Hormone found in many animals, humans may induce birth

ANN ARBOR—Feeling trapped in a dead-end job? Stressed-out by a demanding boss? Harassed by whiny toddlers? Then consider the escape mechanism of the lowly tadpole. Sensing drought or a shrinking food supply in its home pond, the tadpole produces a hormone that accelerates its transformation into a toad or frog—allowing it to grow legs and walk away from a stressful environment.

In an article published in the current issue of Hormones and Behavior, University of Michigan biologist Robert J. Denver identifies this stress hormone, called corticotropin-releasing hormone or CRH. Found in all vertebrates from fish to mammals, increased levels of CRH have been shown to induce early birth in pregnant sheep and possibly humans, as well. “CRH appears to be the primary neuroregulatory hormone produced by all vertebrates under stress,” said Denver, an assistant professor of biology and assistant research scientist in the U-M Reproductive Sciences Program.

“CRH gives a larvae or fetus the ability to adapt to a changing environment by controlling the timing of its own development,” Denver said.

The metamorphosis from tadpole to toad is a complex process directed by the brain and involving interacting hormones from the pituitary, thyroid and adrenal glands. In his experiments, Denver discovered that CRH increased production of two key hormones in this process—thyroid stimulating hormone (TSH) and adreno-corticotropin hormone (ACTH). “The fact that CRH affects the thyroid, as well as the adrenal glands, was a surprise,” Denver said. “It opens a whole range of possibilities for CRH’s importance in the development of many organisms.”

Because CRH is present in and may regulate development of all vertebrates, it must have originated millions of years ago when vertebrate animal life first appeared in Earth’s ancient oceans, according to Denver. “Animals able to respond adaptively to stressful changes in the aquatic environment were more likely to survive and reproduce than those who couldn’t,” he said. “So the genes responsible for production of CRH and targets of CRH action were conserved or passed down through the generations as life evolved into different forms.”

Denver used western spadefoot toads in his laboratory experiments. These desert amphibians breed in rain-filled ponds that can dry up within days. To survive in such an unpredictable environment, adult toads have developed the ability to breed almost immediately after it rains. Tadpoles of some spadefoot toad species can complete their metamorphosis just eight days after they hatch.

When Denver gradually lowered the water level in the tadpoles’ lab aquariums, the tadpoles responded with increased production of CRH-like peptides 22 days after hatching. “Developmental change accelerated 25 to 26 days after hatching in the decreasing water group compared with the high water group,” Denver said. “None of the tadpoles kept in high water environments had metamorphosed at 36 days post-hatch when all tadpoles kept in a decreasing water environment had already changed into toads.”

Injecting the tadpoles with CRH-like peptides also accelerated their development, according to Denver, with significant body changes appearing just eight days after the injections started. Treating the tadpoles with CRH antagonists blocked the developmental response to pond drying.

While the developmental process is more complex in mammals than in amphibians, CRH appears to be just as important in regulating the transition from the womb’s aquatic environment to terrestrial life at birth. Studies with sheep show that fetal CRH “clearly plays a role in the timing of gestation,” Denver said. “Dramatic increases in human maternal and fetal blood CRH levels have been found in pregnancies complicated by medical conditions that result in pre-term birth.

“We tend to think of the womb as a benign, nurturing environment,” Denver added. “But it may not be so nurturing when it gets too tight in there or toxic waste products start to build up. If the developing fetus senses a deteriorating environment, producing CRH may be its way of accelerating the developmental changes it needs to survive outside the womb and how it signals the mother that it’s time to be born.”

Denver’s research is funded by the National Science Foundation and the U-M Office of the Vice President for Research. U-M undergraduates Marnie Phillips and Lewis Krain assisted with the research project.