Developmental Origins of Disease
"If it’s a gene that is impacted by the environmental chemical, people put the genetic cause first
and view the environmental consideration as a secondary component of the problem.
Research might show that a genetic component counts for only 50 or 30 percent of all
cases of disease, but we never ask about the remaining 50 or 70 percent."
Jerry Heindel, PhD, currently serves as a scientist with the Population Health Branch of the National Institute of Environmental Health Sciences, where he develops and administers the NIEHS grants program in endocrine disruptors, developmental basis of diseases, reproductive toxicology, and obesity. He also coordinates the virtual consortium of researchers studying the effects of bisphenol A. He previously held faculty positions at the University of Texas Medical School at Houston and the University of Mississippi. He earned his PhD at the University of Michigan, in biochemistry.
Interviewed by Amy Coombs, April 2014
Can you explain what is meant by the developmental origins of disease?
Disease can show up at any time in life, and the fact that you are 60 and get cancer doesn’t mean the cancer actually started at the point of diagnosis or even at the time that symptoms arose. Over the last ten years or so, we have learned that many diseases start in utero or in the fetus even though the disease doesn’t show up until later in life. For some the disease may appear when they are two or three years old or when they are teenagers. For others it might be later.
How did you become interested in this field?
My responsibility is to help fund research that answers questions about the effects of chemicals on the endocrine system and human reproductive health. We initially focused on teratology. In this field scientists would give a toxicant to a pregnant animal and then look for low birth weight or birth defects in the offspring. There were others studying the effects of chemicals on adults, but researchers had a hard time linking exposure in the adult to disease in the adult.
We would try to link exposures at age 35, for example, to cancer at age 40, and it couldn’t be done. Around this time scientist linked malnutrition during development to low birth weight and adult heart problems. This raised awareness that adult disease could be related to environmental influences during the fetal period, even if the disease would not show up until later in life. Since not all tissues fully develop during the fetal period, we now focus on development as the sensitive window. The sensitive period can extend beyond the womb while the tissue is developing during childhood or possibly even puberty. This led us to start a program designed to address the developmental origins of disease focusing not on nutrition but on environmental pollutants. .We now study developmental exposure and then follow up through the entire lifespan.
Toxicology has a history of looking at the acute, short-term effects of exposures. What should we be doing to assess the long-term effects of exposures, particularly in critical windows of development?
There are tissues in adults that are very sensitive, but in general, if you remove exposure to a toxicant, the effects will go away in an adult. If the toxicant reduces the sperm count, you can sometimes reverse this effect by removing exposure. The same thing it true with insulin sensitivity and sugar. These are acute adult exposures. In contrast, developmental exposures can last forever. The effect remains long after the exposure is gone, and there are many critical windows of sensitivity. The problem is that we don’t know how many critical windows there are or when each occurs. We know fetal development and pregnancy are times of sensitivity, but early childhood, puberty, and old age are also possible periods of developmental concern.
The effects of exposures on fetal somatic cells and fetal germ cells may be quite different, could you explain what those differences might be?
If you affect a somatic cell during development, the changes may persist forever as the cell will continue to divide over the course of a lifetime. However when the animal dies, the effect dies. In contrast, if you affect the germ cells, they are responsible for making the next generation, so the impacts may continue in future generations.
The research field appears to be bifurcated into those who study ambient environmental exposures (air pollution, BPA, etc), and those who study pharmaceutical exposures. How do these fields consider endocrine disruption differently?
Drugs are specifically designed to regulate specific pathways. They are supposed to either up regulate or down regulate a pathway to protect the patient, who knows what they are taking and when. There is a clear expected outcome that can be used as a basis for comparison if something goes wrong. This is all regulated by the Food and Drug Administration.
On the other hand, we have a very different case with environmental exposures. We often don’t know where environmental chemicals come from, and we don’t know when we are exposed. Thus, we don’t know what the outcomes will be.
You have said, "A bad start lasts a lifetime." Can you elaborate on that?
If you are exposed to certain chemicals during development, then the effects of those chemicals can often last a lifetime. The chemical is gone, but the changes caused by the chemical persist. The diseases can show up throughout your lifespan.
What do you think are the three most urgent unaddressed or under-addressed issues facing public health research today? What are the gaps?
One major problem is that scientists are not always working together to address the topic. For example, from my view, 90 percent of the world is focused on genetics and the way that genes cause disease. We know environmental exposure also plays a role. But there is little focus on the role of environment and little interaction between the fields
A related issue is that there is a lack of focus on disease prevention. We do know that reducing stress, improving diet, and limiting exposure to environmental chemicals can help reduce the chance of disease over a lifetime. This is why we use the phrase ‘developmental origins of health and disease.’ If you do a good job during development, it can impact your health, and it is a lot better to prevent something than try to stop the disease once you have it.
Endocrine disruption can have dramatically different impacts at different stages of development: germline, embryo, fetus, infant, childhood, adult. Can you provide some examples of these differential impacts?
Interviewed by Amy Coombs, April 2014
Can you explain what is meant by the developmental origins of disease?
Disease can show up at any time in life, and the fact that you are 60 and get cancer doesn’t mean the cancer actually started at the point of diagnosis or even at the time that symptoms arose. Over the last ten years or so, we have learned that many diseases start in utero or in the fetus even though the disease doesn’t show up until later in life. For some the disease may appear when they are two or three years old or when they are teenagers. For others it might be later.
How did you become interested in this field?
My responsibility is to help fund research that answers questions about the effects of chemicals on the endocrine system and human reproductive health. We initially focused on teratology. In this field scientists would give a toxicant to a pregnant animal and then look for low birth weight or birth defects in the offspring. There were others studying the effects of chemicals on adults, but researchers had a hard time linking exposure in the adult to disease in the adult.
We would try to link exposures at age 35, for example, to cancer at age 40, and it couldn’t be done. Around this time scientist linked malnutrition during development to low birth weight and adult heart problems. This raised awareness that adult disease could be related to environmental influences during the fetal period, even if the disease would not show up until later in life. Since not all tissues fully develop during the fetal period, we now focus on development as the sensitive window. The sensitive period can extend beyond the womb while the tissue is developing during childhood or possibly even puberty. This led us to start a program designed to address the developmental origins of disease focusing not on nutrition but on environmental pollutants. .We now study developmental exposure and then follow up through the entire lifespan.
Toxicology has a history of looking at the acute, short-term effects of exposures. What should we be doing to assess the long-term effects of exposures, particularly in critical windows of development?
There are tissues in adults that are very sensitive, but in general, if you remove exposure to a toxicant, the effects will go away in an adult. If the toxicant reduces the sperm count, you can sometimes reverse this effect by removing exposure. The same thing it true with insulin sensitivity and sugar. These are acute adult exposures. In contrast, developmental exposures can last forever. The effect remains long after the exposure is gone, and there are many critical windows of sensitivity. The problem is that we don’t know how many critical windows there are or when each occurs. We know fetal development and pregnancy are times of sensitivity, but early childhood, puberty, and old age are also possible periods of developmental concern.
The effects of exposures on fetal somatic cells and fetal germ cells may be quite different, could you explain what those differences might be?
If you affect a somatic cell during development, the changes may persist forever as the cell will continue to divide over the course of a lifetime. However when the animal dies, the effect dies. In contrast, if you affect the germ cells, they are responsible for making the next generation, so the impacts may continue in future generations.
The research field appears to be bifurcated into those who study ambient environmental exposures (air pollution, BPA, etc), and those who study pharmaceutical exposures. How do these fields consider endocrine disruption differently?
Drugs are specifically designed to regulate specific pathways. They are supposed to either up regulate or down regulate a pathway to protect the patient, who knows what they are taking and when. There is a clear expected outcome that can be used as a basis for comparison if something goes wrong. This is all regulated by the Food and Drug Administration.
On the other hand, we have a very different case with environmental exposures. We often don’t know where environmental chemicals come from, and we don’t know when we are exposed. Thus, we don’t know what the outcomes will be.
You have said, "A bad start lasts a lifetime." Can you elaborate on that?
If you are exposed to certain chemicals during development, then the effects of those chemicals can often last a lifetime. The chemical is gone, but the changes caused by the chemical persist. The diseases can show up throughout your lifespan.
What do you think are the three most urgent unaddressed or under-addressed issues facing public health research today? What are the gaps?
One major problem is that scientists are not always working together to address the topic. For example, from my view, 90 percent of the world is focused on genetics and the way that genes cause disease. We know environmental exposure also plays a role. But there is little focus on the role of environment and little interaction between the fields
A related issue is that there is a lack of focus on disease prevention. We do know that reducing stress, improving diet, and limiting exposure to environmental chemicals can help reduce the chance of disease over a lifetime. This is why we use the phrase ‘developmental origins of health and disease.’ If you do a good job during development, it can impact your health, and it is a lot better to prevent something than try to stop the disease once you have it.
Endocrine disruption can have dramatically different impacts at different stages of development: germline, embryo, fetus, infant, childhood, adult. Can you provide some examples of these differential impacts?
It takes a higher exposure to make an adult sick than a child—at least usually. If you remove the chemical exposure, the effect goes away—even if an individual adult doesn’t recover after the chemical is removed, the larger trend at the population level is that you see an effect after exposure but not in control cases when there is no exposure.
If you have exposure at any other time, say during embryonic or fetal development, or during infancy or childhood, you may see an effect that lasts a lifetime. At least it’s more likely that you will see a long-term consequence. Of course the effect will depend on the chemical and the tissue it effects as well as the window of exposure. If the chemical impacts the heart, it is probably going to have the greatest impact during embryonic development when the heart forms. This occurs very early on. If the chemical is impacting the reproductive system, it might have the greatest impact a little later when the fetus is developing germ cells. If obesity and diabetes are a concern, then exposure in utero and during infancy is a top consideration.
Anything else you would like to tell us about gene-environment interaction in critical windows of development?
The key thing is that we need to think more broadly about disease. We need to get people to think beyond genetics. If it’s a gene that is impacted by the environmental chemical, people put the genetic cause first and view the environmental consideration as a secondary component of the problem. Research might show that a genetic component counts for only 50 or 30 percent of all cases of disease, but we never ask about the remaining 50 or 70 percent. If there is an environmental component, we need to look at the impacts over the course of life due to exposure during different developmental windows. Once we can show developmental origins and impacts on the germline, we need to look for effects on children, grandchildren and even great-grandchildren. We are still getting data on the impacts to great-grandchildren due to exposure in animal studies, but it appears to be a very important impact.
If you have exposure at any other time, say during embryonic or fetal development, or during infancy or childhood, you may see an effect that lasts a lifetime. At least it’s more likely that you will see a long-term consequence. Of course the effect will depend on the chemical and the tissue it effects as well as the window of exposure. If the chemical impacts the heart, it is probably going to have the greatest impact during embryonic development when the heart forms. This occurs very early on. If the chemical is impacting the reproductive system, it might have the greatest impact a little later when the fetus is developing germ cells. If obesity and diabetes are a concern, then exposure in utero and during infancy is a top consideration.
Anything else you would like to tell us about gene-environment interaction in critical windows of development?
The key thing is that we need to think more broadly about disease. We need to get people to think beyond genetics. If it’s a gene that is impacted by the environmental chemical, people put the genetic cause first and view the environmental consideration as a secondary component of the problem. Research might show that a genetic component counts for only 50 or 30 percent of all cases of disease, but we never ask about the remaining 50 or 70 percent. If there is an environmental component, we need to look at the impacts over the course of life due to exposure during different developmental windows. Once we can show developmental origins and impacts on the germline, we need to look for effects on children, grandchildren and even great-grandchildren. We are still getting data on the impacts to great-grandchildren due to exposure in animal studies, but it appears to be a very important impact.