产前雄性激素暴露和多囊卵巢综合征的跨代易感性

The effects of how obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring are unclear. We found that daughters of PCOS mothers are more likely to be diagnosed with PCOS in a Swedish nationwide register-based cohort and a clinical case-control study from Chile. Further, female mice (F0) with PCOS-like traits induced by late gestation injection of dihydrotestosterone, with and without obesity, produced female F1–F3 offspring with a PCOS-like reproductive and metabolic phenotypes. Sequencing of single MII oocytes from F1–F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of PCOS mothers and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

多囊卵巢综合征（PCOS）女性的肥胖与雄激素水平升高如何影响其子代，目前尚不明确。本研究通过瑞典全国登记队列研究与智利的一项临床病例对照研究发现，PCOS母亲所生的女儿罹患PCOS的风险更高。进一步的动物实验显示，通过妊娠晚期注射双氢睾酮（dihydrotestosterone）诱导出PCOS样特征的雌性小鼠（F0代，伴或不伴肥胖），其产下的F1至F3代雌性子代均呈现PCOS样生殖与代谢表型。对F1至F3代子代的单个第二次减数分裂中期（MII）卵母细胞进行测序后发现，各代均存在共同及特有的基因表达改变。值得注意的是，本病例对照研究中PCOS母亲的女儿以及无亲缘关系的PCOS女性的血清样本中，有4个基因同样存在差异表达。本研究结果为PCOS母亲的雌性子代存在跨代效应提供了科学证据，并为预测未来世代的PCOS表型筛选出了潜在候选基因。