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Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.

ABSTRACT: The fetal brain is highly plastic and is not only receptive to but requires cues from its environment to develop properly. Based on an understanding of evolutionary biology, developmental plasticity, and life history theory, one can predict that stressors are an important environmental condition that may influence brain development. In fact, the available empirical evidence appears to support the notion that exposure to excess stress in intrauterine life has the potential to adversely affect short- and long-term neurodevelopmental outcomes with implications for altered susceptibility for mental health disorders in childhood and adult life. In this presentation, we provide a rationale for proposing that endocrine and inflammatory stress mediators are key candidate pathways for programming brain development. These mediators are responsive to a diverse set of intrauterine perturbations and alter key signaling pathways critical for brain development, including but not limited to mammalian target of rapamycin, Wnt (wingless), Sonic hedgehog, and reelin signaling. We suggest that recent advances in neuroimaging and other methods now afford us an unprecedented opportunity to advance our understanding of this important topic. Additionally, we provide empirical evidence from two recently published papers for fetal programming of human brain development. We conclude by suggesting some future directions for expanding this field of research.

SUBMITTER: Buss C

PROVIDER: S-EPMC3837231 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.

Buss Claudia C Entringer Sonja S Wadhwa Pathik D PD

Science signaling 20121009 245

The fetal brain is highly plastic and is not only receptive to but requires cues from its environment to develop properly. Based on an understanding of evolutionary biology, developmental plasticity, and life history theory, one can predict that stressors are an important environmental condition that may influence brain development. In fact, the available empirical evidence appears to support the notion that exposure to excess stress in intrauterine life ...[more]

PMID: 23047922

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Project description:BackgroundMaternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive.MethodsEthanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16-17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1?, IFN ?, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-?, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes.ResultsWe show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1?, IFN-?) in fetal brain tissue observed at 6-24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1?, IFN-?, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-?, CXCL10, CCL22, Chi, Arg, and CCR2).ConclusionsTaken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors.

Dataset Information

Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.

Publications

Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.

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