Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl2 (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4+FoxP3+CD25+ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8+CD223+ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific.

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Diesel exhaust particles (DEPs), generated by heavy-duty diesel engines in various industries, can adsorb over 450 different organic compounds, including mutagenic and carcinogenic polycyclic aromatic hydrocarbons (1). With diameters < 2 µm, these fine respirable particles can remain airborne for long periods of time and deposit in great numbers deeply in the lungs. For these reasons, exposure of truckers, railroad and construction workers, and engine mechanics to DEPs is an occupational health concern. A report from the U.S. Department of Labor showed that the worst-case mean exposures to DEPs in underground metal and nonmetal mines are about 2,000 µg/m 3 , with maximum measurements as high as 3,650 µg/m 3 (2). Epidemiologic studies have also shown a consistent association between elevated levels of particulate matter in ambient air and increased incidence of pulmonary infections (3) or increased respiratory mortality and morbidity in high-risk groups (4,5). Because DEPs are a major component of particulate air pollution in most industrialized urban areas, their effect on pulmonary infections is of great environmental and occupational concern.The principal function of pulmonary host defense mechanisms is to clear inhaled particles or microorganisms from the lungs and prevent infections. Among the various cell types involved in the innate immune system, alveolar macrophages (AMs) are responsible for the clearance of inhaled particles and/or microorganisms from the distal airways and alveolar spaces. These cells engulf inhaled particles or microorganisms and become activated to release reactive oxygen species (ROS), cytokines, and a variety of mediators that are capable of killing microorganisms (6,7). It has been well documented that AM-derived proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), provide innate resistance to bacterial infection, promote the inflammatory process by recruiting neutrophils into the air spaces, and stimulate these phagocytes to release ROS and enzymes (7,8). A successful pulmonary host defense, on the other hand, also needs specific cell-mediated immunity (9). In this aspect, studies have already shown that AMs, through their secretion of cytokines in response to specific antigen exposure, provide a critical link between these two systems. For example, Hsieh et al. (10) showed that the production of IL-12 by macrophages is a key process for the development of the appropriate CD4 + T helper (Th) subset during the immune response to Listeria monocytogenes infection. IL-12, in fact, not only initiates but also plays an important role in maintaining the Th1 response (11). This cytokine is produced very rapidly after infection, thus serving as an early marker for the study of DEP effect(s) on cell-mediated immunity.Studies from our laboratory as well as from others have suggested that DEPs may suppress host immunity by suppressing mucociliary clearance and the phagocytic activity of AMs (12,13), reducing interferon production in response to viral ...

Atrazine is a widely used herbicide applied to corn, sugar and other crops as a broad leaf weed inhibitor. Using the Balb/c mouse model, we have determined that prenatal/lactational exposure to atrazine alters adult immune function. Pregnant Balb/c dams were exposed subcutaneously for 21 days via time release pellets to 700 microg per day of atrazine beginning between days 10 and 12 of pregnancy. Prenatal/Lactational exposure caused no overt physical malformations in the offspring and had no effect on the number of litters carried to term or the litter size. Upon reaching early adulthood (approximately 3 months of age), the state of their immune system was evaluated. There were no changes in body weight or in the organ to body weight ratio of the spleen. Additionally, no changes were observed in the number of CD8+ T cell, CD4+ T cell, or B220+ B cell subpopulations in the spleen. T cell function was assessed by measuring proliferation and cytolytic activity after in vitro allogeneic stimulation. Male mice which had been prenatally/lactationally exposed to atrazine had an increase in both T cell proliferation and cytolytic activity. The humoral immune response was assessed after immunization with heat killed Streptococcus pneumoniae (HKSP). There was a significant increase in the number of HKSP-specific IgM secreting B cells in the spleen of prenatal/lactational exposed male mice. Inasmuch as atrazine is a widespread environmental contaminant, this immunopotentiation raises concerns that it may potentiate clinical diseases, such as autoimmune disease and hypersensitivity, and needs to be carefully monitored and studied.

Osteoclasts are specialized macrophage derivatives that secrete acid and proteinases to mobilize bone for mineral homeostasis, growth, and replacement or repair. Osteoclast differentiation generally requires the monocyte growth factor m-CSF and the TNF-family cytokine RANKL, although differentiation is regulated by many other cytokines and by intracellular signals, including Ca2+. Studies of osteoclast differentiation in vitro were performed using human monocytic precursors stimulated with m-CSF and RANKL, revealing significant loss in both the expression and function of the required components of store-operated Ca2+ entry over the course of osteoclast differentiation. However, inhibition of CRAC using either the pharmacological agent 3,4 dichloropropioanilide (DCPA) or by knockdown of Orai1 severely inhibited formation of multinucleated osteoclasts. In contrast, no effect of CRAC channel inhibition was observed on expression of the osteoclast protein tartrate resistant acid phosphatase (TRAP). Our findings suggest that despite the fact that they are downregulated during osteoclast differentiation, CRAC channels are required for cell fusion, a late event in osteoclast differentiation. Since osteoclasts cannot function properly without multinucleation, selective CRAC inhibitors may have utility in management of hyperresorptive states.