title: The impact of maternal synthetic glucocorticoid administration in late pregnancy on fetal and early neonatal hypothalamic-pituitary-adrenal axes regulatory genes is dependent upon dose and gestational age at exposure.
abstract: In this study, we determined the gene and/or protein expression of hypothalamic-pituitary-adrenal (HPA) axis regulatory molecules following synthetic glucocorticoid exposures. Pregnant sheep received intramuscular saline or betamethasone (BET) injections at 104 (BET-1), 104 and 111(BET-2) or 104, 111 and 118 (BET-3) days of gestation (dG). Samples were collected at numerous time-points between 75 dG and 12 weeks postnatal age. In the BET-3 treatment group, fetal plasma cortisol levels were lower at 145 dG than controls and gestational length was lengthened significantly. The cortisol:adrenocorticotropic hormone (ACTH) ratio in fetal plasma of control and BET-3 fetuses rose significantly between132 and 145 dG, and remained elevated in lambs at 6 and 12 weeks of age; this rise was truncated at day 145 in fetuses of BET-3 treated mothers. After BET treatment, fetal and postnatal pituitary proopiomelanocortin mRNA levels were reduced from 109 dG to 12 weeks postnatal age; pituitary prohormone convertase 1 and 2 mRNA levels were reduced at 145 dG and postnatally; hypothalamic arginine vasopressin mRNA levels were lowered at all time-points, but corticotrophin-releasing hormone mRNA levels were reduced only in postnatal lambs. Maternal BET increased late fetal and/or postnatal adrenal mRNA levels of ACTH receptor and 3β hydroxysteroid dehydrogenase but decreased steroidogenic acute regulatory protein and P450 17-α hydroxylase. The altered mRNA levels of key HPA axis regulatory proteins after maternal BET injections suggests processes that may subserve long-term changes in HPA activity in later life after prenatal exposure to synthetic glucocorticoids.
authors: 1 School of Women's and Infants' Health, The University of Western Australia, WA, Australia.
authors: S
authors: S
authors: Li
authors: 1 School of Women's and Infants' Health, The University of Western Australia, WA, Australia.
authors: T J M
authors: TJ
authors: Moss
authors: 1 School of Women's and Infants' Health, The University of Western Australia, WA, Australia.
authors: I
authors: I
authors: Nitsos
authors: 4 Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada.
authors: S G
authors: SG
authors: Matthews
authors: 1 School of Women's and Infants' Health, The University of Western Australia, WA, Australia.
authors: J R G
authors: JR
authors: Challis
authors: 1 School of Women's and Infants' Health, The University of Western Australia, WA, Australia.
authors: J P
authors: JP
authors: Newnham
authors: 5 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.
authors: D M
authors: DM
authors: Sloboda
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001623:Betamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D018043:Receptors, Corticotropin / Q000378:metabolism; D012756:Sheep; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D005938:Glucocorticoids; D010750:Phosphoproteins; D018043:Receptors, Corticotropin; D000098682:Steroidogenic Acute Regulatory Protein; D001623:Betamethasone; D015096:3-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone