Yale researchers have discovered a way to identify cells damaged from prenatal exposure to harmful agents — such as drugs, radiation and heat — that become more vulnerable to stress after birth.
Led by medical school professor Pasko Rakic and neuroscience research scientist at Children’s Research Institute Masaaki Torii, the study presents an in utero model that explains the development of psychiatric disorders and other stress-induced diseases later in life. These findings can be applied to provide early detection and treatment in disease pathogenesis within an individual, according to Rakic. The research was published in Proceedings of the National Academy of Science on Jan. 25.
“For example, of 10 soldiers exposed to the atrocities of war, eight of them may return and live normal lives, but two consequently suffer from post-traumatic stress disorder,” Rakic said. “We hoped to explain this phenomenon and understand why some are more vulnerable to stress.”
When a fetus is exposed to harmful agents that could affect development of the brain in utero, cells protect themselves by forming heat shock factor 1 as a defense mechanism, said Kazue Hashimoto-Torii, a neuroscience research scientist at Children’s Research Institute and first author on the study.
Even though this factor helps the cell to survive, it stays in the cell, Hashimoto-Torii added. If too much of the factor is generated, the cell may die. Although it looks normal, when the cell is exposed again to harmful agents, it is weaker and more vulnerable.
“From small amounts [of exposure to harmful agents], the cells will survive because of the HSF1,” Rakic said. “However, it turns out that later on, they are more susceptible to these sources of stress — whether physical or psychological.”
For example, pregnant women can harm their fetuses by taking antidepressants or drugs of abuse, including marijuana and cocaine. This is a large crisis in downtown New Haven, said Rakic, making this study particularly applicable.
The researchers developed a method to recognize the presence of HSF1, allowing them to identify neurons that survived prenatal exposure but became more vulnerable after birth.
A neutral red fluorescent protein was linked to the heat shock factor in their mouse model, Hashimoto-Torii explained. The pregnant mice were exposed to ethanol once a day, activating the HSF1 response. After then exposing the mice to environmental stressors, the researchers used the fluorescent label to observe how much of the heat shock factor was produced by the embryos.
“The normal mouse, which was not exposed previously, was exposed to the harmful agent and nothing happened,” Rakic said. “However, the mouse that was already vulnerable — exposed to the agent before birth — got more sick than the others.”
These results are especially significant, because previously damaged cells seem normal and work normally until you expose them to these agents, Rakic explained.
This transgenic reporter mouse model allows the researchers to test the effect of different amounts of the harmful agent on fetal cells.
“We think there is a threshold and we are looking to see what that is,” Rakic said. For example, when referring to fetal alcohol syndrome, scientists mean drinking much more than one glass of wine a day, he added.
However, the investigators are limited by individual variations. Even the mice, which are inbred and thus more similar, have different levels of tolerance and vulnerability to the agents.
Returning to his earlier example, Rakic noted that their research could be used to lower the incidence of PTSD in veterans. When potential soldiers try to join the army, the vulnerability of their cells can be tested and those with highly vulnerable cells — those who were exposed to drugs in utero — should not join.
Hashimoto-Torii also introduced a related paper by the group that was accepted the week of Feb. 6 by Nature Communications. The study explained that HSF1 is expressed in a random manner, which is what causes the high variability and unpredictability of negative effects from prenatal exposure to harmful agents.
Many other labs have asked to use the mouse model, which the researchers will share, according to Rakic. Scientists can now explore the possibility of adding other factors and designing drugs to help the cells fight these sources of stress.
The research was funded by the National Institutes of Health and the Kavli Institute for Neuroscience at Yale.