Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology.
Glucocorticoid overexposure in utero may underlie the association between low birth weight and subsequent development of common cardiovascular and metabolic pathologies. Previously, we have shown that prenatal dexamethasone (DEX) exposure in rat reduces birth weight and programs the hypothalamic-pituitary axis and fasting and postprandial hyperglycemia in adult males and hypertension in adult males and females. This study aimed to determine 1) whether there were gender differences in prenatal DEX-programmed offspring, and 2) whether the renin-angiotensin system (RAS) plays a role in the programming of hypertension. Rats exposed to DEX in utero (100 microg.kg(-1).day(-1) from embryonic days 14-21) were of lower birth weight (by 12%, P < 0.01) and displayed full catch-up growth within the first month of postnatal life. DEX-treated male offspring in adulthood selectively displayed elevated plasma adrenocorticotropic hormone (by 221%) and corticosterone (by 188%, P < 0.05), postprandial insulin-glucose ratios (by 100%, P < 0.05), and hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (by 38%, P < 0.05). Conversely, DEX-programmed females were hypertensive (by 11%, P < 0.05), with elevated hepatic angiotensinogen mRNA expression (by 9%, P < 0.05), plasma angiotensinogen (by 61%, P < 0.05), and renin activity (by 88%, P < 0.05). These findings demonstrate that prenatal glucocorticoids program adulthood cardiovascular and metabolic physiology in a gender-specific pattern, and that an activated RAS may in part underlie the hypertension associated with prenatal DEX programming.
O'Regan
D
D
Endocrinology Unit, Molecular Medicine Centre, School of Molecular and Clinical Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK.
Kenyon
C J
CJ
Seckl
J R
JR
Holmes
M C
MC
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000187:drug effects; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012727:Sex Characteristics
D005938:Glucocorticoids; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone