Use of a Mouse In Vitro Fertilization Model to Understand the Developmental Origins of Health and Disease Hypothesis
Use of a Mouse In Vitro Fertilization Model to Understand the Developmental Origins of Health and Disease Hypothesis
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DOI：
10.1210/en.2013-2081
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发表时间：
2014-05-01
期刊：
影响因子：
4.8
通讯作者：
Rinaudo, Paolo F.
中科院分区：
文献类型：
--
作者：
Feuer, Sky K.;Liu, Xiaowei;Rinaudo, Paolo F.
健康和疾病的发育起源假说认为，在发育的关键时期，体内平衡的改变可能使个体易患成人发病的慢性疾病，如糖尿病和代谢综合征。临床上用于治疗不孕症患者的植入前胚胎操作是否会扰乱体内平衡并影响长期生长和代谢仍存在争议。为了解决这一争议，我们评估了体外受精（IVF）对小鼠出生后生理的影响。我们证明，即使在被认为是小鼠胚胎培养的最佳条件下，IVF和胚胎培养也会改变成年小鼠的出生后生长轨迹、脂肪积累和葡萄糖代谢。血清中无偏代谢谱和胰岛和胰岛素敏感组织（肝脏、骨骼肌和脂肪组织）的微阵列分析揭示了代谢稳态的广泛变化，其特征在于全身性氧化应激和线粒体功能障碍。采用一种候选方法，我们确定了硫氧还蛋白相互作用蛋白（TXNIP），一个关键分子参与整合细胞营养和氧化状态与代谢反应，作为标记物植入前应激和证明组织特异性表观遗传和转录TXNIP失调在选定的成年组织。重要的是，TXNIP表达的失调与Txnip启动子处H4乙酰化的富集相关，Txnip启动子在脂肪组织中从胚泡阶段持续到成年期。我们的数据支持植入前胚胎对环境干扰的脆弱性，并表明IVF受孕可以通过代谢，转录和表观遗传机制重新编程代谢稳态，对成年生长和健康产生持久影响。这项研究具有广泛的临床意义，并强调了继续随访IVF受孕后代的重要性。
The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.