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ReViews Developmental Immunotoxicology: Focus on Health Risks Rodney R. Dietert* Department of Microbiology and Immunology, C5-135 VMC, College of Veterinary Medicine, Cornell UniVersity, North Tower Road, Ithaca, New York 14853 ReceiVed June 1, 2008
Developmental immunotoxicity (DIT) has gained attention with the recognition that many chronic diseases of increasing incidence feature immune dysfunction as a component of the disease. The maturing immune system represents a vulnerable target for toxicants as it progresses through a series of novel prenatal and perinatal events that are critical for later-life host defense against a wide array of diseases. These critical maturational windows display a particular sensitivity to chemical disruption with the outcome usually taking the form of persistent immune dysfunction and/or misregulation. For this reason, health risks are significantly increased following early life vs adult immunotoxic exposure. Additionally, DITassociated health risks are not readily predicted when based on adult-exposure safety data or via the evaluation of an unchallenged immune system in developmental toxicity testing. The same toxicant [e.g., heavy metals, 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD)] may disrupt different immune maturational processes depending upon the specific developmental timing of exposure and the target organ dose at a given stage of development. Therefore, a single toxicant may promote different immune-associated diseases that are dependent upon the specific window of early life exposure, the gender of the exposed offspring, and the genetic background of the offspring. This perspective considers the linkage between early life chemical exposure, DIT, and the postnatal immune dysfunctions associated with a variety of childhood and adult diseases. Because DIT is linked to a majority of the most significant childhood chronic diseases, safety testing for DIT is a pivotal issue in the protection of children’s health. Contents 1. Introduction 2. Chemical Disruption of the Developing Immune System 3. DIT Testing To Reduce Health Risks 4. Prenatal Immune Insult, Postnatal Immune Dysfunction, and Disease 5. Diseases of Concern with DIT 6. Susceptibility to Infections and Cancer 7. Allergic Diseases and Asthma 8. Autoimmune Diseases 9. Diseases and Disorders Connected to Inflammatory Misregulation and Damage 10. Conclusions
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1. Introduction Developmental immunotoxicology (DIT) is a subarea of immunotoxicology focusing on the effects of exposure to biological materials, chemicals, drugs, medical devices, physical factors (e.g., ionizing and ultraviolet radiation), and, in certain instances, physiological factors (as defined by ref 1) on the developing immune system. It encompasses exposures during any period of nonadult life, producing adverse outcomes that may arise at any time during childhood or adulthood. The resulting diseases of concern with DIT are prominent across * To whom correspondence should be addressed. Tel: 607 253-4015. Fax: 607 253-3384. E-mail:
[email protected].
children, adult, and geriatric populations (2). As a result, DIT plays a role in life-long health and quality of life. Adverse outcomes of DIT may take several forms including immunosuppression, autoimmunity, allergic responses (to chemicals or other allergens), and/or misregulated inflammation. Because the immune system is dispersed throughout most tissues and organs, exposure of humans or wildlife to chemicals and drugs is certain to involve some immune cell exposure regardless of the route of exposure. The key in immunotoxicity safety screening is to identify those immune system exposures that increase health risks, particularly among the most susceptible subpopulations. The risk of DIT is a primary concern under the overall umbrella of a fetal basis for later-life diseases. Because the developing immune system is more sensitive to toxicant-induced alteration than that of the adult (3-5) and the increased disease burden can span a lifetime, avoidance of DIT should be a major component in prenatal-perinatal preventative medicine. Avoiding toxic exposure offers a major opportunity for reducing childhood and adult health risks along with the associated burdens on both the health care system and the family financial base. Additionally, the opportunity to improve the quality of life for a significant percentage of children provides an added incentive to pursue effective DIT safety screening. This perspective of DIT will emphasize the broad spectrum of diverse diseases that are associated with chemically induced DIT and the chemicals and drugs that have been reported to elevate disease risk via the disruption of critical prenatal-perinatal immune maturational events. This developmental roadmap to
10.1021/tx800198m CCC: $40.75 2009 American Chemical Society Published on Web 09/11/2008
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a well-functioning immune system in the newborn has several potential pitfalls or “windows” during which immune vulnerability to toxicants is unparalleled with time periods in later life (3, 6, 7). For this reason, insufficient attention has been directed toward the risk of environmentally induced immune dysfunction in children and the ramifications of a subsequent life-long chronic disease. Protection of the developing immune system against early life insult should be a significant component of health risk reduction, as it has significant potential to reduce health care needs in later life. However, there is a major deficit for identifying DIT presented by current regulations covering the toxicological assessment of chemicals and drugs. The need to close this safety gap to address diseases of increasing societal concern is discussed.
2. Chemical Disruption of the Developing Immune System Studies comparing the effects of chemical toxicants on the immune system have consistently demonstrated an age-based difference in sensitivity between the nonadult and the adult. As reviewed in Luebke et al. (4) and Dietert and Piepenbrink (3), this differential sensitivity takes numerous forms. For example, age-based comparisons of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) in the rat suggest that 100-fold lower exposure doses are required to induce immunotoxicity prenatally than are needed in the adult (4). An immediate cause for concern is the potential application of an age-based uncertainty factor for protection against DIT when only adult immunotoxicity data are available. The example with TCDD suggests that an uncertainty factor of 10 is most likely to be inadequate to ensure protection of a fetus from DIT via extrapolation from adult safety data. Beyond dose sensitivity differences, early life exposures are more likely to produce persistent adverse immune outcomes as compared with transitory effects in the adult. The spectrum of adverse effects, magnitude of specific alterations, and potential for later-life, unanticipated, environmentally triggered immune problems are all increased with early life vs adult exposures to toxic chemicals. The heightened sensitivity of the young for immunotoxicity is linked, at least in part, to disruption of novel prenatal/neonatal immune maturational events that are required to set the template for immune responses throughout life. Specific critical windows of maturational events exist prenatally/perinatally (e.g., negative selection against autoreactive T lymphocytes in the developing thymus). Either adults lack these events completely or their laterlife disruption is less catastrophic once a fully matured immune system is in place and functioning. This fact alone has implications for future safety testing.
3. DIT Testing To Reduce Health Risks Developmental immunotoxicity evaluation is not routine for the determination of chemical or drug safety, and even direct functional testing of adult exposure for immunotoxicity is not required in primary toxicological screening under most regulations. The only exception for immunotoxicity screening pertains to EPA regulation of pesticides. It has been suggested that DIT testing would be performed only if triggered by a finding of environmental chemical- or drug-induced adult immunotoxicity. However, the lack of relative sensitivity or even relevance of the adult immune system as a toxicologic target as compared with the immune system of the nonadult raises serious questions about such a testing scheme (reviewed in ref 3). Of concern is the fact that dose sensitivity, range of adverse effects, likelihood
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of persistence, and ranges of health implications are far more problematic with early life immunotoxicity than following adult exposure to immunotoxicants. Additionally, the nature of the dysfunctional and misregulated changes to the developing immune system is such that the changes can be missed if the evaluation of DIT is not performed following infectious agent challenge or immunization. This need to detect chemical/druginduced dysfunction calls into question testing strategies emphasizing histopathological changes of an unchallenged immune system (5) as a prerequisite (trigger) before immune challenge and multifunctional assessment would be conducted. Two significant levels of concern exist in the current testing gap for DIT safety. First, current recommendations for adult immunotoxicity evaluation would not even include functional tests of a challenged immune system unless appropriate “cause for concern” has been triggered (e.g., immunohistological changes). Therefore, even for the adult, immune functional data are not always available. Safety is then based on nonfunctional data (e.g., largely morphometric analysis) derived from a resting immune system. However, beyond that concern, it has been suggested that indication of xenobiotically induced immunosuppression in adults be used as a “cause for concern” trigger before regulatory agencies would expect DIT testing (8). The biological implausibility of reliance on an adult trigger as a surrogate for the developing immune system is illustrated in Figure 2. The complete lack of equivalency across key immune processes between the late fetus-early neonate and the adult is striking. Therefore, placing complete dependency upon a biologically irrelevant form of the immune system (fully mature immune system) to predict the risk of disruption of the developing (prenatal-perinatal) immune system processes is a questionable approach immunologically. This might be less problematic, except that the diseases of greatest concern connected to DIT are the very ones that have been increasing in incidence in the human population [e.g., childhood asthma, allergies, lupus, and rheumatoid arthritis (RA)]. These are discussed further in the following sections.
4. Prenatal Immune Insult, Postnatal Immune Dysfunction, and Disease Immune development is critical for establishing the capability of distinguishing self from nonself for the purpose of host defense. Therefore, significant reduction in the capacity to fight invading pathogens or misdirected immune responses against self-leading to autoimmunity is readily recognized as an outcome of developmental immunotoxicity. However, the homeostatic regulation of tissues and organs is an additional function of cellular components of the immune system (e.g., resident macrophage populations). If the establishment of these cells in organs or their subsequent function is impaired via chemical exposure, this can result in functional alteration and/or pathology to the tissue. In this latter case, any immune system involvement may be less apparent unless the mechanistic pathway of the damage is known. The in utero environment is thought to play a major role in the risk of later life disease (9-14). Bjorksten (15) recently described the capacity of the prenatal environment to contribute to disrupted immune regulation in which the risk is elevated for both Th1-mediated autoimmune responses and Th-2 mediated allergic disease. Additionally, improper fetal inflammatory responses can be associated with later disease outcomes (16).
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Figure 1. Environmental chemical and drug toxicants (left) that disrupt one or more critical prenatal-perinatal immune maturational events (center). Disruption of these novel immune processes in early life results in postnatal immune dysfunction. The immune dysfunction can take numerous forms and has been linked to elevated risk of specific childhood and adult diseases (right). Because single chemicals may produce multiple adverse outcomes, several disease risks may be impacted depending upon the exact prenatal-perinatal timing, the levels of exposure, the gender of the offspring, and the genetic background. Abbreviations: PCBs, polychlorinated biphenyls; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCE, trichloroethylene.
5. Diseases of Concern with DIT One of the challenges in fully appreciating the role of DIT in disease risk is that many of the diseases impacted are relatively common (allergies, asthma, type 1 diabetes, and atherosclerosis); hence, studies must be conducted that can detect chemical immune-based changes in disease incidence. Additionally, some diseases are categorized not by their environmentally linked immune dysfunction but rather by the damaged physiological system requiring therapeutic intervention (e.g., the gastrointestinal system in inflammatory bowel disease and celiac disease, the cardiovascular system in atherosclerosis, the endocrine system in autoimmune thyroiditis, and the neurological system in multiple sclerosis). An additional challenge is that
exposure to one chemical may influence the risk of several seemingly diverse immune-inflammation-related diseases. As discussed in the following sections, in utero exposure to TCDD is now known to produce a range of immunotoxic outcomes that potentially influence the risk of several childhood and adult diseases. However, in earlier TCCD research, only a subset of the adverse immune outcomes had been detected (e.g., immunosuppression). As a broader array of immune tests was utilized, a more complete view of the range of health risks has emerged extending beyond immunosuppression to include autoimmunity and misregulated tissue inflammation. For this reason, additional DIT research is needed. Additional research would aid in the identification of xenobiotics capable of
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Figure 2. Pitfalls in (i) the use of adult-exposure data for developmental immune hazard identification as well as (ii) the requirement for positive results in adult immunotoxicity testing to trigger subsequent DIT testing. For this adult-only testing strategy to be effective, the fully matured adult immune system must be equivalent to the developing immune system as a toxicological target. However, biologically, this is not plausible. Examples of five adult and perinatal immune conditions are illustrated that need to be accepted as equivalent across ages (i.e., ) rather than *) to use this approach. The adult conditions need to be similar enough to that of the fetus and neonate that high-dose adult-exposure immunotoxicity results could be expected to provide effective hazard identification for the developing immune system. Because the immune conditions are strikingly different across ages, the strategy lacks biological plausibility. Therefore, there is little assurance that the adult immune system is an effective surrogate for the identification of xenobiotic hazards for the developing immune system.
producing DIT and better define the health risks resulting from specific early life exposures.
6. Susceptibility to Infections and Cancer DIT plays a significant role in the susceptibility to infectious agents as well as in the risk of cancer, and the disease implications of immunosuppression resulting from DIT have been recently reviewed (1). Among diseases involving infectious agents of concern with DIT are neonatal sepsis (17), otitis media (18-20), influenza (21, 22), and other preventable childhood infections (23). The occurrence of an increased risk of middle ear infections (otitis media) with increased risk of allergy is another example in which targeted immunosuppression is combined with exaggerated or misdirected responses (24, 25). An increased risk of cancer is one of the adverse outcomes of DIT. This can occur via dysfunctional immune responses, which may encompass (i) increased mutagenesis via misdirected chronic inflammation, (ii) inappropriate growth promotion of transformed cells, or (iii) suppressed host immune responses to tumors. Among the cancers apparently linked with DIT is childhood leukemia (26). Greaves (27) suggested that an early life immune dysfunctional response to common childhood infections is a key factor in this disease, and McArthur et al. (28) reported similar findings. Environmental chemicals are capable of producing immune dysfunction and increasing the risk of cancer across several categories of toxicants. For example, prenatal exposure to both arsenic and tobacco smoke produce adverse outcomes that appear to increase the risk of cancer in addition to producing cell-mediated immunosuppression (29, 30).
7. Allergic Diseases and Asthma The environmentally influenced status of the immune system at birth has been linked to the risk of several manifestations of allergic disease including neonatal atopic dermatitis (31), rhinitis (32), and asthma (33, 34). Other respiratory illnesses also fit part of the immune maturational concern associated with DIT (35). Allergic asthma has been a focus of DIT-oriented research, and several environmental risk factors have been identified. Maternal smoking is a significant risk factor, and several research groups have reported this association with increased risk of asthma (36-38). However, other environmental chemicals and drugs are important risk factors as well. Shaheen et al. (39) found a link between late gestational use of paracetamol and the risk of asthma, wheezing, and increased IgE levels, and a similar association was reported more recently by Rebordoso et al. (40). Among other important environmental risk factors for childhood asthma is diesel exhaust (41). Beyond asthma, Johansson et al. (32) reported an increased risk of childhood rhinitis associated with maternal smoking. Additionally, McKeever et al. (42) reported an increased risk for several childhood allergic diseases following maternal use of antibiotics during pregnancy.
8. Autoimmune Diseases DIT and autoimmune disease can take many forms that affect different target organs depending upon the timing of chemical exposures, the nature of the resulting immune dysfunction, and the genetic background of the exposed susceptible population. Chemical disruption over several windows of prenatal-perinatal immune development can impact the risk of autoimmunity. Some chemically induced autoimmune conditions focus on Th1-
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biased immune responses, and others are associated with Th2 skewing, while still others seem to require major inflammatory dysfunction. Additionally, inappropriate promotion of autoreactive T cell clones by the developing thymus or ineffective Treg function in the periphery can provide toxicant-associated routes to autoimmune disease (43). Autoimmune diseases linked to environmentally influenced immune dysfunction that can be affected are a wide array of target systems and organs. These include the endocrine organs (e.g., thyroid), the neurological system (e.g., multiple sclerosis), the pancreas (type 1 diabetes), and the hepatic (autoimmune hepatitis), cardiovascular (autoimmune myocarditis), and gastrointestinal systems (celiac disease). Alternatively, the resulting autoimmunity can produce systemic effects [e.g., RA or systemic lupus erythymatosus (lupus)]. Significant research information supports the connection between prenatal-perinatal environmentally induced immunotoxicity, postnatal immune dysfunction, and autoimmunity (44-46). For example, lupus has both prenatal risk factors such as mercury and estrogen and early life immune alterations (47). Celiac disease, which also has an allergic component, can occur at any age, although a majority of cases are diagnosed in adults (48). Immune dysfunction is a major factor based on the cause of death in a celiac disease population in Sweden (49). Additionally, celiac disease appears to have early life environmental risk factors (50). Beyond heavy metals and estrogenic compounds, numerous other early life chemical risk factors have been identified in autoimmune disease. For example, maternal tobacco smoke elevates the risk of rheumatoid arthritis (51) in the offspring, produces an increased risk of asthma and certain allergic diseases (36, 52), and produces immune dysfunction (29, 52). The role of immune dysfunction resulting in RA has been recently reviewed by Cope et al. (53).
9. Diseases and Disorders Connected to Inflammatory Misregulation and Damage Several diseases and disorders have prenatal environmental risk factors, inflammatory insult, and/or later-life immune dysfunction associated with them. Of note is the fact that these diseases involve tissue damage arising from misregulation of inflammatory cells that may either be restricted to a window of prenatal development or continue after birth. The latter is usually reflected by the overproduction of myelomonocytic metabolites or cytokines. Additionally, initial tissue damage may result in autoantibody production and further insult to the organ or physiological system. Several disorders or neurocognitive deficits connected to the brain fall within this category. For example, autism and autism spectrum disorders are candidates for DIT influence because they feature both early life environmental risk factors and associated immune dysfunction (reviewed in refs 7 and 54). Deficits in postnatal IQ are associated with exposure to lead during the same period in which lead alters dendritic cells and elevates macrophage production of reactive oxygen intermediates (55, 56). It has been suggested that an increased risk of schizophrenia in the offspring results from immune activation during pregnancy (57), and schizophrenia has prenatal risk factors associated with immune activation and alteration (58). Neurological diseases of later life may also be connected to DIT. Gestational environment is thought to be important in both Parkinson’s disease (59) as well as Alzheimer’s disease (60). Additionally, both diseases show evidence of immune/inflammatory dysregulation (61-65).
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Beyond the neurological system, it was recently suggested that DIT is an important factor in the risk of atherosclerosis, which is possibly affected by developmental programming of the immune system (66). A hallmark of the disease is misregulation of immune inflammatory components (67). The disease is also associated with a variety of autoimmune conditions (68, 69). Likewise, inflammatory bowel disease is characterized by immune dysfunction (70-72) and has been proposed to be influenced by the early life chemical environment (73, 74).
10. Conclusions The impetus for DIT safety testing of environmental chemicals and drugs stems from two findings that have helped to define the health benefits to be gained via such testing. First, the developing immune system is more sensitive to toxicants than that of the adult (1, 4, 5, 45, 75) and in ways that cannot be readily predicted by adult safety testing (3). Second, many chronic diseases that have been increasing in incidence (childhood asthma and allergies, autism, childhood leukemia, type 1 diabetes, celiac disease, rheumatoid arthritis, and lupus) feature both early life environmental risk factors and immune dysfunction/misregulation (1, 2, 7, 26, 76). The lack of similarities (Figure 2) between the fully matured immune system of the adult and the developing immune system calls into question safety testing strategies that require xenobiotically induced adult immunotoxicity as a prerequisite for DIT testing. Immune function and health risks are intrinsically intertwined. Therefore, identification of chemical hazards for the developing immune system and protection against chemically induced immune dysfunction and immune-inflicted tissue damage provides a major opportunity to reduce health risks for the most significant chronic diseases of children and adults. Acknowledgment. I thank Janice M. Dietert for her editorial assistance.
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