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A study of mice and human cells provides insight into how genes and environment can interact to induce preterm birth. The findings hint at new ways to treat women at risk for this condition. Very little is known about why some babies—about one in ten worldwide—are born prematurely. Many factors can contribute, including genetic predisposition, increased maternal age, infection and inflammation, and oxidative stress. The relative contributions of the various factors and their interactions are a black box. To begin to study such questions, Yasushi Hirota and his colleagues had previously developed a mouse model of preterm birth. These mice have a uterine deletion of Trp53, which encodes the tumor suppressor protein p53. About half of these mice undergo spontaneous preterm birth, a phenotype that has been traced to premature senescence of the decidua, the endometrial stromal tissue that is modified during gestation. Drugs that counteract decidual senescence, such as rapamycin, which targets the senescence-associated signaling molecule mTORC1, are effective in this mouse model. In the new study, Jeeyeon Cha et al. exposed these mice to a mild inflammatory insult with lipopolysaccharide (LPS), which provoked preterm birth in 100 percent of the animals. The combination of genetic and environmental insult affected the decidua and increased inflammation, as indicated by prostaglandin synthesis, and it also quelled production of progesterone by the ovary. Even a small amount of LPS trigged a drop in serum levels of progesterone, an effect only observed at high doses of LPS in wild-type animals. The researchers could prevent preterm birth in the mice without inducing adverse effects in the mothers or their offspring by treatment with both rapamycin and progesterone. Progesterone is sometimes used clinically to fend off preterm birth, though its effectiveness is limited and only some women benefit. The therapeutic potential of combinations of progesterone with other agents, such as rapamycin, may be a fruitful avenue of investigation. The researchers’ observations in human cells support this approach; for instance, they observed higher mTORC1 signaling in decidua of mothers who had given birth prematurely. Moreover, adding progesterone or rapamycin or both to cultured human decidual cells quelled the inflammatory response to LPS. Exactly how p53 deletion and LPS signaling interact to yield effects on the decidua and ovarian secretion of progesterone is, as yet, unclear. But the researchers suggest that a healthy decidua is key to proper birth timing, particularly since the decidua may in turn signal the ovary.

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