Oxytocin’s new role in delaying embryo development revealed

Oxytocin, a hormone already known for its role in childbirth, milk release, and mother-infant bonding, may have a newfound purpose in mammalian reproduction. In times of maternal stress, the hormone can delay an embryo's development for days to weeks after conception, a new study in rodents shows. According to the authors, the findings about so-called "diapause" may offer new insights into pregnancy and fertility issues faced by humans.

Led by researchers at NYU Langone Health, the study explored diapause, in which an embryo temporarily stops growing early in its development before it attaches to the lining of its mother's uterus, a key step leading to the formation of the placenta. Known to occur in species ranging from armadillos to giant pandas to seals, diapause is thought to have evolved to help expectant mothers preserve scarce resources (e.g., breast milk) by delaying birth until they have enough to successfully take care of their offspring.

Although recent studies have uncovered evidence that a form of diapause may occur in humans, the underlying mechanisms behind it have until now remained unclear.

The findings in mice showed that one type of stress that may cause diapause is milk production and release (lactation), as it requires a mother to expend bodily nutrients to both nursing, already-born pups and to those growing in the womb. The study revealed that the time between conception and birth (gestation) - typically 20 days for these animals – was delayed by about a week in pregnant rodents that were already nursing a litter.

Further, the research team showed that this delay was brought about by a rise in the production of oxytocin, levels of which are known to go up as a mother lactates. To confirm this role for the hormone, the researchers exposed mouse embryos in the lab to a single dose (either 1 microgram or 10 micrograms) of oxytocin, and found that even these small amounts delayed their implantation in the uterus by as much as three days. Beyond just pausing pregnancy, the team found that surges of the chemical large enough to that mimic the amounts and timing measured during nursing caused loss of pregnancy in the mice in nearly all cases.

Our findings shed light on the role of oxytocin in diapause. Because of this newfound connection, it is possible that abnormalities in the production of this hormone could play roles in infertility, premature or delayed birth, and miscarriage."

Moses Chao, PhD, study co-author, professor in the Departments of Cell Biology, Neuroscience, and Psychiatry, NYU Grossman School of Medicine

A report on the findings is publishing online March 5 in the journal Science Advances in a special issue focused on women's health.

In another part of the study, the team searched for a mechanism that would allow embryos to react to an oxytocin surge. They found that the hormone can bind to special proteins called receptors on the surface of a layer of cells known as the trophectoderm, which surrounds the early embryo and eventually forms the placenta.

Notably, mouse embryos that were genetically altered to disable oxytocin receptors lived long enough to implant into their mother's placenta at much lower rates than normal embryos. This suggests that the ability to respond to oxytocin spikes, and therefore go into diapause, is somehow important for the developing pups' survival, says Chao, who plans to examine this protective function in more detail.

"Despite being extremely common, infertility and developmental issues that can arise during pregnancy remain poorly understood and can have a lasting, devastating impact on parents and their children," said study senior author Robert Froemke, PhD. "Having a deeper understanding of the factors that contribute to these problems may allow experts to better address them in the future," added Froemke, the Skirball Professor of Genetics in the Department of Neuroscience at NYU Grossman School of Medicine.

Also a professor in the Department of Otolaryngology-Head and Neck Surgery, Froemke says that the researchers next plan to examine how cell growth gets turned back on after diapause. In addition, the team plans to explore how diapause may affect offsprings' health and development after birth, and determine whether and how their discoveries can inform reproductive medicine.

Froemke cautions that while the study results are promising, mice and humans - while both mammals - have significant differences in their reproductive processes. He adds that the current investigation did not assess the role that other pregnancy-related hormones, such as estrogen and progesterone, may play in diapause. Froemke is also a member of NYU Grossman School of Medicine's Institute for Translational Neuroscience.

Funding for the study was provided by National Institutes of Health grants T32MH019524, NS107616, and HD088411.

In addition to Moses and Froemke, other NYU Langone researchers involved in the study are Luisa Schuster, PhD; Habon Issa, PhD; Janaye Stephens, BS; Michael Cammer, MFA, MAT; Latika Khatri; Maria Alvarado-Torres; Jie Tong, PhD; Orlando Aristizábal, MPhil; Youssef Wadghiri, PhD; Sang Yong Kim, PhD; Catherine Pei-ju Lu, PhD; and Silvana Valtcheva, PhD. Jessica Minder, PhD, a former graduate student at NYU Langone and a current postdoctoral associate at the University of California, Berkeley, served as the study lead author.