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Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions
Jeeyeon Cha, … , Sudhansu K. Dey, Yasushi Hirota
Jeeyeon Cha, … , Sudhansu K. Dey, Yasushi Hirota
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):4063-4075. https://doi.org/10.1172/JCI70098.
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Research Article Reproductive biology Article has an altmetric score of 46

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

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Abstract

There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P4), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P4 may help reduce the incidence of preterm birth in high-risk women.

Authors

Jeeyeon Cha, Amanda Bartos, Mahiro Egashira, Hirofumi Haraguchi, Tomoko Saito-Fujita, Emma Leishman, Heather Bradshaw, Sudhansu K. Dey, Yasushi Hirota

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Figure 5

Levels of IL-6 and IL-8 and expression of PTGS2 and AKR1C1 in cultured human term decidual cells following exposure to LPS.

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Levels of IL-6 and IL-8 and expression of PTGS2 and AKR1C1 in cultured h...
(A and B) Decidual cells isolated from human term placentae showed increased secretion of IL-6 and IL-8 into culture media when exposed to LPS for 24 hours in culture; the levels were attenuated by treatment with rapamycin and/or P4 (mean ± SEM; *P < 0.05 compared with vehicle-treated control; **P < 0.05 compared with LPS-treated cells). ELISA for IL-6 (n = 8) and IL-8 (n = 7) were repeated using independent samples. (C) qPCR results showed dose-dependent increases in decidual PTGS2 expression levels 6 hours after LPS exposure. Experiments were repeated in 3 independent samples (mean ± SEM; *P < 0.05 compared with control). (D) Western blotting showed increases in decidual COX2 levels. One representative blot from 3 independent experiments is shown. (E) qPCR showed dose-dependent increases in decidual AKR1C1 expression levels 6 hours after LPS exposure. Experiments were repeated in 3 independent samples (mean ± SEM; *P < 0.05 compared with control).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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