title: Perinatal dexamethasone-induced alterations in apoptosis within the hippocampus and paraventricular nucleus of the hypothalamus are influenced by age and sex.
abstract: Exposure to high levels of glucocorticoids (GCs) during development leads to long-term changes in hypothalamic-pituitary-adrenal (HPA) axis regulation, although little is known about the neural mechanisms that underlie these alterations. In this study, we investigated the effects of late gestational (days 18-22) or postnatal (days 4-6) administration of the GC receptor agonist dexamethasone (DEX) on an apoptosis marker in two brain regions critical to HPA axis regulation, the hippocampus and the hypothalamic paraventricular nucleus (PVN). One day after the final DEX injection, male and female rats were sacrificed, and brains were processed for immunohistochemical detection of cleaved caspase-3, an apoptotic cell death indicator. DEX increased cleaved caspase-3 immunoreactivity in the CA1 hippocampal region of both sexes following prenatal but not postnatal treatment. Prenatal DEX also increased caspase-3 immunoreactivity in the CA3 region, an elevation that tended to be greater in females. In contrast, postnatal DEX resulted in a much smaller, albeit significant, induction in CA3 caspase-3 compared with prenatal treatment. Quantitative real-time PCR analysis revealed that prenatal but not postnatal DEX-induced hippocampal cleaved caspase-3 correlated with elevated mRNA of the proapoptotic gene Bad. Few caspase-3-ir cells were identified within the PVN regardless of treatment age, although postnatal but not prenatal DEX increased this number. However, the region immediately surrounding the PVN (peri-PVN) showed significant increases in caspase-3-ir cells following pre- and postnatal DEX. Together these findings indicate that developmental GC exposure increases apoptosis in HPAaxis-associated brain regions in an age- and sex-dependent manner.
authors.affiliation: Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA. d.zuloaga@arizona.edu
authors.forename: Damian G
authors.initials: DG
authors.lastname: Zuloaga
authors.forename: David L
authors.initials: DL
authors.lastname: Carbone
authors.forename: Alicia
authors.initials: A
authors.lastname: Quihuis
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hiroi
authors.forename: David L
authors.initials: DL
authors.lastname: Chong
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Handa
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003907:Dexamethasone / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D009421:Nervous System Malformations / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012737:Sex Factors
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone