GOVERNMENT & POLICY
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FETAL ORIGINS OF DISEASE
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Efforts are under way to link CHEMICAL EXPOSURES in utero with adult disease
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A GROWING BODY of scien-
tific research suggests that exposure to chemical toxicants in the womb can lead to chronic health problems, including obesity, diabetes, heart disease, and cancer, later in life. Although scientists agree that the evidence is compelling, many of them are frustrated because such data aren’t being used in regulatory decision-making and risk assessment. To help bridge the gap between emerging scientific research and environmentalhealth regulatory decisions, a standing committee of the National Academies held a two-day workshop last month in Washington, D.C. The committee, along with a handful of invited toxicologists and risk assessors, debated whether predicting adult disease from in utero and postnatal indicators is ready for prime-time risk assessment. Researchers presented two case studies to demonstrate CRITICAL TIME how science is emerging in this processes include DNA methylaChemical exposures tion, histone modification, and area. One case study examined in the womb fetal origins of obesity, insulin the formation of microRNAs, all may increase resistance, and high blood pres- susceptibility to of which fine-tune gene expressure, and another investigated sion to help prepare an organism disease later in life. adult diseases associated with for what it will encounter later in utero exposure to arsenic. in life. The scientists showed that “It has long been accepted under- and overnutrition, intrauterine that our genes together with adult lifestyle growth restriction, and exposure to chemidetermine our phenotype and susceptibilcal toxicants and certain drugs in utero can ity to a whole range of chronic diseases,” lead to changes in gene expression, tissue noted Karen A. Lillycrop, a biochemist at function, and developmental pathways the University of Southampton, in Engthat increase susceptibility to various disland. “But there is now increasing evidence eases later in life. that the prenatal and early postnatal enviIn both case studies, epigenetics—the ronment also play a key role in determining processes that alter gene expression withour susceptibility to such diseases.” out changing the gene sequence—played a Scientists at the workshop showed key role in the development of disease. Such that epigenetic biomarkers can be used to WWW.CEN-ONLINE.ORG
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SHU T T ERSTO CK
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OTHER FACTORS besides nutrition also
are responsible for epigenetic changes. Bruce Blumberg, a developmental biologist at the University of California, Irvine, presented work from his lab showing that in utero exposure to obesogens—chemicals that stimulate fat storage—can lead to weight gain and obesity later in life. In particular, Blumberg showed that tributyltin binds to receptors that regulate hormonal control of fat cell development and lipid balance. The end result is increased expression of adipogenic pathway genes, increased stem cell differentiation into adipocytes, and obesity. “Diet and exercise are insufficient to explain the obesity epidemic, particularly in six-month-old babies,” Blumberg emphasized. “Prenatal obesogen exposure reprograms exposed animals to be fat,” he said. Many chemicals have been found to be obesogens, including prescription drugs and environmental contaminants, Blumberg noted. He pointed to data in the literature showing obesity correlated with exposure to the antidiabetic drugs Actos and Avandia, atypical antipsychotics, antidepressants, COX-2 inhibitors, environmental estrogens such as bisphenol A and perfluorinated octanoic acid, phthalates, nicotine, air pollution, benzo[a]pyrene, and fructose. “What we don’t know is how many obesogens are out there,” Blumberg stressed. “Is there just this small handful, hundreds, thousands? We don’t know the answer. We don’t know what the body burden is in people either. We don’t know what all the modes of action are.” In addition to obesity, the workshop
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explored fetal origins of other diseases such as heart disease and cancer. Several scientists presented data suggesting an association between these diseases and in utero exposure to arsenic. Michael P. Waalkes, a researcher in the National Toxicology Program’s inorganic toxicology group, reported that fetal exposure to inorganic arsenic in drinking water alters stem cell numbers and their activity, leading to cancer in mice. And once the cancer stem cells form, they are permanent, Waalkes noted. He showed that arsenic exposure causes decreased expression of the PTEN tumor suppressor gene, leading to an overabundance of cancer stem cells. Other epigenetic changes induced by arsenic exposure were revealed by J. Christopher States, a molecular biologist at the University of Louisville School of Medicine. States showed that fetal arsenic exposure accelerates and exacerbates atherogenesis—the formation of plaque in arteries—and leads to an increased risk of cardiovascular disease. He also showed that prenatal arsenic exposure leads to DNA methylation changes in the liver causing it to persistently overactivate inflammation pathways. Similarly, Joseph H. Graziano, a professor of environmental health sciences and pharmacology at Columbia University, explored the consequences of prenatal and postnatal exposure to arsenic in Bangladesh, where high levels of arsenic naturally contaminate groundwater used as drinking water. He too discovered altered DNA methylation and gene expression induced by arsenic. The affected genes are involved in inflammation, cell signaling, stress response, and apoptosis. IN GENERAL, participants at the work-
shop agreed that the evidence linking earlylife changes to disease outcomes in adults is pretty convincing. But many of them said more examples are needed before such science can be incorporated into regulatory decision-making and risk assessment. “While it seems reasonable that these changes would drive the later effects, the certainty that these are the cardinal causative pathways needs bolstering,” said Robert E. Chapin, a reproductive toxicologist with Pfizer. “And would these pathways, if measured early, report all the obesogens and carcinogens? How many different ways are there to get to the final outcome?” A similar point was brought up by WWW.CEN-ONLINE.ORG
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GOVERNMENT & POLICY
CHRISTO P H BO CK
Theodore Slotkin, a developmental neually help EPA and other agencies make rotoxicologist at Duke University Medical decisions, said Bruce Fowler, a toxicoloCenter. “The causes of obesity are many. gist at the Agency for Toxic Substances & Totally different mechanisms may have Disease Registry. Unless grant reviewers different epigenetic changes, and yet the start thinking about the practical outcomes disease outcome is the same,” he said. of the data, researchers will continue to “There isn’t the time and money to conpursue basic scientific interests first, he nect every chemical to every possible pointed out. outcome. From the point of view of the The Food & Drug Administration is regulators, without causal mechanisms, also interested in understanding the we are right back at square one.” long-term effects of early-life chemical Slotkin suggested that rather than looking at the most common outcomes, such as obesity and heart disease, researchers should look at the most uncommon outcomes. He pointed out that the connection between smoking and lung cancer was made in the 1930s “because lung cancer was a disease that never happened.” Many workshop participants said that they are frustrated because their results aren’t being used in risk assessments. “What kind of data do we PROGRAMMING LIFE Methyl need to produce that will exposures because many groups attached to DNA alter have the most impact in drugs can interfere with gene expression without risk assessment?” Blumdevelopmental pathways, changing the gene sequence. berg asked. said Deborah K. Hansen, “For science to be usea research biologist with ful, it has to answer speFDA’s National Center for cific questions that a risk manager wants Toxicological Research. But “if you interto know about,” said Ila Cote, a senior vene for one outcome, you can alter somescience adviser at the Environmental Prothing else that may end up being adverse,” tection Agency’s National Center for Enshe cautioned. vironmental Assessment. “What are the It remains to be seen how many chemiadverse effects, at what concentrations; cals to which children are exposed in the are subpopulations affected; and how cerwomb are responsible for causing or intain are the data?” creasing the susceptibility to disease later But Cote acknowledged that there are in life. And it is unlikely that regulatory also social and political barriers to getting agencies will use this emerging science in new science into risk assessments. “Lawrisk assessments any time soon. Nonetheyers would much rather you continue to less, despite their frustration, many scido it the way you’ve always done it than to entists are optimistic that they are on the make a shift,” she said. “Both the vigorous right path. discussions you can get in with stakehold“The chance to set up a process that ers and this requirement that whatever could actually help prevent many of your decisions are they have to stand up in our major current adulthood diseases court tend to make government scientists and increase improved outcomes for all pretty darn conservative.” kids—that’s got to be seen as the most Another problem has to do with getting compelling opportunity we’ve ever had,” funding for the type of work that regulaChapin remarked. “This is not an issue tory agencies such as EPA find useful. For of, ‘Should we do this?’ I think we’ve got example, the National Institutes of Health to at least look and see how prevalent the rarely funds experiments that could actueffects are.” ■ WWW.CEN-ONLINE.ORG
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