Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta
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Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta. / Wieczorek, Agnes; Perani, Clara V; Nixon, Mark; Constancia, Miguel; Sandovici, Ionel; Zazara, Dimitra E; Leone, Gustavo; Zhang, Ming-Zhi; Arck, Petra C; Solano, Maria Emilia.
In: AM J PHYSIOL-ENDOC M, Vol. 317, No. 1, 01.07.2019, p. E109-E120.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta
AU - Wieczorek, Agnes
AU - Perani, Clara V
AU - Nixon, Mark
AU - Constancia, Miguel
AU - Sandovici, Ionel
AU - Zazara, Dimitra E
AU - Leone, Gustavo
AU - Zhang, Ming-Zhi
AU - Arck, Petra C
AU - Solano, Maria Emilia
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1152/ajpendo.00551.2018
DO - 10.1152/ajpendo.00551.2018
M3 - SCORING: Journal article
C2 - 30990748
VL - 317
SP - E109-E120
JO - AM J PHYSIOL-ENDOC M
JF - AM J PHYSIOL-ENDOC M
SN - 0193-1849
IS - 1
ER -