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Prenatal Exposure to Proinflammatory Cytokines May Increase Risk of Psychiatric Disorders by Sex 45 years later in Adulthood

Key findings

  • Data from a longitudinal family study were used to examine the impact of maternal prenatal immune activity on sex differences in the brain circuitry regulating stress in the adult offspring 45 years later; the focus was the hypothalamus and hippocampus, key regulators of the stress response that are highly sexually dimorphic
  • 80 study subjects, now in their mid-40s, underwent functional MRI while participating in a physiologic stress test; the results were associated with cytokine levels measured in their mothers during the third trimester of pregnancy
  • Lower maternal levels of TNF-a, a pro-inflammatory cytokine and primary coactivator of the hypothalamic–pituitary–adrenal (HPA) axis, were significantly associated with higher hypothalamic activity in both sexes
  • Higher maternal levels of IL-6, another pro-inflammatory cytokine and activator of the HPA axis, were significantly associated with higher hippocampal activity, but only in women
  • These and other sex-dependent results may contribute to understanding sex differences in psychiatric disorders and other chronic diseases—and how to prevent them

Repeated and prolonged negative stress is associated with an increased risk of numerous chronic diseases, including psychiatric and cardiovascular disorders. In fact, it's well established that prenatal stress affects a person's risk of certain disorders later in life.

Prenatal stress is also thought to contribute to sex differences in disease risk. Key regulators of the stress response, the hypothalamus and hippocampus, are highly sexually dimorphic (they develop differently in the male and female brain in utero). Developmental disruptions can have long-lasting effects on sex-dependent diseases such as major depressive disorder (MDD) and schizophrenia.

Jill M. Goldstein, PhD, MPH, executive director of the Innovation Center on Sex Differences in Medicine and the Helen T. Moerschner Endowed MGH Research Institute Chair in Women's Health, and colleagues in the Department of Psychiatry and Department of Obstetrics and Gynecology at Massachusetts General Hospital, and colleagues have been researching the effects of prenatal stress on psychopathology in offspring for the past decade. For example, they previously reported in Translational Psychiatry, that adult risk of MDD can be affected by in utero exposure to maternal immune activity. Yet exactly how that activity affects the brain circuitry of offspring has been unclear.

Now, Dr. Goldstein and colleagues have determined that adverse levels of maternal pro-inflammatory cytokines and the balance of pro- to anti-inflammatory cytokines influence the brain development of offspring in a sexually dimorphic manner that persist across the lifespan. Their report appears in PNAS.

Study Methods

The study participants were 80 adult offspring from the New England Family Study whose mothers had cytokine concentrations measured at the start of the third trimester of pregnancy. The cytokines evaluated were TNF-α, IL-1β and IL-6, which are pro-inflammatory and primary coactivators of the hypothalamic–pituitary–adrenal (HPA) axis, and IL-10, which is anti-inflammatory and can be used to estimate pro- to anti-inflammatory cytokine imbalance.

Now in their mid-40s, about half the participants had a psychiatric disorder in remission and half were psychiatrically healthy:

  • 40 men (average age 46)—11 with MDD, three with bipolar disorder (BPD) and six with schizophrenia
  • 40 women (average age 46)—14 with MDD, six with BPD and one with schizophrenia

The participants underwent functional MRI while viewing negative images, a standardized task proven to activate stress response neural circuitry. The team examined how the brain responded to negative versus neutral images as a function of prenatal exposure to maternal cytokines.


In both male and female offspring, but particularly in women, lower levels of maternal TNF-α were associated with higher hypothalamic activity in response to negative stimuli.

In men alone, lower maternal TNF-α levels were also associated with higher functional connectivity between the hypothalamus and anterior cingulate cortex.


Higher maternal TNF-α:IL-10, indicating inadequate anti-inflammatory response, was associated with sex-dependent differences in hippocampal activation, and in connectivity between the hippocampus and hypothalamus. The hippocampus provides negative feedback to the hypothalamus in response to negative stressful stimuli, enabling the HPA axis to inhibit the release of corticotropin-releasing hormone (CRH) and regulate arousal due to stress.

  • Men exposed in utero to higher TNF-α:IL-10 showed lower connectivity between the hypothalamus and hippocampus and thus less able to inhibit the higher activity of the hypothalamus by the hippocampus
  • Women with higher prenatal TNF-α:IL-10 exposure exhibited higher connectivity between hippocampus and hypothalamus but lower hippocampal activation; thus, like men, they had less ability to downregulate hypothalamic arousal and CRH release


Higher maternal IL-6 was associated with hypoactivity in the left hippocampus, particularly in women, again suggesting less ability to inhibit arousal in the hypothalamus.

Interpreting the Results

This study suggests prenatal exposure to an imbalance of maternal immune activity at a key period of sex-sensitive brain development sets the stage for hypersensitivity to negative stressful events throughout life. The sex-dependent effect is quantitative and may contribute to understanding sex differences in psychiatric disorders and other chronic diseases—and how to prevent them prior to onset.

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