Environmental toxicants and the developing immune system: a missing link in the global battle against infectious disease?

Abstract

There is now compelling evidence that developmental exposure to chemicals from our environment contributes to disease later in life, with animal models supporting this concept in reproductive, metabolic, and neurodegenerative diseases. In contrast, data regarding how developmental exposures impact the susceptibility of the immune system to functional alterations later in life are surprisingly scant. Given that the immune system forms an integrated network that detects and destroys invading pathogens and cancer cells, it provides the body’s first line of defense. Thus, the consequences of early-life exposures that reduce immune function are profound. This review summarizes available data for pollutants such as cigarette smoke and dioxin-like compounds, which consistently support the idea that developmental exposures critically impact the immune system. These findings suggest that exposure to common chemicals from our daily environment represent overlooked contributors to the fact that infectious diseases remain among the top five causes of death worldwide.

1.1 Environmental exposures may impact susceptibility to infectious disease

Infectious disease remains a major global health concern; in fact, respiratory infections are the third most common cause of death worldwide, leading to over four million deaths each year. In low income countries, four of the top five leading causes of death are due to infectious disease [1] (see Figure 1). But perhaps what is even more striking is that in high income countries infectious diseases, in particular lower respiratory tract infections, remain among the top five causes of death. These deaths are occurring even with significant advances in medical research and therapeutics, raising the question: what factors contribute to vulnerability to infectious disease? Even when considering the same type of infection, there is a wide spectrum of clinical outcomes for infected individuals, ranging from sub-clinical to mild to severe and, at times, lethal. Genetics and age impact the susceptibility to and severity of infection, but other factors that influence infection rates and disease pathophysiology are not fully understood [2, 3]. Several studies have suggested that environmental pollutants, such as pesticides, air pollution and cigarette smoke contribute to poorer clinical outcomes after infection [4–8]. In this review, we explore the emerging idea that maternal and early-life exposures to common environmental contaminants have a critical but underappreciated impact on susceptibility to infection later in life.

Figure 1. Lower respiratory tract infections are among the top five causes of death worldwide.

Data are adapted from a recent WHO report on the global burden of disease [1]. Data are based on information from 2004, in which an estimated 59 million people died, with 4.2 million deaths attributed to lower respiratory tract infections, and at least another 7 million deaths due to other infectious diseases. The primary differences between affluent and poor countries with respect to antecedents of mortality are that in low income countries, the major causes of death are infectious diseases, and over 1/3 of all deaths are children under 14 years of age. In middle income countries, chronic diseases begin to contribute to major causes of death; however tuberculosis remains a major source of morbidity and mortality. In high income countries, nearly half the population lives to 70 years of age and chronic illnesses predominate as major causes of death; although lower respiratory tract infections persist among the top 5 killers even in the world’s most affluent nations.

1.2 Developmental exposure to environmental agents impacts adult health

The developmental origin of health and disease concept, which is also referred to as the Barker hypothesis and the fetal basis of adult diseases, holds that environmental signals influence development and thereby alter health later in life [9]. Information about the maternal environment is communicated to the fetus transplacentally, and to the infant via lactation, thereby instructing fetal and early-life development. Insults during this period can lead to subtle alterations in development that permanently affect function. This concept has been demonstrated for a number of diseases, as exposure to pollutants or even alterations in the maternal diet have been associated with increased risk of cardiovascular disease, stroke, obesity, and cancer later in life [10–12]. Although it has received less attention, environmental agents also influence the development and programming of the immune system. Proper immune development is critically important, as even slight changes can decrease resistance to infectious disease, reduce vaccine efficacy, and diminish tumor surveillance. Imbalances in immune function can also enhance responsiveness to non-pathogenic antigens, as is the case in autoimmune disease and hypersensitivity reactions. Furthermore, it is now appreciated that immune deregulation underlies the pathophysiology of many chronic diseases; thus, there is tremendous impetus to understand how the early life environment affects the programming of the developing immune system [13].

1.3 Immune system development is an intricate process

Although the length of gestation differs in mice and humans, the process of immune development is quite similar, sharing the same sites of ontogeny, regulatory factors, and requirement for postnatal development. For example, in both species, development of the immune system involves a coordinated series of events beginning early in gestation and continuing into the postnatal period [14–16]. All leukocyte lineages arise from a small population of pluripotent hematopoietic stem cells (HSCs), and the primary site of hematopoiesis changes with developmental stage. HSCs undergo a process of self-renewal, and also differentiate into lineage-specific precursors: common lymphocyte precursors (CLPs) or common myeloid precursors (CMPs). CLPs give rise to T and B lymphocytes and natural killer (NK) cells, whereas macrophages, neutrophils, and other leukocyte lineages are derived from CMPs. Although many details of the development of the immune system have been elucidated, it is not fully known how environmental factors alter immune development. Moreover, due to this long and intricate period of development, early life environmental insults have the potential to alter normal immune development, leading to persistent alterations in function, which are not appreciated until adulthood.

1.4 Proper immune function is critical for fighting infection and preventing cancer

As is the case for immune system development, many aspects of immune function are similar in humans and mice. A well-tuned immune system is required to recognize pathogens and fight infection. In humans and mice, immune cells are continuously made and circulate throughout the body. Working in an orchestrated manner, leukocytes are responsible for executing an appropriate immune response. Their function can be measured experimentally by assessing their response to antigenic challenge, such as proliferation, trafficking, cytolytic activity, or their ability to produce the appropriate antibodies or cytokines. Deregulation of any one of these aspects of immune function could lead to an impaired ability to mount an immune response, increasing susceptibility to infection. On the other hand, an overactive immune response could exacerbate pathology through the excessive damage of healthy tissue. Clearly, a proper balance of immune function is critical. It is also important to bear in mind that the immune system is responsible for detecting and destroying cancerous cells and preventing tumor growth. Furthermore, infectious agents and infection-associated inflammation are among the major causes of cancer, with as many as 15% of cancer cases resulting from infections [17, 18]. Thus, subtle changes in immune regulation that perturb immune function have far-reaching health consequences as they can directly impact susceptibility to infections as well as increase vulnerability to cancer.

1.5 Evidence that developmental exposure to environmental contaminants influences susceptibility to infectious disease

The similarities between immune system development and function in humans and mice make mice an appropriate model for studying the long-term effects of developmental immunotoxicants, as they provide a framework for predicting potential outcomes of developmental exposures in humans [19]. In the following sections, we review human and animal data indicating that early life exposure to pollutants leads to increased susceptibility to infectious disease and cancer later in life. Knowing that pollutants can cross the placenta and be passed to infants via lactation, we present data from epidemiological and animal studies that have investigated the long-term impact of developmental exposure on immune function. Specifically, data from developmental exposures to dioxin, polychlorinated biphenyls, polycyclic aromatic hydrocarbons, cigarette smoke, metals, pesticides and a few agents of emerging concern are presented in the following sections. These examples provide insight into how early life exposure to environmental factors alters immune function later in life. Emerging evidence that epigenetic mechanisms are altered by developmental exposure is explored as a possible mechanism of immune system reprogramming, and gaps in knowledge are identified.

2. TCDD, PCBs and PAHs

Exposure to persistent organic pollutants and their affects on human health continues to be a major health concern. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), also known as dioxin, is a byproduct of numerous manufacturing processes, and can be released by the incineration of municipal and medical waste. Polychlorinated biphenyls (PCBs) are chemically very stable, and while this property made them useful as coolants and lubricants in electrical equipment, it has led to their continued presence in the environment more than 30 years after their production stopped. Polycyclic aromatic hydrocarbons (PAHs) are formed from the incomplete combustion of many types of organic matter, including fuel, tobacco and garbage. All three of these classes of compounds are ubiquitous environmental contaminants to which humans are regularly exposed. Moreover, these chemicals have been shown to cross the placenta and are excreted into breast milk [20–22], indicating that human exposure occurs during development. Furthermore, TCDD, as well as many other dioxins, PCBs and PAHs are agonists for the aryl hydrocarbon receptor (AhR), an environmental sensor that plays a role in development [23]. TCDD is one of the most commonly used environmental agents for studying the link between AhR and immunotoxicity because of its high affinity and specificity for the AhR. While most of the animal studies use TCDD as a model developmental immunotoxicant, epidemiological data have demonstrated that early life exposure to AhR ligands, including dioxins and PCBs, leads to altered immune function in children [24–31].

2.1 Developmental exposure to TCDD leads to persistent changes in immune function in rodents

Not only is TCDD one of the best studied immunotoxicants, but the theory that maternal and early life exposure to environmental chemicals impacts the developing immune system originated from studies of TCDD conducted over 30 years ago. In these studies, Vos and Moore demonstrated that administering TCDD to pregnant rodents altered immune parameters in their offspring [32]. This work laid the foundation for the concept of developmental immunotoxicology. Subsequent research has further characterized the effects of developmental exposure to TCDD in rodent models, demonstrating that early life exposure to TCDD alters the functional capacity of the offspring’s immune system. For example, impaired lymphocyte functions, including reduction in the proliferative response to mitogens, decreased delayed-type hypersensitivity (DTH) responses, and reduced cytotoxic T lymphocyte (CTL) responses have been reported [32–36]. While maternal or perinatal doses with higher levels of TCDD led to thymic atrophy [32–35, 37–39] and alterations in subpopulations of lymphocyte maturing in the thymus [34, 35, 37–39], these effects on cellularity were transient, resolving within a few weeks after birth. In contrast, alterations in immune function are long lasting and detected into adulthood [36, 40, 41]. Furthermore, persistent functional changes were observed at a maternal dose of TCDD at which no changes in the cellularity of the primary or secondary immune organs were observed [40], suggesting that functional changes are not simply due to altered immune organ cellularity.

Emerging animal data highlight how persistent changes in immune function can increase disease susceptibility. Sugita-Konishi et. al. showed that in mice developmentally exposed to TCDD, there was an increased level of bacteria present following infection with Listeria monocytogenes [41]. Likewise, exposing pregnant mice to TCDD impaired the offsprings’ host responses to influenza virus infection, as demonstrated by a reduction of effector lymphocyte clonal expansion, IFNγ production, and virus-specific antibody production [40, 42]. The decreased T lymphocyte response to influenza virus infection could be transferred with bone marrow cells, demonstrating the developmental exposure to TCDD directly affects the hematopoietic cell population [43].

While many PCBs and PAHs have not been as extensively examined for their immunotoxic effects following developmental exposure in animal models, the epidemiological evidence reviewed below highlights their potential to alter immune function. Collectively, these findings suggest that the AhR pathway plays a critical role in the development of the immune system, as inappropriate AhR signaling by these environmental agents alters normal immune development. Further work is needed to elucidate the mechanism by which exposure to these pollutants leads to a persistent alteration in function, and to carefully sort out the contribution of AhR-mediated and non-AhR-mediated impact of these chemicals.

2.2 Increased incidence of infections correlates with children’s early life exposure to TCDD, PCBs and PAHs

A growing number of studies have investigated the impact of early life exposure to dioxins and PCBs on children’s health, providing evidence that developmental exposure causes alterations in immune function. A few studies suggest that minor changes in relative amounts of peripheral immune cells can result from early life exposures [25, 26, 28, 44–47], and in a cohort of Slovakian children, higher perinatal exposure to PCBs correlated with decreased thymic size, as determined from an ultrasound measurement of thymic index [48]. However, as demonstrated in the animal model of developmental exposure to TCDD, it is the ability of these pollutants to impact immune function that is most striking. Increased incidences of respiratory and ear infections, cough, and sore throat were observed in children with higher early life exposure to dioxins, PCBs and PAHs [25–31]. Further, studies in the Faroe Islands and the Netherlands demonstrated that increased developmental PCB exposure correlated with reduced antibody response to vaccination [24, 30], although no change in antibody response was seen in a cohort of Slovakian infants [49]. Cancer susceptibility may also be increased in offspring of mothers exposed to PAHs, as indicated by the presence of PAH-DNA adducts in cord blood [50–52]. These studies clearly demonstrate the ability of dioxins and related persistent organic compounds to have a long-lasting and deleterious impact on immune function.

3. Cigarette Smoke

Another environmental agent to which developing fetuses and children are frequently exposed is cigarette smoke. While the worldwide rate of smoking during pregnancy is not known, it is estimated that as many as 20% of pregnant women in the United States smoke, and even among those women that quit during pregnancy, two-thirds resume smoking within a year [53, 54]. This exposes the fetus and baby to the thousands of chemicals, including over 60 carcinogens, found in tobacco smoke. Some chemicals in cigarette smoke bind the AhR, while others do not; however, the specific contribution of the various constituents of cigarette smoke to adverse health outcomes remains an active area of study. While the precise consequences vary with different cigarette smoke components, the overarching impact is clear: early life exposure to cigarette smoke alters immune responses and may increase the risk of cancer.

3.1 Immune function is altered after early life exposure to cigarette smoke in humans and rodents

Early life exposure to cigarette smoke has been shown to affect infectious disease susceptibility in childhood. Adverse outcomes of prenatal or neonatal cigarette smoke exposure include increased bronchitis, upper respiratory tract infections, ear infections, pneumonia and rate of hospitalizations [55–59]. While the mechanism for this increased susceptibility is not known, human and animal data point to an alteration in immune function. Examining lymphocytes purified from cord blood of exposed neonates, Noakes et. al. found altered levels of cytokines after stimulation [60, 61], while Devereux et. al. observed increased lymphocyte proliferation after stimulation [62]. Peripheral blood lymphocytes collected from children whose parents smoked prenatally and throughout their early lives produced less IFNγ when stimulated [63]. Studies in rodents present a clear picture of reduced lymphocyte responsiveness. For example, Ng et. al. observed a decreased lymphocyte response [64, 65], while Sing et. al. found reduced response of lymphocytes, and decreased antibody production after antigenic challenge [66]. Prenatal exposure to benzo[a]pyrene (BaP) [67] or nicotine [68], which are components of cigarette smoke, also suppressed lymphocyte responses, which in the case of BaP persisted to 18 months of age. Interestingly, mice developmentally exposed to cigarette smoke had higher viral burdens when challenged with respiratory syncytial virus (RSV) in early life [69]. As in the case of TCDD and PCBs, further work is needed to elucidate the mechanism by which early life exposure reprograms immune function, especially considering the prevalence of these pollutants.

3.2 Developmental exposure to cigarette smoke may be linked to increased incidence of cancer

A recent review of the epidemiological literature illustrated that there is not a consensus regarding the association between maternal smoking and childhood leukemia, with only a limited number of studies showing a positive association [70]. However, the risk of hepatoblastoma and non-Hodgkin’s lymphoma in children increased with maternal or parental smoking [71–73], and maternal smoking was associated with slightly increased rates of central nervous system tumors [74–77]. Animal data provide a further link between developmental exposure to cigarette smoke, the incidence of cancer, and the altered function of the immune system. Mice perinatally exposed to dibenzopyrene, a component of cigarette smoke, had increased formation of aggressive lung and liver lymphomas [78]. In separate studies using a mouse model of prenatal cigarette smoke exposure, male offspring presented an increased incidence of tumor formation after challenge with lymphoma cells. Further, cells from these exposed mice exhibited reduced CTL activity and lymphocyte expansion after mitogen stimulation, suggesting that the functional immune changes could underlie the offspring’s increased cancer susceptibility [64, 65].

4. Metals

There is a great deal of concern about exposures to metals and their adverse affects on human health. Metals such as arsenic and lead are found naturally in the earth’s crust, and high levels of arsenic in rocks can lead to contaminated groundwater sources. Lead has had many industrial uses, and although it is no longer an additive in gasoline or paint, it continues to be a widespread pollutant, and is added to certain products despite continued concern about toxicity. The link between metals and immune function has been studied for many years, and as reviewed in Dietert et. al., developmental exposure to lead results in persistent immune alterations in rodents, including reduced antibody levels, altered cytokine production and decreased DTH response [79]. Below we highlight arsenic, another metal of worldwide concern. We explore emerging data that suggest further efforts are warranted to investigate the link between developmental exposure to arsenic and increased susceptibility to infections and cancer.

4.1 Arsenic exposure during development may lead to altered disease susceptibility in children

Data linking early life exposure to heavy metals and altered immune function are emerging, with a growing literature implicating arsenic as a developmental immunotoxicant. Arsenic crosses the placenta [80], but unlike TCDD and other lipophillic pollutants, is not found extensively in breast milk [81]. A cohort of children in Bangladesh who were developmentally exposed to arsenic via contaminated groundwater have increased infant death rates, increased incidence of respiratory infections, and reduced thymic index lasting until 12 months of age [82, 83]. Interestingly, children with early life arsenic exposure were less prone to developing the skin lesions that are characteristic of acute exposure [84]. Increased urine arsenic levels in children correlated with decreased proliferation from their isolated lymphocytes [85]. While immune function has not been assessed in an animal model after developmental exposure to arsenic, adult mice acutely exposed to arsenic via drinking water exhibited changes in the expression of genes involved in mounting an immune response, specifically those involved in innate immunity [86, 87], and had decreased lymphocyte proliferation [88]. Further, acute exposure of adult mice to arsenic led to an impaired immune response to influenza virus infection, as exhibited by increased morbidity and viral titer, and decreased immune cell infiltrates early during infection [89]. These findings, combined with the epidemiological data of developmental exposure, highlight the need for functional immune assessment in a developmental model of arsenic exposure.

4.2 In rodents, cancer incidence is increased after gestational exposure to arsenic

Only a limited number of epidemiological studies in humans have looked at cancer incidence and early life arsenic exposure. Most have not found an association between arsenic and childhood cancers [90], although early life exposure to high levels of arsenic in a Chilean cohort correlated with increased incidence of lung cancer and nonmalignant airway destruction [91]. In rodents, however, increased cancer susceptibility has been demonstrated after developmental exposure to arsenic. Mice gestationally exposed to arsenic had increased tumor incidence [92]. Moreover, tumor incidence increased when mice were exposed to arsenic and diethylstilbesterol (DES) or tamoxifen, which are estrogenic compounds [93–95]. While the mechanism for this altered susceptibility has not fully been elucidated, intriguing data implicate a change in epigenetic regulation as an underlying mechanism. Chen et. al. found that exposing a rat liver cell line to arsenic led to S-adenosyl methionine (SAM) depletion and DNA hypomethylation [96]. Similarly, treatment of a keratinocyte cell line with arsenic depleted SAM, decreased DNA methylation, and decreased expression of DNA methyltransferases [97]. Interestingly, estrogen receptor-alpha (ERα) activation at gestational day 18 was associated with arsenic induced tumors [98], and arsenic mediated over-expression appears to be due, at least in part, to promoter hypomethylation [99]. Further evidence linking arsenic to epigenetic regulatory machinery is provided by a study in which gestational exposure of mice led to a suppression of genes for methionine metabolism, which could lead to the reduced SAM levels observed in vitro [100]. Understanding how developmental exposure to arsenic alters epigenetic regulation may provide a framework in which to evaluate other developmental immunotoxicants.

5. Pesticides

Pesticides represent another class of ubiquitous pollutants, with many different types being used in agricultural applications, in the workplace, and in the home. More than 5 billion pounds of pesticides are used annually worldwide, with about 25% being used in the United States [101]. Pesticide exposure occurs during their application, via their drainage into water supplies, and through the consumption of food. Levels of pesticides detected in amniotic fluid demonstrate that the fetus has direct exposure to at least some pesticides during development [102]. Studies in rodents highlight the potential for developmental exposure to pesticides to impact immune function, and epidemiological evidence suggest a link to increases in childhood cancers.

5.1 In rodents, early life exposure to pesticides leads to altered immune function

Although epidemiological data looking at immune function are lacking, studies in rodents suggest that perinatal exposure to pesticides alters immune function. For example, developmental exposure of rodents to atrazine, one of the most commonly used herbicides, altered proliferative responses in both B and T lymphocytes [103, 104]. Alterations in immune function after gestational exposure to chlordane have been well studied, and include decreased killing of tumor cells by macrophages, altered NK cell activity, altered T lymphocyte responses, and enhanced survival to influenza virus infection [105–109]. Further assessment of disease-related immune endpoints is needed in both animal models of developmental exposure and in the human population. Also needed are assessments of the impact of developmental and early life exposure to numerous other pesticides—and combinations of pesticides—on immune function.

5.2 Maternal exposure to pesticides may increase risk of childhood cancer

Two recent meta-analyses have shown that maternal exposure to pesticides, either occupational or residential, was associated with an elevated risk of childhood leukemia [110, 111]. Zahm and Ward reviewed the epidemiology literature and found some evidence of elevated risk of leukemia and other cancers in children with early life exposure [112]; these findings were upheld when revisited a decade later [113].

6. Environmental agents for which there is an emerging concern

There are numerous other chemicals to which we are exposed in our daily life. For most, studies to examine whether they adversely impact the developing immune system or alter susceptibility to infectious disease have not been conducted. Likewise, for many of these chemicals, we do not yet fully understand their mechanism of action as toxicants to complex mammalian development and physiology. Despite these gaps in knowledge, it is increasingly recognized that early life exposures can have a profound impact on the developing immune system, and may thereby contribute to disease later in life. In the following section, we explore the available data for a few examples of ubiquitous pollutants to which many people are continuously exposed, such as perfluorinated compounds, solvents, and plastics.

6.1 PFOS and PFOA

Perfluorooctane sulfonic acid (PFOS) and perfluorononanoic acid (PFOA) are widely used for their non-stick, fire resistant, and stain repellent properties. These chemicals have recently been recognized as a class of potentially harmful pollutants, but few studies have investigated their impact on development or their immunomodulatory properties. In studies of acute administration to adult rodents, PFOS exposure increased NK cell activity and decreased antibody production [114]. Exposure to sulfluramid, another perfluorinated compound used as a pesticide, led to reduced antibody production [115]. Developmental exposure to PFOS led to reduced NK cell activity, antibody production and B lymphocytes numbers [116]. This work suggests that further investigation of immune function after developmental exposure to fluorinated compounds is necessary.

6.2 Solvents

Solvents, such as toluene and trichloroethylene (TCE), are used in paints, adhesives, and cleaners. While the function of the immune system after developmental exposure to solvents has not received extensive attention in humans, maternal and paternal occupational exposure to solvents has been linked to increased incidence of childhood leukemias [117–121], although not all studies found an association [122]. Animal data suggest that solvents can be developmental immunotoxicants. For example, perinatal toluene exposure modulated Th1 and Th2 responses after exposure to peptidoglycan, a toll-like receptor (TLR) ligand [123]. Early life exposure of mice to trichloroethylene decreased antibody production, increased thymic cellularity, and altered lymphocyte responses [124–126]. These data are suggestive, and support the idea that rigorous examination of the impact of maternal and early-life exposure to environmentally relevant levels of solvents on the ability to fight infection and detect and destroy tumor cells is needed.

6.3 BPA and Phthalates

Plastics have widespread use throughout the world, but little is known about the immunomodulatory properties of their chemical components. Two components of plastics that have garnered considerable attention are bisphenol A (BPA) and phthalates. BPA is a monomer used in polycarbonate plastics and epoxy resins, while phthalates are used as softeners in many products. The extent to which humans have been exposed to BPA and phthalates is widespread: 93% of NHANES (National Health and Nutrition Examination Survey) participants had detectable levels of BPA in their urine [127], while 75% had phthalate metabolites present [128]. Furthermore, levels of BPA in amniotic fluid were three to four-fold higher than in maternal serum [129]. Detectable levels of phthalate metabolites were also found in amniotic fluid [130]. Because of these findings, active research is being conducted to determine the health outcomes from early life exposure to these chemicals.

Only one animal study has investigated the impact of developmental exposure to phthalates on immune function, and in that study no change was seen in the DTH response in rats with gestational exposure to the phthalate DEHP [131]. However, epidemiological studies investigating phthalate exposure in children found increased risk of respiratory symptoms such as wheeze and allergic indications [132]. Due to these findings, and the high levels of exposure in humans, further studies in humans and rodents are critically needed to clearly understand whether and how developmental and early life exposure to phthalates impacts the immune system.

In contrast to scant data on phthalates and immune system, there are several animal studies to support the idea that exposure to BPA alters immune function. In one study, mice with prenatal exposure to BPA showed increased lymphocyte proliferation after Listeria major infection, along with increased cytokine production and a reduction in the number of regulatory T cells [133]. Increased lymphocyte proliferation and numbers of splenic T lymphocytes have also been reported, but the consequences of these changes remain unclear [134]. Although there is a dearth of information looking at the immune response to infection, early-life exposure to BPA has been suggested to alter the mechanisms underlying oral tolerance to the model antigen ovalbumin, and enhance the development of an asthmatic phenotype [135, 136]. Furthermore, acute exposure of adult rodents to BPA altered the levels of cytokines and antibodies produced, leading to enhanced autoantibody production [137–140]. While these data suggest BPA has the capacity to modulate the developing immune system, more studies are needed to determine if developmental exposure to BPA alters disease susceptibility later in life, and to elucidate the underlying mechanisms.

7. Future Directions

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, 100, 143]. Furthermore, changes in epigenetic mechanisms have been linked to early life exposure to BPA, although not in the context of studies of immune function [144–147]. 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 [10–12]. 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.