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Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.

ABSTRACT: Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5-deficient (Fkbp5-/-) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5+/+ mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5, decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor (Oxtr) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress-induced FKBP51. In contrast, Fkbp5-/- mice exhibit prolonged gestation and are completely resistant to maternal stress-induced PTB and labor-inducing uterine changes detected in stressed Fkbp5+/+ mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress-induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB.

SUBMITTER: Guzeloglu-Kayisli O

PROVIDER: S-EPMC7980401 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.

Guzeloglu-Kayisli Ozlem O Semerci Nihan N Guo Xiaofang X Larsen Kellie K Ozmen Asli A Arlier Sefa S Mutluay Duygu D Nwabuobi Chinedu C Sipe Bradley B Buhimschi Irina I Buhimschi Catalin C Schatz Frederick F Kayisli Umit A UA Lockwood Charles J CJ

Proceedings of the National Academy of Sciences of the United States of America 20210301 11

Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5-deficient (Fkbp5-/-) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR ...[more]

PMID: 33836562

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Project description:ImportancePreterm birth is a major contributor to neonatal morbidity and mortality, and considerable differences exist in rates of preterm birth among maternal racial and ethnic groups. Emerging evidence suggests pregnant individuals born outside the US have fewer obstetric complications than those born in the US, but the intersection of maternal nativity with race and ethnicity for preterm birth is not well studied.ObjectiveTo determine if there is an association between maternal nativity and preterm birth rates among nulliparous individuals, and whether that association differs by self-reported race and ethnicity of the pregnant individual.Design, setting, and participantsThis was a nationwide, cross-sectional study conducted using National Center for Health Statistics birth registration records for 8 590 988 nulliparous individuals aged 15 to 44 years with singleton live births in the US from 2014 to 2019. Data were analyzed from March to May 2022.ExposuresMaternal nativity (non-US-born compared with US-born individuals as the reference, wherein US-born was defined as born within 1 of the 50 US states or Washington, DC) in the overall sample and stratified by self-reported ethnicity and race, including non-Hispanic Asian and disaggregated Asian subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Pacific Islander, Vietnamese, and other Asian), non-Hispanic Black, Hispanic and disaggregated Hispanic subgroups (Cuban, Mexican, Puerto Rican, and other Hispanic), and non-Hispanic White.Main outcomes and measuresThe primary outcome was preterm birth (<37 weeks of gestation) and the secondary outcome was very preterm birth (<32 weeks of gestation).ResultsOf 8 590 988 pregnant individuals included (mean [SD] age at delivery, 28.3 [5.8] years in non-US-born individuals and 26.2 [5.7] years in US-born individuals; 159 497 [2.3%] US-born and 552 938 [31.2%] non-US-born individuals self-identified as Asian or Pacific Islander, 1 050 367 [15.4%] US-born and 178 898 [10.1%] non-US-born individuals were non-Hispanic Black, 1 100 337 [16.1%] US-born and 711 699 [40.2%] non-US-born individuals were of Hispanic origin, and 4 512 294 [66.1%] US-born and 328 205 [18.5%] non-US-born individuals were non-Hispanic White), age-standardized rates of preterm birth were lower among non-US-born individuals compared with US-born individuals (10.2%; 95% CI, 10.2-10.3 vs 10.9%; 95% CI, 10.9-11.0) with an adjusted odds ratio (aOR) of 0.90 (95% CI, 0.89-0.90). The greatest relative difference was observed among Japanese individuals (aOR, 0.69; 95% CI, 0.60-0.79) and non-Hispanic Black individuals (aOR, 0.74; 0.73-0.76) individuals. Non-US-born Pacific Islander individuals experienced higher preterm birth rates compared with US-born Pacific Islander individuals (aOR, 1.15; 95% CI, 1.04-1.27). Puerto Rican individuals born in Puerto Rico compared with those born in US states or Washington, DC, also had higher preterm birth rates (aOR, 1.07; 95% CI, 1.03-1.12).Conclusions and relevanceOverall preterm birth rates were lower among non-US-born individuals compared with US-born individuals. However, there was substantial heterogeneity in preterm birth rates across maternal racial and ethnic groups, particularly among disaggregated Asian and Hispanic subgroups.

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Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.

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Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.

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