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Linking Early Environmental Exposures to Adult Diseases

All complex diseases have beenshown to have both a geneticand environmental component.A growing body of research is beginning to suggest that manychronic adult diseases and disorders, including asthma, diabetes andobesity, may be traced back toexposures that occur during

development. Research supported by the National Institute ofEnvironmental Health Sciences(NIEHS) and others are ndingthat in utero or neonatal exposuresto environmental, dietary and behavioral changes may makepeople more susceptible todiseases later in life.

The Developmental Hypothesis

The reason people think that

susceptibility to disease may be established during pre-birthis due to both human anddevelopmental toxicology

RESEARCH FINDINGSIt would be difficult to follow humans for60 years to see if they develop diseasesbased on what they were exposed tobefore birth. For this reason, almost alldata showing developmental exposuresleading to increased susceptibility todisease later in life have been done inanimal models. With the use of new technologies, however, researchers areable to examine gene expression changesin tissues during development and tolink them to onset of disease later in life,providing a framework to understand theimpact that environmental factors maybe having on programming the body forfuture diseases. Some human studieshave corroborated what we have seen inanimals, including the long-term effectsof Diethylstilbestrol (DES), smoking andsome heavy metals like mercury.

Diethylstilbestrol (DES), a medicationused from the 1940s–1970s to prevent

miscarriages in high risk pregnancies,is the best proof of principle supporting the developmental basis of adult diseasehypothesis. DES has been shown to causean increased risk of vaginal, uterine andbreast cancer in humans and animalmodels. It has also been shown to causeuterine fibroids in mouse models andDES-exposed women. NIEHS researchersalso found that the adverse effects ofDES in mice can be passed to subsequent

generations, even though they were notdirectly exposed. Researchers have alsolinked developmental exposures to avariety of environmental chemicals toincreased susceptibility to infertility,

studies in animals. Researcherslike David Barker, for example, putforward the “fetal programming ordevelopmental basis of health anddisease” hypothesis, after ndingan association between low birthweight and coronary heart disease.Barker found that a malnourishedfetus will adapt its metabolism in

the womb to survive until birth, but these changes then increasea person’s risk of disease later inlife, such as heart disease, diabetesand possibly cancer. This idea thatthe human fetus is vulnerable tooutside inuences, and that whatwomen eat and perhaps even breathe during pregnancy canimpact children into adulthoodand possibly even futuregenerations as well, is a growing

area of research. Little is currentlyknown about the mechanisms bywhich fetal insults lead to alteredprogramming and to diseaselater in life.

PO Box 12233 • Research Triangle Park, NC 27709

Phone: 919-541-3345 • www.niehs.nih.gov

October 2008

National Institutes of Health

U.S. Department of Health and Human Services

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  endometriosis, uterine fibroids,obesity, neurodegenerative diseasesand cardiovascular and lung diseases.There are also some data suggesting that infertility due to environmental

exposures during development canbe transmitted up to four generationsafter exposure. These studies indicate that a person’s fertility may evenbe the result of what her greatgrandmother was exposed to whileshe was in utero , suggesting again that what a woman may be exposed to during her pregnancy can affect thefertility of her children, grandchildrenand great grandchildren. Mechanismsinvolved in the transmission of

 the altered programming due toexposures during development havebeen shown to involve epigeneticevents or changes in gene function that occur without a change in theDNA sequence.

 

Timing and Duration of Exposure

From NIH-supported researchwe know that there are criticalperiods of vulnerability in the

developmental process. This iswhen cell growth is occurring,tissues are forming, and the body is still without an immunesystem, blood brain barrier,DNA repair system or anydetoxication system to riditself of chemicals or to protectitself, making the timing andduration of environmentalexposures critical. Thedevelopmental period isalso the most sensitive timefor the development of theepigenetic system. This systemcontrols gene expression intissues and these changes can be transmitted across generations.Thus, changes in the epigeneticsystem provide a mechanism forenvironmental exposures to haveeffects long after the exposure.

The level of response to a givendose may change dramaticallydepending on the stage of

development at which a fetusis exposed. All of this new researchis indicating that a “four-century-oldparadigm, which states that ‘thedose makes the poison,’ needs to be expanded to emphasize that ‘thetiming makes the poison’ as well.

Even seemingly minor exposuresduring early development can lead

 to functional deficits and increased

disease risks later in life. 

Early Prevention is Critical

If the “developmental basis ofdisease” hypothesis proves true,then there is an even greater needto change our focus from treatingdiseases after they are detectedto prevention. Doctors have longhoped for ways to prevent orreverse health problems beforethey become chronic diseases.Given that many disorders ariseduring fetal development fromdisruptions in the dynamic butstill poorly understood interplayof genes, environment and nutrition,prevention may have to occurdecades before a symptomeven appears.

NIEHS Research Directions

NIEHS is committed tounderstanding the link betweenearly environmental exposuresand adult diseases. To accomplishthis, NIEHS will:

• Continue to lead a trans-NIH to determine the factors, suchas the environment, that regulateor turn genes on and off. TheRoadmap Epigenomic Program will produce a map of theepigenomes of normal humancells, to serve as a reference fordiseased cells, allowing us tounderstand how environmentalfactors can change patterns relatedto the link between exposuresand disease.

• Encourage the developmentof more sensitive exposureassessments.

• Encourage the use of storedhuman samples obtained at birth,to link developmental exposuresto diseases in humans later in life

• Work with others to dene biomarkers of exposure and

effect in rodent models thatcan be translated to humans,to indicate potential increasein susceptibility to diseaselater in life.

• Continue to play a leadershiprole in promoting partnerships

 between scientists and communitymembers, to study environmentalhealth concerns, and translate theresults to the public, including

encouraging more participation by members of the media andcommunication experts.

For more information

on the National Institute of

Environmental Health Sciences,

please go to our website at :

http://www.niehs.nih.gov/ 

National Institute of Environmental Health Sciences

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