Developmental Programming and Epigenetic Modifications in Rat with Prenatal Stress

Rationale: Barker et al. (1989) noted that low birth weight was associated with an increased risk of adverse outcomes in adulthood, such as coronary heart disease, stroke, high blood pressure, and type 2 diabetes. In this regard, Gluckman et al. (2007) proposed the concept of development of health and disease (DOHaD) by observing the enduring effects of the fetal environment on physical health and disease in adulthood. The perinatal period is particularly sensitive to a variety of insults during which stress-regulating systems can be permanently altered and neuropsychopathologies ensue (Huang 2011a; Huang 2011b). Prenatal stress results in an enhanced production of stress hormones by the mother during critical periods of fetal brain development. Prenatal stress has been demonstrated to influence neurohormonal system of the offspring and results in long-term alterations of behaviors, cognitive deficits, and results enduring increase in hypothalamic-pituitary-adrenal axis activity (Weinstock, 2001). Epigenetic modifications are most commonly regulated by either direct methylation of DNA or by posttranslational modifications of histones. Epigenetic modulation of gene transcription may be affected by early-life adversity that may persistent into adulthood (Roth et al., 2009; Huang et al., 2012). In addition, epigenetic modulation of genes is related to both normal brain physiologic activity (Day and Sweatt, 2011) and neurodegeneration (Peleg et al., 2010). Thus, this project will investigate the epigenetic programming effects of prenatal stress offspring in both acute and chronic brain dysfunction. There will be 2 main groups for the first year, i.e. control and prenatal stress offspring group, and each group is further divided into acute and chronic stages, respectively. In addition, there will be 4 major groups in both second and third year in this proposal: control group, prenatal stress offspring group, prenatal stress offspring plus melatonin group, and prenatal stress offspring plus epigenetic modification drug group. The prenatal stressed pregnant rats undergo daily 6 hour of immobilization stress from gestational days 14 to 21. The end point of acute stage is postnatal day 11 that corresponding to a human neonate. The end point of chronic stage is postnatal day 120 that corresponding to a human adult. Through this proposal, the underlying molecular mechanisms involving epigenetic programming of brain dysfunction in prenatal stress offspring can be answered.

Project ID:PC10401-0213
External Project ID:NSC102-2314-B182-025-MY3