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.

Athinoula Martinos Center for Biomedical Imaging Department of Radiology Massachusetts General Hospital Harvard Medical School Boston MA 02129

Central European Institute of Technology Masaryk University 601 77 Brno Czech Republic

Department of Epidemiology and Population Health Brown University Providence RI02912

Department of Epidemiology Columbia University Mailman School of Public Health New York NY 10032

Department of Obstetrics and Gynecology Massachusetts General Hospital Boston MA 02114

Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston MA 02114

Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston MA 02114;

Division of Women's Health Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA 02115

Northeastern University Interdisciplinary Science and Engineering Complex Northeastern University Boston MA 02120

Social and Behavioral Sciences Branch Division of Intramural Population Health Research Eunice Kennedy Shriver National Institute of Child Health and Human Development and Department of Mental Health Johns Hopkins Bloomberg School of Public Health Baltimore MD 21205

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