Reconciling the nutritional and glucocorticoid hypotheses of fetal programming.
Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low-protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11β-HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11β-HSD2 activity near term by ∼25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11β-HSD2-independent mechanisms. Consistent with this, heterozygous 11β-HSD2(+/-) crosses showed that although both LP and 11β-HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11β-HSD2. Instead, the LP diet induced the fetal hypothalamic-pituitary-adrenal axis per se. Thus, maternal malnutrition and placental 11β-HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.
Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. elizabeth.cottrell@manchester.ac.uk
Elizabeth C
EC
Cottrell
Megan C
MC
Holmes
Dawn E
DE
Livingstone
Christopher J
CJ
Kenyon
Jonathan R
JR
Seckl
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D005260:Female; D047109:Fetal Development; D005938:Glucocorticoids / Q000502:physiology*; D017403:In Situ Hybridization; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D009752:Nutritional Status; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy
D017931:DNA Primers; D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D003345:Corticosterone