Introduction: Epidemiological studies show a link between prenatal exposure to stress or infections and the subsequent development of behavioural pathologies such as schizophrenia. Antenatal stress results in elevation of maternal plasma glucocorticoids, disturbs the development of the fetal hypothalamic-pituitary-adrenal axis, and steroidogenic activity of the adrenal cortex. The long-term effects on adrenal steroidogenesis and ensuing function have not been elucidated. We recently reported fetal adrenal production of dehydroepiandrosterone (DHEA) in the spiny mouse (Acomys cahirinus)1. We therefore determined the effect of brief maternal exposure to stress at mid-pregnancy on offspring brain, behavior and adrenal function.
Methods: Pregnant spiny mice were treated with dexamethasone (DEX; 60 h; 125 µg/kg) or saline by osmotic minipump, or polyriboinsonic-polyriboctidilic acid (Poly I:C; single injection; 0.5mg/kg) at day 20 of gestation (0.5 term). Expression of steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3βHSD), 17-hydroxylase and 17-20lyase (p450c17), and cytochrome b5 (cytb5) were determined by immunohistochemistry (IHC) in adrenal glands at 100dPN (post natal age). DHEA, testosterone, and cortisol were measured by radioimmunoassay. Animals injected with Poly I:C, or saline at 20 days gestation were culled for fetal cytokine mRNA analysis (24h after exposure to Poly I:C) or delivered their offspring for behavioural assessment between 20 and 80 dPN before tissue collection at 100dPN. All brains were analysed using IHC for microglia activation (Iba1), neuronal migration (Reelin) and astrocytes (GFAP).
Results: Male adult offspring from mothers treated with DEX at mid gestation showed significantly reduced expression of StAR, p450c17, and cytb5 in the adrenal zona reticularis. Plasma DHEA was significantly decreased in male offspring from DEX-treated dams; plasma cortisol was unaffected in either sex, so that the DHEA:cortisol ratio was significantly lower in males only. In contrast, plasma testosterone concentrations were significantly increased in male offspring from DEX-treated vs saline treated dams.
Poly I:C treatment at mid-pregnancy did not affect plasma cortisol concentrations in adult offspring, but did result in decreased mRNA expression of inflammatory cytokines in the fetal brain, suggesting activation of the maternal/fetal HPA axis. Poly I:C treatment significantly impaired non-spatial memory, learning tasks, and spontaneous motor activity in adult offspring. Brain histology revealed significant decreases in reelin, increased GFAP expression, and increased numbers of activated microglia, specifically in the hippocampus.
Conclusion: These results show that even a brief period of stress/infection at mid-gestation can result in long-term and pronounced endocrine, neurological and behavioural abnormalities in adult offspring, all considered relevant to psychiatric disease. These changes may occur in response to an interaction between the immune system and the HPA axis, quite possibly mediated by an increase in maternal glucocorticoids and alterations in the DHEA-to-cortisol ratio, suggesting a mechanism by which maternal insults contribute to the risk of neurodevelopmental disorders such as schizophrenia in humans.