N-乙酰-L-半胱氨酸可减少肥胖父亲睾丸中的ROS,但不能保护后代免受cyp19a1和IGF11/H19 ICR位点表观遗传特征的影响。

IF 4.6 2区 生物学 Q2 CELL BIOLOGY Frontiers in Cell and Developmental Biology Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI:10.3389/fcell.2024.1450580
Arianna Pastore, Nadia Badolati, Francesco Manfrevola, Serena Sagliocchi, Valentina Laurenzi, Giorgia Musto, Veronica Porreca, Melania Murolo, Teresa Chioccarelli, Roberto Ciampaglia, Valentina Vellecco, Mariarosaria Bucci, Monica Dentice, Gilda Cobellis, Mariano Stornaiuolo
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引用次数: 0

摘要

简介受孕前父亲的营养状况对后代成年后患代谢性疾病的风险有显著影响。对人类队列和动物模型的研究表明,父亲肥胖会改变精子的表观遗传学(DNA甲基化、原胺-组蛋白置换和非编码RNA含量),从而导致后代的不良健康结果。迄今为止,将父亲的营养转化为精子表观遗传学变化的机理事件仍不清楚。高脂饮食(HFD)导致的父亲肥胖会增加性腺活性氧(ROS),而ROS会调节精子发生过程中参与DNA表观遗传修饰的酶。因此,生殖腺的ROS池可能负责通过生殖细胞将父亲的健康状况传递给胚胎:方法:通过调节雄性小鼠性腺中的 ROS 含量,评估了 ROS 在父系代际传递中的作用。N-乙酰半胱氨酸(NAC)是一种抗氧化剂 GSH 的前体,它能抵消高氟酸睾丸氧化应激。雄性小鼠被分为四个饲喂组:i) 对照组;ii) 高纤维食物组;iii) NAC存在下的对照组;iv) NAC存在下的高纤维食物组。8 周后,雄性与喂食对照组饲料的雌性交配。然后评估抗氧化剂治疗是否能防止肥胖的父亲将高氟酸诱导的代谢紊乱性状遗传给后代。后代断奶后食用常规控制饮食至第 16 周,然后进行代谢评估。此外,还利用桑格测序和甲基化依赖性 qPCR 评估了子代 gDNA 中基因组区域 IGFII/H19 和 cyp19a1 的甲基化状态:结果:补充 NAC 可保护母鼠免受高纤维食物诱导的体重增加、高胰岛素血症和葡萄糖不耐受的影响。NAC 降低了肥胖父亲性腺中的氧化应激,提高了精子活力。然而,NAC 并不能阻止表观遗传修饰从父亲传给后代。无论 NAC 治疗与否,喂食高密度脂蛋白胆固醇的父亲的雄性后代都表现出高胰岛素血症、葡萄糖不耐受和雄性激素过低。此外,他们还表现出表观遗传控制位点 IGFII/H19 和 cy19a1 的甲基化改变:结论:虽然补充 NAC 可改善高密度脂蛋白喂养雄性小鼠的健康状况和精子质量,但并不能防止代谢紊乱的表观遗传传递给后代。不同剂量的 NAC 和 NAC 以外的抗氧化剂可能是阻止父代代谢紊乱性状代际传递的替代品。
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N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at cyp19a1 and IGF11/H19 ICR loci.

Introduction: Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells.

Methods: The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8 weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region IGFII/H19 and cyp19a1 in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR.

Results: Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci IGFII/H19 and cy19a1.

Conclusion: Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.

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来源期刊
Frontiers in Cell and Developmental Biology
Frontiers in Cell and Developmental Biology Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
9.70
自引率
3.60%
发文量
2531
审稿时长
12 weeks
期刊介绍: Frontiers in Cell and Developmental Biology is a broad-scope, interdisciplinary open-access journal, focusing on the fundamental processes of life, led by Prof Amanda Fisher and supported by a geographically diverse, high-quality editorial board. The journal welcomes submissions on a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics, with sections focusing on signaling, adhesion, migration, cell death and survival and membrane trafficking. Additionally, the journal offers sections dedicated to the cutting edge of fundamental and translational research in molecular medicine and stem cell biology. With a collaborative, rigorous and transparent peer-review, the journal produces the highest scientific quality in both fundamental and applied research, and advanced article level metrics measure the real-time impact and influence of each publication.
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