Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2014464118.
Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.
压力与许多慢性疾病有关，从胎儿发育时期的宫内暴露（产前压力）开始，就会影响后代日后患疾病的风险。在之前的研究中，我们证明了母体宫内免疫活性异常会对后代七岁时的性别差异神经发育和成年后患重度抑郁症和精神病的风险产生不利影响。在这里，我们假设母体促炎细胞因子的宫内暴露对调节后代应激和免疫功能的特定大脑回路具有性别依赖性影响，这种影响会在整个生命周期中持续存在。我们使用一个独特的产前队列，在 80 名成年后代中测试了这一假设，这些后代按性别平均分配，从宫内发育到中年进行随访。功能磁共振成像结果表明，宫内暴露于促炎细胞因子与 45 年后对负面应激刺激的大脑活动和连通性的性别差异显著相关。较低的母 TNF-α 水平与两性的下丘脑活动增加显著相关，而只有男性的下丘脑和前扣带之间的功能连通性更高。较高的产前 IL-6 水平与女性单独的海马活动增加显著相关。当与 IL-10 的抗炎作用相关时，TNF-α:IL-10 的比值与海马活动和与下丘脑的功能连通性的性别依赖性影响相关。总的来说，结果表明，母体宫内促炎细胞因子水平不良和促炎细胞因子与抗炎细胞因子的平衡以性别二态的方式影响后代的大脑发育，并在整个生命周期中持续存在。
