Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

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 b..., Materials and Methods Ethical Approvals The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The cohort study was approved by the regional ethical review board in Stockholm, Sweden (diary number 2013/862-31/5; 2016/1214-32). The requirement for informed consent was waived because the study was register-based, and the included individuals were not identifiable at any time. Animal experiments were done in accordance with the legal requirements of the European Community (SJVFS 2017:40) and the directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes and approved by the Stockholm Ethical Committee for Animal Research (Dnr. No. 10798-2017). Animal care and procedures were controlled by Comparative Medicine Biomedicum (KM-B), Karolinska Institutet, Stockhol..., ,多囊卵巢综合征（polycystic ovary syndrome, PCOS）女性患者的肥胖与高雄激素状态，及其对后代精神健康的影响方式与程度，目前尚不明确。本研究依托瑞典人群健康登记数据开展分析，结果显示，PCOS母亲所生女儿被诊断为焦虑障碍的风险升高78%。 随后我们构建了妊娠晚期雄激素暴露诱导的PCOS样小鼠（F0）模型，并设置伴/不伴饮食诱导的母体肥胖组，结果发现第一代（F1）雌性后代出现焦虑样行为，且该表型可通过雌性生殖系跨代传递至雄激素暴露谱系的第三代雌性后代（F3）。与之相反，通过雄性生殖系传递时，雄激素暴露与肥胖谱系的第三代雄性后代（mF3）同样表现出焦虑样行为。本研究通过靶向筛选杏仁核内的分子靶点，鉴定出5个与焦虑样行为相关的差异表达基因，详见材料与方法。 伦理审批 本研究所有涉及人体的操作均符合相关国家及机构人体实验伦理标准，并遵循2008年修订版《1975年赫尔辛基宣言》。本队列研究经瑞典斯德哥尔摩地区伦理审查委员会批准（登记号：2013/862-31/5；2016/1214-32）。由于本研究基于登记数据开展，所有纳入对象全程均无法被识别，故豁免知情同意要求。 动物实验严格遵循欧洲共同体相关法律要求（SJVFS 2017:40）及欧洲议会《关于科学用途动物保护的2010/63/EU指令》，并经斯德哥尔摩动物研究伦理委员会批准（登记号：10798-2017）。动物饲养与实验操作由卡罗林斯卡学院生物医学比较医学中心（KM-B）负责监管，相关内容详见后续记录。