We have presented data from a number of studies demonstrating that developmental exposure to environmental pollutants leads to persistent changes in immune function. When examined, these changes in function contribute to deregulated immune responses following infection. However, even for the best characterized developmental immunotoxicants, animal models examining susceptibility to infectious disease are generally just emerging. In the example of dioxin-like compounds, epidemiological data show that children with developmental exposure have increased susceptibility to infections. While only a few animal models have been developed to address this question, they support the epidemiological data showing defects in multiple facets of the immune response to infection. More research using animal models that faithfully study aspects of host defenses against human pathogens are needed. These models should include viral, bacterial and parasitic infections, and consider pathogens that elicit acute and resolving disease as well as those that result in latent illness. Moreover, studies that seek to better understand how developmental exposures impact innate and inflammatory responses to infection are sorely needed. These studies will, collectively, help to elucidate the mechanisms underlying this increased susceptibility, and will provide an essential foundation on which to test the developmental immunotoxicity of emerging agents. Moreover, the widespread use of these models will become especially important as we move forward to consider the effect of developmental exposure to mixtures of environmental insults.
The studies presented here strongly suggest that early life insults can reprogram normal immune development, leading to persistent functional alterations. The mechanisms for this have not yet been elucidated, but changes in epigenetic regulation are thought to play a large part [141
]. Epigenetic mechanisms involve modifications to DNA and chromatin to regulate gene activation and silencing, and play a role in cell proliferation and differentiation [142
]. In the cases of arsenic and pesticides, several studies suggest that exposure to these environmental agents alters epigenetic regulatory mechanisms [99
]. Furthermore, changes in epigenetic mechanisms have been linked to early life exposure to BPA, although not in the context of studies of immune function [144
]. These findings are intriguing, but more research is needed to determine if alterations in epigenetic regulatory mechanisms are directly linked to changes in immune function. The role that epigenetic mechanisms play in the normal physiological development of the immune system is not fully known; therefore, discoveries about how developmental exposures disrupt epigenetic programming during immune system development will help us to understand the normal programming of the immune system.
While the studies reviewed here focus on how developmental exposure alters vulnerability to infectious disease, early life exposure to environmental insults can lead to a number of adverse health outcomes in adulthood, such as cardiovascular disease, stoke, obesity, and cancer [10
]. Indeed, to truly appreciate the impact of environmental exposures on health and disease, we need to think very broadly about how environmental exposures influence the etiology of complex diseases. Using infectious diseases as an example shows that this link can be direct, such as a decreased ability to destroy the pathogen. However, the consequences can be indirect too. Developmental exposures that lead to an immune system with a diminished capacity to fight infection may also reduce the body’s ability to detect and destroy tumor cells, thereby increasing risk of cancer. The recently released President’s Cancer Panel 2008–2009 Annual Report highlights the growing, yet limited body of research linking suspected environmental factors with immune dysfunction and the development of cancer and other disease [148
]. Thus, decreases in immune responses not only mean infections persist longer, which has an immediate impact on the overall wellness of society, but there is an increased risk of cancer. Furthermore, some environmental agents may increase inflammatory responses. While this is a normal and important response to infection, deregulated inflammation has been shown to exacerbate infection-associated pathology and increase cancer [18
]. Thus, a better understanding of how environmental factors reprogram immune development will lead to a more in depth appreciation of the general mechanisms underlying developmentally-programmed diseases. Additionally, these studies will provide a new framework for considering the developmental impact of other agents, such as alcohol consumption, pharmaceuticals, or even maternal diet and/or stress [149
]. As the field moves forward, new findings will also lead to the discovery of novel immunomodulatory strategies and interventions to reduce the impact of environmental factors on human health.
In spite of tremendous improvements in health care, infectious diseases continue to be a substantial burden on human health. As we seek to prevent disease and improve therapeutic treatments, we need to better understand the factors that contribute to the persistence of these agents as threats to global health. Indeed, disease prevention and the translation of basic research into better health, opportunities identified as important efforts for the future by the National Institutes of Health, can be achieved in this field with the continued identification of environmental factors with adverse effects on the developing immune system and the subsequent elimination of those exposures [150
]. To accomplish this goal, it is clear that we need to determine precisely how early life exposures to pollutants impact the developing immune system. There are many excellent rodent models in which this endeavor can be successfully accomplished. Moreover, there are numerous opportunities in which these studies can and ought to be integrated with epidemiological studies that include tests of immune function. In this manner, rodent-based, mechanistic studies and population-based epidemiological studies can be woven together and efficiently translated into effective public health and prevention strategies.