STANFORD F C.Obesity management in women of reproductive age[J].JAMA,2021,325(5):433-434.

    • [4] WIMALAWANSA S J.Associations of vitamin D with insulin resistance,obesity,type 2 diabetes,and metabolic syndrome[J].J Steroid Biochem Mol Biol,2018,175:177-189.

    • [5] CUNNINGHAM T K,ALLGAR V,DARGHAM S R,et al.Association of vitamin D metabolites with embryo development and fertilization in women with and without PCOS undergoing subfertility treatment[J].Front Endocrinol(Lausanne),2019,10:13.

    • [6] LIU T,QU J,TIAN M,et al.Lipid metabolic process involved in oocyte maturation during folliculogenesis[J].Front Cell Dev Biol,2022,10:806890.

    • [7] GOMES R M,BUENO F G,SCHAMBER C R,et al.Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance[J].J Nutr Biochem,2018,61:24-32.

    • [8] TORTORIELLO D V,MCMINN J,CHUA S C.Dietaryinduced obesity and hypothalamic infertility in female DBA/2J mice[J].Endocrinology,2004,145(3):1238-1247.

    • [9] XU P,HUANG B Y,ZHAN J H,et al.Insulin reduces reaction of follicular granulosa cells to FSH stimulation in women with obesity-related infertility during IVF[J].J Clin Endocrinol Metab,2019,104(7):2547-2560.

    • [10] LAINEZ N M,COSS D.Obesity,neuroinflammation,and reproductive function[J].Endocrinology,2019,160(11):2719-2736.

    • [11] PINBORG A,GAARSLEV C,HOUGAARD C O,et al.Influence of female bodyweight on IVF outcome:a longitudinal multicentre cohort study of 487 infertile couples[J].Reprod Biomed Online,2011,23(4):490-499.

    • [12] HAN L S,WANG H,LI L,et al.Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway[J].J Pineal Res,2017,63(3):e12431.

    • [13] WANG H J,ZHU S,WU X H,et al.NAMPT reductioninduced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice[J].Aging Cell,2021,20(11):e13496.

    • [14] HAN L S,REN C,LI L,et al.Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes[J].Nat Genet,2018,50(3):432-442.

    • [15] LUZZO K M,WANG Q,PURCELL S H,et al.High fat diet induced developmental defects in the mouse:oocyte meiotic aneuploidy and fetal growth retardation/brain defects[J].PLoS One,2012,7(11):e49217.

    • [16] WANG D N,SUN H Z,ZHANG J Q,et al.FKBP25 regulates meiotic apparatus during mouse oocyte maturation[J].Front Cell Dev Biol,2021,9:625805.

    • [17] SMITS A,MAREI W F A,DE NEUBOURG D,et al.Diet normalization or caloric restriction as a preconception care strategy to improve metabolic health and oocyte quality in obese outbred mice[J].Reprod Biol Endocrinol,2021,19(1):166.

    • [18] STAROSTIK M R,SOSINA O A,MCCOY R C.Singlecell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism[J].Genome Res,2020,30(6):814-825.

    • [19] LAN M,HAN J,PAN M H,et al.Melatonin protects against defects induced by deoxynivalenol during mouse oocyte maturation[J].J Pineal Res,2018,65(1):e12477.

    • [20] RUSSO M,FORTE G,MONTANINO OLIVA M,et al.Melatonin and myo-inositol:supporting reproduction from the oocyte to birth[J].Int J Mol Sci,2021,22(16):8433.

    • [21] SABEN J L,BOUDOURES A L,ASGHAR Z,et al.Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations [J].Cell Rep,2016,16(1):1-8.

    • [22] ST JOHN J C,SRIRATTANA K,TSAI T S,et al.The mitochondrial genome:how it drives fertility[J].Reprod Fertil Dev,2017,30(1):118-139.

    • [23] VAN DEN AMEELE J,LI A Y Z,MA H,et al.Mitochondrial heteroplasmy beyond the oocyte bottleneck [J].Semin Cell Dev Biol,2020,97:156-166.

    • [24] HOU Y J,ZHU C C,DUAN X,et al.Both diet and gene mutation induced obesity affect oocyte quality in mice[J].Sci Rep,2016,6:18858.

    • [25] ALEXOPOULOS S J,CHEN S Y,BRANDON A E,et al.Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice[J].Nat Commun,2020,11(1):2397.

    • [26] PERKINS A T,DAS T M,PANZERA L C,et al.Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors[J].Proc Natl Acad Sci U S A,2016,113(44):E6823-E6830.

    • [27] ZHANG L,HAN L S,MA R J,et al.Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes[J].Cell Cycle,2015,14(18):2959-2968.

    • [28] GAO M,LI X Y,HE Y F,et al.SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation[J].FASEB J,2018,32(11):6228-6238.

    • [29] GRINDLER N M,MOLEY K H.Maternal obesity,infertility and mitochondrial dysfunction:potential mechanisms emerging from mouse model systems[J].Mol Hum Reprod,2013,19(8):486-494.

    • [30] WU L L,RUSSELL D L,WONG S L,et al.Mitochondrial dysfunction in oocytes of obese mothers:transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors[J].Development,2015,142(4):681-691.

    • [31] OZCAN L,TABAS I.Role of endoplasmic reticulum stress in metabolic disease and other disorders[J].Annu Rev Med,2012,63:317-328.

    • [32] ZHANG T,XI Q S,WANG D,et al.Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging:an analysis using single-cell RNAsequencing of mouse oocytes[J].J Ovarian Res,2019,12(1):53.

    • [33] ZHAO L,LU T,GAO L,et al.Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice[J].J Anim Sci Biotechnol,2017,8:62.

    • [34] DE CABO R,MATTSON M P.Effects of intermittent fasting on health,aging,and disease[J].N Engl J Med,2019,381(26):2541-2551.

    • [35] YU S C,GAO L P,ZHANG C,et al.Glycine ameliorates endoplasmic reticulum stress induced by thapsigargin in porcine oocytes[J].Front Cell Dev Biol,2021,9:733860.

    • [36] OAKES S A.Endoplasmic reticulum stress signaling in cancer cells[J].Am J Pathol,2020,190(5):934-946.

    • [37] SANTOS L E,FERREIRA S T.Crosstalk between endoplasmic reticulum stress and brain inflammation in Alzheimer's disease[J].Neuropharmacology,2018,136(Pt B):350-360.

    • [38] YANG M Y,WANG Y B,HAN B,et al.Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells[J].Acta Pharmacol Sin,2018,39(1):48-58.

    • [39] SHIMOURA N,NAGAI H,FUJIWARA S,et al.Exacerbation and prolongation of psoriasiform inflammation in diabetic obese mice:a synergistic role of CXCL5 and endoplasmic reticulum stress[J].J Invest Dermatol,2018,138(4):854-863.

    • [40] SZPIGEL A,HAINAULT I,CARLIER A,et al.Lipid environment induces ER stress,TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes[J].Diabetologia,2018,61(2):399-412.

    • [41] VILLALOBOS-LABRA R,SUBIABRE M,TOLEDO F,et al.Endoplasmic reticulum stress and development of insulin resistance in adipose,skeletal,liver,and foetoplacental tissue in diabesity[J].Mol Aspects Med,2019,66:49-61.

    • [42] HSIEH C L,HUANG H S,CHEN K C,et al.A novel salicylanilide derivative induces autophagy cell death in castration-resistant prostate cancer via ER stress-activated PERK signaling pathway[J].Mol Cancer Ther,2020,19(1):101-111.

    • [43] SINGH A K,ZHAO B,LIU X,et al.Selective targeting of TET catalytic domain promotes somatic cell reprogramming[J].Proc Natl Acad Sci U S A,2020,117(7):3621-3626.

    • [44] MULHOLLAND C B,NISHIYAMA A,RYAN J,et al.Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals[J].Nat Commun,2020,11(1):5972.

    • [45] GU T P,GUO F,YANG H,et al.The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature,2011,477(7366):606-610.

    • [46] HUANG J L,RU G Z,SUN J J,et al.Elevated RIF1 participates in the epigenetic abnormalities of zygotes by regulating histone modifications on MuERV-L in obese mice[J].Mol Med,2022,28(1):17.

    • [47] DI FRANCESCO A,DI GERMANIO C,BERNIER M,et al.A time to fast[J].Science,2018,362(6416):770-775.

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