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

Agnes Wieczorek, Clara V. Perani, Mark Nixon, Miguel Constancia, Ionel Sandovici, Dimitra E. Zazara, Gustavo Leone, Ming Zhi Zhang, Petra C. Arck, María Emilia Solano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)E109-E120
JournalAmerican Journal of Physiology-Endocrinology and Metabolism
Issue number1
Early online date16 Apr 2019
Publication statusPublished - 1 Jul 2019

Keywords / Materials (for Non-textual outputs)

  • 11β-hydroxysteroid dehydrogenases
  • Antenatal stress
  • Corticosteroidbinding globulin
  • Fetus
  • Glucocorticoids
  • Placental transporters


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