Monday, February 25, 2013

Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

Image from "Transgenerational programming of maternal behaviour by prenatal stress," Ward et al. BMC Pregnancy and Childbirth, 2013, 13(Suppl 1):S9.

A couple of days ago, I posted an overview article on the science of epigenetics that looked specifically at how experience can impact our offspring (the article did not mention this, nor did I in my brief commentary, but this is painfully obvious in intergenerational trauma [interestingly, the Native American uses the term "intergenerational trauma," but the Jewish community uses the term "transgenerational trauma"]).

A new article in PLoS ONE looks at how maternal stress can trigger markers for psychological diseases (psychiatric and neurological) in their offspring. The abstract and introduction to the article are included below. The article id open access and be found at the link embedded in the title.

Figure 1. Gestational stress disrupts antepartum maternal behaviour. Time spent engaged in tail chasing behaviours and the number of rotations performed at 19–18 hours prior to delivery (all data transformed to square root). Gestational stress decreased the time spent in tail chasing activities and the number of rotations, indicating reduced maternal preparatory activity (n = 6 non-stress controls, n = 9 gestational stress). *p≤0.05, mean ± SEM.

Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

Fabiola C. R. Zucchi, Youli Yao, Isaac D. Ward, Yaroslav Ilnytskyy, David M. Olson, Karen Benzies, Igor Kovalchuk, Olga Kovalchuk, Gerlinde A. S. Metz


The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.
Full Citation: 
Zucchi FCR, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, et al. (2013) Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring. PLoS ONE 8(2): e56967. doi: 10.1371/journal.pone.0056967


The gestational state is a period of particular vulnerability for both the mother and her offspring. Experience of distress during pregnancy may critically determine maternal health and alter offspring brain physiology and behaviour with life-long consequences [1], [2]. Gestational stress disrupts post-partum maternal care, which impedes brain and behavioural development of the offspring [3], [4]. It was proposed that the effects of maternal care are possibly transmitted across generations through non-genomic mechanisms [3]. Mechanisms of transfer include altered gestational endocrine milieu, maternal behaviour and transgenerational epigenetic programming [5][9]. Moreover, gestational stress directly influences fetal brain development and programming of hypothalamic-pituitary-adrenal (HPA) axis function [10], [11] to induce life-long changes in stress responsiveness [12] and possibly enhanced vulnerability to psychiatric conditions, including depression and bipolar affective disorder [13][16] and schizophrenia[17][20]. The prefrontal cortex in particular is relevant to mental health disorders, which may be precipitated or exaggerated by stress, pregnancy and childbirth [21][23].

Behavioural and physiological changes in stressed mothers and their offspring may be linked to altered gene expression in the brain, which is epigenetically regulated by experience. Epigenetic changes, including expression of microRNA (miRNA) enable rapid adjustments in gene expression without altering nucleotide sequences. Altered miRNA expression was suggested to prime neuroplasticity and physiological processes in response to early environment [8], [24] and the experience of stress [7], [25]. miRNA may be a critical component to mediate the effects of prenatal stress and maternal care on offspring development [26], [27]. Notably, miRNA expression is altered in many common psychiatric and neurological disorders, such as bipolar disorder, schizophrenia, autism, depression, and inflammatory conditions [28][33]. Most of these conditions share a suspected etiology that includes both the influence of adverse perinatal origins as well as a transcriptomic component, suggesting that epigenetic regulation of gene expression may represent a central common feature in individual disease etiology [34].

Here we provide a link between gestational adverse experience and epigenetic re-programming of the transcriptome by means of miRNA in the brains of gravid dams and their offspring. Maternal stress altered maternal antepartum behaviour and brain miRNA expression patterns in the frontal cortex, a region involved in maternal care, decision-making and stress responses. These changes translated to altered offspring miRNA signatures related to disease. Our observations allow proposing a mechanism by which gestational experience modulates gene expression with possibly life-long phenotypical consequences in the offspring.
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