Multigenerational Effects of Gestational Testosterone Excess

妊娠期睾酮过多对多代人的影响

• 批准号: 10472234
• 负责人: Rodolfo C. Cardoso
• 金额: $ 15.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472234
• 关键词: Adipocytes; Adipose tissue; Affect; Age; Androgens; Animal Model; Animals; Bioinformatics; Clinical; DNA; DNA Methylation; DNA analysis; Data Analyses; Development; Dissection; Endocrine System Diseases; Epigenetic Process; Etiology; Exposure to; Female; Future; Genetic Transcription; Genomics; Hyperandrogenism; Hyperinsulinism; Hypertension; Hypothalamic structure; Impairment; Insulin Resistance; Intervention; Libraries; Liver; Manuscripts; Mediating; Mediator of activation protein; Metabolic; Metabolic dysfunction; Methylation; Michigan; Neurosecretory Systems; Obesity; Phenotype; Play; Polycystic Ovary Syndrome; Predisposition; Pregnancy; Preparation; RNA; RNA analysis; Reproductive Health; Research; Role; Severities; Sheep; Structure of nucleus infundibularis hypothalami; System; Testosterone; Texas; Tissue Banks; Tissues; Universities; Visceral; Woman; adverse outcome; body system; cardiometabolism; epigenome; excessive weight gain; human tissue; in utero; offspring; organ growth; postnatal; postnatal development; prenatal; prenatal exposure; prevent; reproductive; reproductive function; sheep model; tissue resource; transcriptome; transcriptome sequencing

ABSTRACT Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting ~5 million women in the U.S. and over 100 million globally. Clinical and animal studies provide strong evidence indicating that elevated androgen levels in utero increase the offspring’s susceptibility to develop the PCOS phenotype. The metabolic system is particularly susceptible to the deleterious effects of prenatal androgen excess. Studies in sheep demonstrate that prenatal exposure to testosterone excess results in postnatal development of numerous cardiometabolic perturbations, including insulin resistance, increased adiposity, altered adipocyte size and distribution, and hypertension. Therefore, prenatal androgen excess impacts both the reproductive and metabolic systems, and reproductive perturbations (e.g., functional hyperandrogenism) impair metabolic function, whereas metabolic imbalances (e.g., insulin resistance and hyperinsulinemia) can impact reproductive function, thus forming a vicious cycle. Postnatal adiposity enhances the severity of the impact of prenatal testosterone excess. Consequently, interventions targeting multiple organ systems may be needed to prevent the manifestation of adverse outcomes programmed prenatally. Recent research provides strong evidence for the involvement of epigenetic processes, such as DNA methylation, in the etiology of PCOS. Because studies involving human tissues are less feasible, particularly those involving neuroendocrine and metabolic tissues, animal models of PCOS phenotype provide valuable tissue resources to answer mechanistic questions. We propose to study the impact of prenatal T excess and postnatal adiposity on transcriptome and epigenome of the arcuate nucleus, liver and adipocyte tissue, Our studies will help advance our fundamental understanding of the organizational role that androgens play in organ development and elucidate the epigenetic and transcriptional mechanisms mediating the effects of prenatal T excess on metabolic and reproductive health in this sheep model. A better understanding of the epigenetic and transcriptional mediators of metabolic dysfunction in this sheep model of PCOS can aid in the future development of targeted interventions.

抽象的 多囊卵巢综合征（PCOS）是繁殖年龄女性最常见的内分泌疾病， 在美国影响约500万妇女，全球超过1亿。临床和动物研究提供了强大的 证据表明，子宫内雄激素水平升高增加了后代发展的敏感性 PCOS表型。代谢系统特别容易受到产前有害影响 雄激素超过。绵羊的研究表明，产前暴露于睾丸激素超过结果 众多心脏代谢扰动的产后发展，包括胰岛素抵抗，增加 肥胖，脂肪细胞的大小和分布改变以及高血压。因此，产前雄激素超过 影响生殖和代谢系统以及生殖扰动（例如功能 高狂力主义）损害代谢功能，而代谢失衡（例如胰岛素抵抗和 高胰岛素血症可能会影响复制功能，从而形成恶性循环。产后肥胖增强 产前睾丸激素影响的严重程度超过了。因此，针对多器官的干预措施 可能需要系统以防止产前编程的不良结果表现。最近的 研究为表观遗传过程（例如DNA）提供了有力的证据 甲基化，在PCOS的病因中。因为涉及人体组织的研究不太可行，所以 特别是涉及神经内分泌和代谢组织的人，PCOS表型的动物模型 提供宝贵的组织资源来回答机理问题。我们建议研究 产前T超过和产后肥胖对弧形核的转录组和表观基因组的肥胖， 肝脏和脂肪细胞组织，我们的研究将有助于提高我们对 雄激素在器官开发中扮演的组织角色，并阐明表观遗传和 介导产前T的影响超过代谢和生殖的转录机制 这种绵羊模型中的健康。更好地了解 这种PCOS的绵羊模型中的代谢功能障碍可以帮助未来的发展 干预措施。