title: 5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats.
abstract: Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.
authors.affiliation: The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, United Kingdom, p.j.brunton@ed.ac.uk.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Brunton
authors.affiliation: Centro Infant, Biomedical Research Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, 90610-000, Brazil.
authors.forename: Marcio V
authors.initials: MV
authors.lastname: Donadio
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Song T
authors.initials: ST
authors.lastname: Yao
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Greenwood
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Jonathan R
authors.identifier: http://orcid.org/0000-0001-5150-6624
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, BS1 3NY, United Kingdom, Department of Physiology, University of Malaya, Kuala Lumpur, Malaysia 50603, and.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-2946-0353
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000235:genetics / Q000378:metabolism; D015113:Androstane-3,17-diol / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000254:growth & development; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000254:growth & development; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy; D011280:Pregnanolone / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D017552:Solitary Nucleus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D015113:Androstane-3,17-diol; D011280:Pregnanolone; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: 3β-androstanediol; 5α-reductase; adenoviral vector; allopregnanolone; estrogen receptor-β, prenatal stress