If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F₀) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F₁) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F₃) in the androgenized lineage. In contrast, following the male germline, F₃ male offspring (mF₃) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F₃ females in the androgenized lineage and eight genes in the obese lineage. In mF₃ male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F₁ and F₂ offspring in the female germline did not develop anxiety-like behavior, while the F₂ male offspring (mF₂) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

多囊卵巢综合征（PCOS）妇女的肥胖和雄激素水平升高是否以及如何影响其后代的精神健康状况尚不清楚。使用瑞典人口健康登记数据，我们发现患有PCOS的母亲的女儿被诊断出患有焦虑症的风险增加了78％。接下来，我们生成了妊娠后期雄激素暴露引起的PCOS样小鼠（F ₀）模型，无论是否饮食引起的母体肥胖，都表明第一代（F ₁）雌性后代会发展出焦虑样行为，这就是通过雌性种系进行跨代传播，进入雄激素化世系的第三代雌性后代（F ₃）。相反，遵循雄性生殖系F ₃雄性后代（mF ₃）在雄激素源和肥胖谱系中表现出焦虑样行为。使用针对性的方法来搜索杏仁核内的分子靶标，我们确定了雄激素化谱系中F ₃雌性和肥胖谱系中的八个基因中涉及焦虑样行为的五个差异表达基因。在mF ₃雄性后代中，肥胖谱系中的三个基因表达失调，而雄激素化谱系中的三个基因均失调。最后，我们使用连续雄激素暴露的PCOS小鼠模型进行了体外受精（IVF）。我们表明，IVF在雌性种系中产生F ₁和F ₂后代并没有发展出类似焦虑的行为，而F ₂雄性种系中的雄性后代（mF ₂）发生了。我们的发现提供了证据，表明PCOS患儿的母体中雄激素水平升高和母体肥胖可能是焦虑症经世代传播的危险。