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. 2021 Apr 13;118(15):e2014464118.
doi: 10.1073/pnas.2014464118.

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

Jill M Goldstein  1   2   3 , Justine E Cohen  4   3 , Klara Mareckova  5 , Laura Holsen  6 , Susan Whitfield-Gabrieli  7 , Stephen E Gilman  8 , Stephen L Buka  9 , Mady Hornig  10
Affiliations

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

Jill M Goldstein et al. Proc Natl Acad Sci U S A. .

Abstract

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.

Keywords: functional brain imaging; prenatal immune programming; prenatal stress; sex; stress circuitry.

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Conflict of interest statement

Competing interest statement: J.M.G. is on the scientific advisory board for, and has equity interest in, Cala Health (a neuromodulation company). J.M.G.’s interests are managed by Massachusetts General Hospital and Mass General Brigham HealthCare in accordance with their conflict of interest policies. However, the work in the study presented here was conducted prior to that relationship, so there is no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Prenatal exposure to lower levels of TNF-α predicted increased BOLD signal in the HYPO in all subjects, independent of sex and diagnosis.
Fig. 2.
Fig. 2.
Prenatal exposure to increased ratios of TNF-α to IL-10 predicted response in the left HIPP with sex-dependent effects. Increased TNF-α:IL-10 predicted decreased left HIPP-BOLD response in female offspring but increased left HIPP-BOLD response in male offspring.
Fig. 3.
Fig. 3.
Functional connectivity between the HYPO and the left ACC increased as a function of prenatal exposure to TNF-α in male, but not female, offspring.
Fig. 4.
Fig. 4.
Maternal ratio of TNF-α to IL-10 predicted functional connectivity between the HYPO and right HIPP in a sex-dependent manner. Higher prenatal TNF-α:IL-10 was associated with increased connectivity between the HYPO and right HIPP in female offspring but decreased connectivity between the two regions in male offspring.
Fig. 5.
Fig. 5.
This diagram summarizes the main findings of the paper with prenatal immune exposure shown on the left and the effects on stress response circuitry on the right. Effect sizes for activation results are β/SD and for connectivity results are R2.
See this image and copyright information in PMC

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