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The Journal of Neuroscience, September 3, 2008, 28(36):9055-9065; doi:10.1523/JNEUROSCI.1424-08.2008

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Behavioral/Systems/Cognitive
Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy

Bridget R. Mueller and Tracy L. Bale

Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Tracy L. Bale, 201E School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104. Email: tbale{at}vet.upenn.edu

Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPAR (peroxisome proliferator-activated receptor ), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3 (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.

Key words: placenta; neurodevelopment; DNA methylation; prenatal stress; depression; affective disorders

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Received April 3, 2008; revised June 30, 2008; accepted July 23, 2008.

Correspondence should be addressed to Dr. Tracy L. Bale, 201E School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104. Email: tbale{at}vet.upenn.edu

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