Developmental Exposures and Lead Induced Immunotoxicity

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Unlike the situation for most chemicals where toxicological data may be limited to adult exposure hazard-identification data, immunotoxicity data for exposure to lead during early development have been obtained in at least three species and in at least two strains within a single species. The overall results support the fact that for some life stages of exposure, lead has the capacity to alter T helper 1 vs. T helper 2 balance; this is perhaps the single most significant hallmark of lead-induced immunotoxicity. Associated with the increase in Th2 function are increases in the production of Interleukin-4 and IgE.

Changes in Th1 vs. Th2 balance appear to be influenced by both environmental and genetic factors and have both biological and clinical ramifications. Th2 activity and IgE levels have been recognized as an important consideration in airway responsiveness and asthma (Sears et al. 1991, Umetsu and DeKruyff 1997; Lutz et al. 1999). Likewise, genetic-related risk factors have been identified for asthma and hyperreactive airways. At least some of the identified genetic polymorphisms seem to influence T helper cell balance as well (Lee et al. 2002a).

The interaction between genotype and environmental exposure is coming under increased examination relative to the risk of asthma (Sengler et al. 2002). There is a strong link between the lead-induced increase in Th2 activity and the associated increases in cytokine and IgE levels. Obviously, segments of the population can vary genetically relative to Th1 vs. Th2 bias. Therefore, for a subpopulation already genetically predisposed more toward Th2 responses than Th1, even modest lead-induced elevations in Th2 cytokines could shift that population into a symptomatology range. This has led several authors to suggest that lead is a potential risk factor contributing to the rise in both childhood asthma and allergic disease (Rabinowitz et al. 1990; Dietert and Hedge 1998; Miller et al. 1998; Chen et al. 1999; Snyder et al. 2000). However, the developmental data also indicate that the risk to the immune system posed by lead exposure is likely to vary widely depending upon the specific life stage of exposure (even within the nonadult).

In experiments using exposure of rats to lead acetate throughout gestation, lactation, and juvenile development, Luster and colleagues reported alterations in both humoral (Luster et al. 1978) and cell-mediated immunity (Faith et al. 1979). Both serum IgG titers and plaque-forming cells were decreased in Sprague-Dawley rats following exposure pre- and postnatally to 25 or 50 ppm lead acetate in the drinking water (Luster et al. 1978). Similarly, the DTH response and T lymphocyte mitogen responses were depressed by exposure to lead (Faith et al. 1979). These studies demonstrated that early exposure to lead at relatively low doses could alter immune function. In these studies, lymphoid organ changes were modest compared with the functional changes. This appears to be another hallmark of lead-induced immuno-toxicity. For low to moderate levels of exposure, cell population/organ changes are modest in comparison to the lead-induced T helper-associated functional changes. One exception to this generalization may occur when postnatal environmental stressors are placed on prenatal lead-exposed animals (Lee et al. 2002b). In other early studies, Talcott and Koller (1983) exposed mice to combinations of lead and poly-chlorinated biphenyls (PCBs) throughout gestation and lactation. They found that lead exposure depressed antibody titers and that combined lead plus PCBs depressed the DTH response. While they did not detect a DTH response change with lead alone, the N numbers were quite modest and the data were pooled from both genders.

Figure 10.1 summarizes the relationship of early exposure to lead, immune functional development, and subsequent immune alterations in both the rat and the chicken. Landmarks of immune development for the rat and the chicken are shown for comparison with the timing of lead exposures and the subsequent immune alterations.

It should be noted that timing does matter relative to early lead exposure. Early gestational (or in the case of the chicken, in ovo) exposure of females to lead does

Landmarks of Early Immune Development

Chicken thymic seeding

Rat exposure Rat exposure Rat exposure

Chicken exposure Chicken exposure Chicken exposure Chicken exposure

Immune Effects Th1 Th2 Macrophages t

Th1 I

Embryonic development of the rat and the chicken (days)

Figure 10.1 The timeline illustrates functional-based windows of early immune development overlaying various embryonic lead-exposure regimes for the rat and the chicken. Ovals indicate the final day of embryonic exposure for the rat or the single day of in ovo lead administration for the chicken. Because cross-fostering was not performed, some low-level lactational transfer of lead was possible in the rat. Arrows indicate the direction of subsequent immune alterations detected in juveniles and adults. ND = not done. Distinctions are apparent among the functional changes induced by early embryonic vs. late embryonic exposure to lead. Information used for the developmental immune landmarks was derived from Dietert et al. (2000) and Gobel (1996).

not pose the same risk for depressing Th1 function as does late gestational exposure (Bunn et al. 2001b; Lee et al. 2001). As shown in Figure 10.1, the second half of embryonic development in the rat and the chicken appears to be a critical window in which the capacity to alter Th1/Th2 balance emerges. This has led to the proposal that even within embryonic development, windows of relative susceptibility and resistance are likely to exist (Bunn et al. 2001b; Dietert et al. 2002). With early exposure to lead, altered macrophage function and some changes in antibody (including autoantibody) production are the primary outcomes. In contrast, late embry-onic/gestational exposure results in severely depressed Th1 function in the offspring. Exposure across the entirety of gestation seems to produce the combined alterations seen from early and late gestational exposures including depressed Th1 function (Miller et al. 1998; Chen et al. 1999; Bunn et al. 2001a, b, c; Lee et al. 2001; Dietert et al. 2002).

What is remarkable about these observations is that lead concentration at birth (in blood) does not appear to be a sole predictor of immunotoxic outcome. Instead, it is critical to know the window of active exposure and likely embryonic uptake of lead. With very early exposures, during the first half of embryonic development, lead is still retained in the late embryonic system at what are apparently sufficient concentrations (based on blood lead levels) to alter T helper function. Yet, T helper balance is not disrupted in the offspring. This suggests that lead might not be bioavailable to alter T helper balance if exposure/uptake precedes the emergence of some critical developmentally timed target. It may be important for future studies to consider active exposure/peak concentrations vs. body burden during specific life stages of development.

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