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Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta.

Accepted version
Peer-reviewed

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Authors

Wieczorek, Agnes 
Perani, Clara V 
Nixon, Mark 

Abstract

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.

Description

Keywords

11β-hydroxysteroid dehydrogenases, antenatal stress, corticosteroid-binding globulin, fetus, glucocorticoids, placental transporters, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Animals, Aromatase, Corticosterone, Female, Fetus, Glucocorticoids, Male, Mice, Mice, Inbred C57BL, Placenta, Pregnancy, Pregnancy Complications, Receptors, Glucocorticoid, Sex Characteristics, Stress, Psychological

Journal Title

Am J Physiol Endocrinol Metab

Conference Name

Journal ISSN

0193-1849
1522-1555

Volume Title

317

Publisher

American Physiological Society

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UU_12012/5)
MRC (MC_UU_00014/4)
Medical Research Council (MC_PC_12012)