Exposure to Inflammation in the Womb Affects Male and Female Offspring Differently in Midlife

April 13, 2021

Men and women whose mothers experienced stressful events during pregnancy regulated stress differently in the brain 45 years later, according to a study published in Proceedings of the National Academy of Sciences (PNAS). Brain images showed that exposure during fetal development to inflammation-promoting natural substances called cytokines, produced by mothers under negative stress, affected brain development differences by sex that continue throughout life. 

“We know that major psychiatric disorders begin in fetal development. We also know these disorders are associated with abnormalities in the brain circuitry that regulates stress--circuitry that is intimately tied to regulating our immune system,” said Jill M. Goldstein, professor of Psychiatry and Medicine at Harvard Medical School, founder and executive director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital, and first author. “Given that the stress circuitry consists of regions that develop differently in the male and female brain during particular periods of gestation and they function differently across our lifespans, we hypothesized that dysregulation of this circuitry in prenatal development would have lasting differential impact on the male and female brain in people with these disorders. “

Using a unique prenatal cohort, the researchers tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife.

Senior author Mady Hornig, MD, associate professor of epidemiology at Columbia University Mailman School of Public Health, said “we learned from our findings that persistent vulnerability to adverse neural responses to negative stressors in the hypothalamus and hippocampus, key components of the stress response circuitry, may be sculpted in part by the nature and timing of the maternal prenatal immune response and its effect on sex-sensitive components of developing brain circuitry.”

The researchers used functional magnetic resonance imaging to measure brain activity by showing differences in blood flow within and between different areas of the brain. The researchers found that exposure to pro-inflammatory cytokines in the womb was associated with sex differences in how areas of the brain are activated and communicate with one another under negative stressful conditions in midlife. 

For example, in both sexes, lower maternal levels of a pro-inflammatory cytokine (TNFα), were significantly associated with higher activity in the hypothalamus, a region of the brain that, among other functions, coordinates brain activity that regulates the release of stress hormones, like cortisol. 

In contrast, lower levels of TNFα were also associated with more active communication between the hypothalamus and the anterior cingulate in men only. The anterior cingulate is an area of the brain associated with impulse control and emotion.
In women only, higher prenatal exposure to interleukin-6, another inflammatory cytokine, was associated with higher levels of activity in the hippocampus, a brain region important for inhibitory control of arousal.
Lastly, they found that the ratio between TNFα and the anti-inflammatory cytokine interleukin-10 was associated with sex-dependent effects on activity in the hypothalamus and its communication with the hippocampus, which provides inhibitory control of arousal in the hypothalamus under stress.

“This work provides another set of clues as to the potential for prenatal neuroimmune disturbances to contribute to life-long differences in how the brains of male and female offspring respond to negative stressors, 45 years later,” noted Hornig. “The unprecedented longitudinal perspective of this pregnancy/birth cohort, with its maternal prenatal blood samples, immune assessments and adult brain imaging studies, affords a unique opportunity to uncover clues that map the trajectory from exposure to dysregulated maternal neuroimmune signaling in prenatal life to sex-dependent abnormalities in brain responses to adverse stressors that persist across a lifetime.”

Other co-authors include: Justine Cohen, Massachusetts General Hospital; Klara M. Mareckova, Masaryk University, Czech Republic; Laura Holsen, Brigham and Women’s Hospital; Susan Whitfield-Gabrieli, Northeastern University; Stephen Gilman, Johns Hopkins Bloomberg School of Public Health; and Stephen Buka, Brown University.
The study was supported by the National Institute of Mental Health.