Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta. Am J Physiol Endocrinol Metab 2019 Jul 01;317(1):E109-E120
Date
04/17/2019Pubmed ID
30990748DOI
10.1152/ajpendo.00551.2018Scopus ID
2-s2.0-85068546357 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-specific effect. However, the underlying mechanisms remain unknown. Maternal glucocorticoids can be elevated by stress and are potential candidates to mediate the effects of stress on the offspring sex-specifically. A comprehensive evaluation of dynamic maternal and placental mechanisms modulating fetal glucocorticoid exposure upon maternal stress was long overdue. Here, we addressed this gap in knowledge by investigating sex-specific responses to midgestational stress in mice. We observed increased levels of maternal corticosterone, the main glucocorticoid in rodents, along with higher corticosteroid-binding globulin levels at midgestation in C57Bl/6 dams exposed to sound stress. This resulted in elevated corticosterone in female fetuses, whereas male offspring were unaffected. We identified that increased placental expression of the glucocorticoid-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; Hsd11b2 gene) and ATP-binding cassette transporters, which mediate glucocorticoid efflux toward maternal circulation, protect male offspring from maternal glucocorticoid surges. We generated mice with an Hsd11b2 placental-specific disruption (Hsd11b2PKO) and observed moderately elevated corticosterone levels in offspring, along with increased body weight. Subsequently, we assessed downstream glucocorticoid receptors and observed a sex-specific differential modulation of placental Tsc22d3 expression, which encodes the glucocorticoid-induced leucine zipper protein in response to stress. Taken together, our observations highlight the existence of unique and well-orchestrated mechanisms that control glucocorticoid transfer, exposure, and metabolism in the mouse placenta, pinpointing toward the existence of sex-specific fetal glucocorticoid exposure windows during gestation in mice.
Author List
Wieczorek A, Perani CV, Nixon M, Constancia M, Sandovici I, Zazara DE, Leone G, Zhang MZ, Arck PC, Solano MEAuthor
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
11-beta-Hydroxysteroid Dehydrogenase Type 2Animals
Aromatase
Corticosterone
Female
Fetus
Glucocorticoids
Male
Mice
Mice, Inbred C57BL
Placenta
Pregnancy
Pregnancy Complications
Receptors, Glucocorticoid
Sex Characteristics
Stress, Psychological
