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

Area of Science:

• Reproductive Biology
• Genetics
• Immunology

Background:

• Preterm birth affects over 15 million newborns annually.
• Gene-environment interactions are implicated as a key factor in preterm birth.
• Understanding these interactions is crucial for developing effective interventions.

Purpose of the Study:

• To investigate the role of gene-environment interactions in preterm birth using a mouse model.
• To identify potential therapeutic targets for preventing preterm birth.

Main Methods:

• Generated a mouse model with uterine deletion of Trp53, leading to spontaneous preterm birth.
• Exposed Trp53-deficient mice to lipopolysaccharide (LPS) to simulate inflammatory insult.
• Treated mice with rapamycin (mTORC1 inhibitor) and progesterone (P4) to assess rescue effects.
• Analyzed decidual senescence, mTORC1 activity, and COX2 signaling in mice and human samples.

Main Results:

• Trp53 deficiency caused spontaneous preterm birth (approx. 50%) linked to decidual senescence, increased mTORC1, and COX2 signaling.
• Inflammatory insult (LPS) in Trp53-deficient mice resulted in 100% preterm birth.
• Combined treatment with rapamycin and progesterone rescued preterm birth in LPS-exposed mice without adverse effects.
• Decidual senescence with increased mTORC1 and COX2 signaling was observed in women with preterm birth.

Conclusions:

• Gene-environment interactions, specifically inflammation superimposed on genetic predisposition, significantly increase preterm birth incidence.
• Combined rapamycin and progesterone treatment shows promise for preventing preterm birth in high-risk individuals.
• Targeting decidual and ovarian pathways offers a novel therapeutic approach for preterm birth.