Transcriptomic mapping of key reproductive and metabolic tissues and oocytes in mouse models of polycystic ovary syndrome. Mus musculus

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with a broad spectrum of clinical manifestations. Excessive androgen production and obesity are key in the PCOS pathogenesis. PCOS-like mouse models induced by androgen exposure includes the prenatal androgenized (PNA), peripubertal androgenized, and overexpression of nerve growth factor in theca cells (17NF), as well as the effect of diet-induced maternal obesity model on offspring. To reveal the molecular features of these models, we performed transcriptomic profiling of hypothalamus, adipose tissue, ovary and MII oocytes. Several common functional pathways were identified among all models despite different gene targets in each model. The largest number of differentially expressed genes (DEGs) were found in the ovaries of 17NF and in the adipose tissues of peripubertal androgenized models. In contrast, hypothalamus is most affected in PNA and maternal obesity modelssuggesting fetal programming effects. The Ms4a6e gene, membrane-spanning 4-domains subfamily A member 6E, a DEG identified in the adipose tissue in all PCOS-like mouse models is also differently expressed in adipose tissue of women with PCOS women, highlighting a conservative disease mechanism. Our comprehensive transcriptomic mapping of key target tissues of the PCOS pathology provides a unique resource when investigating molecular mechanisms induced by androgen exposure and highlights that there are critical windows for androgen administration and maternal obesity. Specifically, these mouse modelsallow us to differentiate the effects of prenatal and postnatal androgen in three commonly used PCOS-like models in contrast to maternal obesity mouse model and associate phenotypes with gene expression for these mouse models

多囊卵巢综合征（Polycystic ovary syndrome, PCOS）是一类具有广泛临床表现谱的异质性疾病。雄激素过度生成与肥胖是多囊卵巢综合征发病机制的核心环节。由雄激素暴露诱导的多囊卵巢样小鼠模型包括产前雄激素处理模型（PNA）、青春期前雄激素诱导模型、卵泡膜细胞神经生长因子过表达模型（17NF），以及饮食诱导的母体肥胖模型对子代的影响。为揭示上述模型的分子特征，本研究对下丘脑、脂肪组织、卵巢及MII卵母细胞（MII oocytes）开展了转录组分析。尽管各模型的基因靶点存在差异，但所有模型均筛选得到了共同的功能通路。17NF模型的卵巢组织与青春期前雄激素诱导模型的脂肪组织中，差异表达基因（Differentially Expressed Genes, DEGs）的数量最多。与之相对，下丘脑在PNA模型与母体肥胖模型中受影响最为显著，提示存在胎儿程序化效应。Ms4a6e基因（跨膜4结构域A亚家族成员6E，membrane-spanning 4-domains subfamily A member 6E）是在所有多囊卵巢样小鼠模型的脂肪组织中鉴定出的差异表达基因，该基因在多囊卵巢综合征女性的脂肪组织中同样存在表达差异，这一发现凸显了保守的疾病发病机制。本研究对多囊卵巢综合征病理关键靶组织的全面转录组图谱分析，为探究雄激素暴露诱导的分子机制提供了独特的研究资源，同时明确了雄激素给药与母体肥胖的关键时间窗口。具体而言，相较于母体肥胖小鼠模型，本研究涉及的三种常用多囊卵巢样小鼠模型可帮助我们区分产前与产后雄激素暴露的生物学效应，并实现模型表型与基因表达的关联分析。