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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

Published online by Cambridge University Press:  25 September 2012

S. Li ,
T. J. M. Moss ,
I. Nitsos ,
S. G. Matthews ,
J. R. G. Challis ,
J. P. Newnham  and
D. M. Sloboda
S. Li*
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Women and Infants Research Foundation of Western Australia, Perth, Australia
T. J. M. Moss
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, VIC, Australia
I. Nitsos
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, VIC, Australia
S. G. Matthews
Affiliation:
Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada
J. R. G. Challis
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada
J. P. Newnham
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Women and Infants Research Foundation of Western Australia, Perth, Australia
D. M. Sloboda
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
*
Address for correspondence: S. Li, School of Women's and Infants’ Health, The University of Western Australia, M550, Crawley, WA 6009, Australia. Email [email protected]
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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.

Keywords

adrenalfetusglucocorticoidhypothalamic–pituitary–adrenal axisprogramming
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 1 , February 2013 , pp. 77 - 89
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012 

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