Chem. Res. Toxicol. 2006, 19, 1121-1124
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PerspectiVe Future of ToxicologysA Shift in the Paradigm: Focus on Human Disease David A. Schwartz* National Institute of EnVironmental Health Sciences and National Toxicology Program, P.O. Box 12233, Research Triangle Park, North Carolina 27709 ReceiVed June 30, 2006
Contents Introduction Environmental Exposures as Probes for Biological Processes Gene-Environment and Environment-Epigenome Interactions in Disease Disease-First Paradigm for Environmental Health Research Exposure Assessment Research Teams of the Future Summary
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Introduction I predict that toxicology in the 21st century will be vastly different than toxicology in the 20th century. Toxicology in the 20th century relied on Congress, regulatory agencies, and courts of law as its logical partners in translating toxicological findings into public health practice. My vision for toxicology in the 21st century would add new partners to this paradigmsbasic biologists, translational and clinical researchers, physicians, and biomedical research centers. This shift will occur due to three major changes. The first is that traditional toxicology has reached its apex, with the major research accomplishmentssidentification of disease links with important pollutants such as polycyclic aromatic hydrocarbons (PAHs), ozone, and metalssalready incorporated into public law. Further accomplishments are possible only at the margins of these basic and important achievements. Second, new research opportunities now exist that can propel toxicology from a predominantly descriptive discipline to one that operates at a mechanistic level, as well as one that can identify the importance of individual susceptibilities in disease causation. Third, environmental exposures can be an important tool for simplifying complex disease processes in ways that can provide greater insight in the mechanistic and genetic underpinnings of these diseases. Currently, the symptoms used for diagnosis of important chronic diseases such as asthma, arthritis, and neurodegeneration provide a very broad “umbrella” for diagnostic purposes, lacking the specificity required for meaningful study. Numerous phenotypes occur within these broad disease categories, and environmental exposures offer a * To whom correspondence should be addressed. Tel: 919-541-3201. Fax: 919-541-2260. E-mail:
[email protected].
way to narrow the pathophysiologic phenotypes in ways that help elucidate the genetics and biology underlying a particular condition.
Environmental Exposures as Probes for Biological Processes Certainly the ability of toxicologists to provide insight into the molecular and genetic processes of biological organisms predates the 21st century. Serving as major landmarks of how environmental exposures can increase understanding of physiologic processes are studies of the metabolic activation of PAHs that began in the late 1960s (1) and accelerated with the discovery that 2,3,7,8-tetrachlorodibenzo-p-dioxin was a much more potent inducer of enzymes involved in these pathways. This body of work led to the identification of the aryl hydrocarbon receptor (AHR), which was found to regulate the genes involved in many metabolic activation processes. Outgrowths of this research have provided insight into transcription, translation, and signal transduction pathways and have important implications for many disease processes, including oxidative stress (2). This early work has also led to the identification of the PAS superfamily of proteins that play important roles in responses to environmental stress, normal physiological processes, and development (3). In fact, defects in these proteins have been associated with tumor promotion, teratogenesis, and immune disorders. The study of the PAS superfamily provides a host of opportunities in applying toxicology to biomedicine, including the development of biomarkers of exposure, defining genetic susceptibility, and providing personalized treatment with therapeutics. Thus, this work serves to illustrate the tremendous potential of investments in environmental health research in understanding basic biological processes and in providing useful applications to disease pathogenesis.
Gene-Environment and Environment-Epigenome Interactions in Disease Individual variation in response to environmental agents is a major impediment to understanding the environmental contribution to disease. These variations in response arise from different susceptibilities, including genetic susceptibilities. With the mapping of the human genome and the powerful research tools arising from its study, environmental health scientists will finally be able to make significant discoveries of the gene-gene and gene-environment interactions that influence both health and disease development. There is no doubting the pivotal role of the gene-environment axis in regulating our health.
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In addition to these structural changes being transmitted to the daughter cells of an organism, it is becoming increasingly apparent that in some cases these changes can be transmitted through subsequent generations. In studies of male mice exposed in utero to either an antiandrogenic compound (vinclozolin) or an estrogenic compound (methoxychlor), treated animals exhibited decreased spermatogenic capacity and increased infertility. Surprisingly, these effects were passed through four generations of mice (4). The effects on reproduction correlated with altered DNA methylation patterns in the germ line, indicating an epigenetic effect. Diet is another important environmental agent that acts on the epigenome. Using a heterozygous mouse Agouti gene model (Avy), where the gene controls coat color, maternal diet during gestation has been shown to affect the coat color of offspring (ranging from yellow to brown) in ways that provides a visual indication of DNA methylation. Moreover, differences in methylation status among Agouti mice also affect the risk of developing other diseases such as obesity and cancer. Dietary components used in these studies were vitamin B12, folic acid, choline, betaine (5), and the soy component, genistein (6). Important epigenetic effects are not limited to the gestational period of life. Environmental agents appear to influence the epigenome throughout life. In studies of identical twins, ages 3-74, it was found that younger twin pairs had similar DNA methylation and histone acetylation patterns. Older twins, particularly if they had different lifestyles or environments, had much different patterns. These researchers found that there were four times as many differentially expressed genes between a pair of 50 year old twins as was found between a pair of 3 year old twins (7). The study of the epigenome is challenging. It is a dynamic system, constantly in flux. Particularly problematical, it does not have the useful “anchor” of a defined nucleic acid sequence such as has been used in the more straightforward study of genetic contributions to disease. Nonetheless, the epigenome promises to be one of the most compelling opportunities for understanding the environmental components of health and disease. As such, it is an area of research in which toxicologists must creatively engage.
Disease-First Paradigm for Environmental Health Research Figure 1. Repression of transcription is one route by which epigenetic mechanisms can adversely impact health. Adapted from ref 15.
Toxicologists of the future, however, will need to be engaged in the study of environmental influences that extend beyond DNA sequence. Epigenetic mechanisms, which can alter gene activity without changing the DNA sequence, are being linked to a variety of illnesses, including cancer, cognitive dysfunction, and respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral diseases. Intriguingly, the “epigenome” appears to be very sensitive to environmental agents. Thus, exploration of the environment-epigenome axis will provide some of the most exciting research opportunities of the 21st century. Epigenetic processes are natural and essential to biological functions. They include DNA methylation, acetylation of the histone proteins in chromatin, imprinting, and posttranslational modifications (one epigenetic mechanism is illustrated in Figure 1).
To remain relevant, environmental health research must move beyond the broad brush strokes of identifying environmental risk factors in disease that have been used in the past. Largescale epidemiology studies such as the Six-Cities (8) and 24Cities Studies (9) have provided important information on disease risks to the general population. They have not, however, been able to provide the equally important information on disease etiology, susceptibility, and disease pathogenesis that could lead to targeted improvement in the health of individuals. This statement is not to imply that public health did not benefit from air pollution standards arising from these studies. It did, but the benefits accrue only to circumstances where pollutant levels decreased. The initial findings of these studies should be a springboard to further explore important processes in lung pathology that can then be translated into public health practices beyond the regulatory arena. My own research in asthma has shown how environmental exposures can be used to identify different pathophysiologic phenotypes, rendering the genetics and biology of this condition more amenable to study. Asthma is a complex disease, involving many exposures and linked to multiple loci throughout the
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genome. By focusing on endotoxin-induced asthma, we were able to demonstrate that polymorphisms in the TLR4 gene, the primary receptor for endotoxin, were associated with a blunted response to endotoxin (10). However, this fundamental finding led to the observation that a blunted innate immune response affected the development of several diseases (11), including atherosclerosis, sepsis, and lung transplant rejection. Thus, specific environmental triggers can serve to narrow the pathophysiological phenotype of a complex human disease and lead to the understanding of the basic biological processes that not only cause that disease but also apply to many different diseases. Toxicology needs to strategically shift its focus to better integrate knowledge generated by environmental health research with the broad spectrum of medical research. A systematic way of implementing this “disease-first” approach would be to select the most important diseases to study based on public health burden, define the molecular changes that are involved in pathogenesis, and then link these biological responses to environmental agents, including lifestyle and dietary factors, that lead to disease (12). Following this disease-first approach would move our field in the direction of reducing the burden of human disease that still remains, despite major improvements in regulatory control of many toxicants.
Exposure Assessment Although current genomic tools have greatly increased our ability to assess individual genetic susceptibility, current exposure assessment tools do not provide the same level of precision or sophistication when we need to assess individual environmental exposures. Lacking precise measures of exposure greatly complicates the ability of toxicologists to study why certain people develop disease and others do not. To determine how our environment, diet, and physical activity contribute to illness, new technologies are needed. Toxicologists will need to harness emerging technologies such as those arising from genomics, transcriptomics, proteomics, metabolomics, and epigenetics, as well as nanotechnology, molecular imaging, and sensor technology, to develop new tools. These tools could measure the biological response to multiple environmental exposures while they are occurring or long after they have occurred. Ideally, these new technologies will generate measurements of personal exposure at multiple points in the continuum from exposure to disease. The goal would be to improve our ability to study this process in its early stages before clinical signs arise. To move the field in this direction, the Secretary of Health and Human Services and the Director of the National Institutes of Health (NIH) have created the Gene and Environment Initiative. This initiative will focus on the role that both genetic variations and environmental exposures play in the development of complex human diseases. Importantly, a component of this initiative will be devoted to improving the precision and utility of exposure assessment toolssboth personal environmental sensors and homeostatic/biological responses to various forms of environmental stress. These personalized measures of exposure will be combined with genomic information to decipher environmental and genetic risk factors for disease development and progression. Ultimately, this knowledge will enable researchers and clinicians to devise ways to prevent, diagnose, and treat common diseases.
Research Teams of the Future The ambitious goals for toxicology listed above require not only technological innovation but also innovation in training
and in research teams. Clearly, we need to find ways to recruit more physician-scientists, as well as to provide more clinical research training for doctoral toxicologists. Research teams of the future will need to have more collaborations across disciplines in order to provide the multiple types of expertise to address the complex research questions of the 21st century. Details of how these training needs can be met and of the new research initiatives of the National Institute of Environmental Health Sciences (NIEHS) are outlined in the most recent Strategic Plan, New Frontiers in Environmental Sciences and Human Health, 2006-2011 (13). This document can be found at http://www.niehs.nih.gov/external/plan2006/home.htm.
Summary In the last century, toxicology has provided some of the major triumphs of public health. As an example, the Environmental Protection Agency estimates that in the year 2010, air pollution reductions arising from the Clean Air Act will prevent 23000 Americans from dying prematurely from air pollutant exposure, avoid 1700000 incidences of asthma attacks and aggravation of chronic asthma, and avert 22000 respiratory-related hospital admissions, 42000 cardiovascular hospital admissions, and 4800 emergency room visits for asthma (14). Much of the science upon which these regulations were based was provided by toxicologists, proving the value of environmental health science in improving the nation’s health. Moving into the 21st century, toxicology will need to expand beyond the regulatory and legislative arena where its findings are translated into public health impact. New advances in genomic, epigenomic, and exposure technologies will provide the impetus to move this field into medical settings. Here, the future of toxicology will reside with its ability to use environmental exposures as a tool to study the early pathogenesis of disease and to help the nation develop early interventions for the multiple chronic diseases that continue to burden our health system. To comment on this and other Future of Toxicology perspectives, please visit our Perspectives Open Forum at http:// pubs.acs.org/journals/crtoec/openforum.
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1124 Chem. Res. Toxicol., Vol. 19, No. 9, 2006 (8) Dockery, D. W., Pope, A., Xu, X., Spengler, J. D., Ware, J. H., Fay, M. E., Ferris, B. G., and Speizer, F. E. (1993) An association between air pollution and mortality in six U.S. cities. New Engl. J. Med. 329, 1753-1759. (9) Raizenne, M., Neas, L. M., Damokosh, A. I., Dockery, D. W., Spengler, J. D., Koutrakis, P., Ware, J. H., and Speizer, F. E. (1996) Health effects of acid aerosols on North American children: Pulmonary function. EnViron. Health Perspect. 104, 506-514. (10) Arbour, N. C., Lorenz, E., Schutte, B. C., Zabner, J., Kline, J. N., Jones, M., Frees, K., Watt, J. L., and Schwartz, D. A. (2000) TLR4 mutation is associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25, 187-191. (11) Cook, D. N., Pisetsky, D. S., and Schwartz, D. A. (2004). Toll-like receptors in the pathogenesis of human disease. Nat. Immunol. 5, 975979.
Schwartz (12) Wilson, S. H., and Schwartz, D. A. (2006) Disease-first: A new paradigm for environmental health science research. EnViron. Health Perspect. 114, A398. (13) NIEHS (2006) New Frontiers in EnVironmental Sciences and Human Health: 2006-2011 Strategic Plan, NIH Publication 2006-218, Public Health Service, U.S. Department of Health and Human Services, Washington, DC. (14) Environmental Protection Agency (1999) Final Report to Congress on Benefits and Costs of the Clean Air Act, 1990 to 2010, EPA 410R-99-001, EPA, Washington, DC. (15) Weinhold, B. (2006) Epigenetics: The science of change. EnViron. Health Perspect. 114, A160-A167.
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