Inflammation is a complex and necessary component of the response to biological, chemical, or physical stimuli, and the cellular and molecular events that initiate and regulate the interactions between the various players in the inflammatory process remain a source of ongoing investigation. In the acute phase of the inflammatory response, cells of the immune system migrate to the site of injury in a carefully orchestrated sequence of events that is facilitated by soluble mediators such as cytokines, chemokines, and acute-phase proteins. Depending on the degree of injury, this acute phase may be sufficient to resolve the damage and initiate healing processes. Persistent inflammation, either as a result of prolonged exposure to stimulation or an inappropriate reaction against self-molecules, can lead to the chronic phase, in which tissue damage and fibrosis can occur. Chronic inflammation has been reported to contribute to numerous diseases, including arthritis, asthma, atherosclerosis, autoimmune diseases, diabetes, and cancer, and to conditions of aging. Hematology and clinical chemistry data from standard toxicology studies can provide an initial indication of the presence and sometimes the location of inflammation. These data may suggest more specific immune function assays that are necessary to determine the presence and/or mechanism(s) of immunomodulation. Although changes in hematology dynamics, acute-phase proteins, complement factors, and cytokines are common to virtually all inflammatory conditions, and can be measured by a variety of techniques, individual biomarkers have yet to be strongly associated with specific pathologic events. Thus, although sensitive indicators of inflammation, these factors generally lack the specificity to identify the offending cause. The profile seen in a given inflammatory condition is dependent on the severity, chronicity, and mechanisms involved in the inflammatory process, as well as the species and the capacity of the individual's immune system to respond and adapt.

Inflammation is a complex and necessary component of an organism's response to biological, chemical or physical stimuli. In the acute phase, cells of the immune system migrate to the site of injury in a carefully orchestrated sequence of events that is mediated by cytokines and acute phase proteins. Depending upon the degree of injury, this acute phase may be sufficient to resolve the damage and initiate healing. Persistent inflammation as a result of prolonged exposure to stimulus or an inappropriate reaction to self molecules can lead to the chronic phase, in which tissue damage and fibrosis can occur. Chronic inflammation is reported to contribute to numerous diseases including allergy, arthritis, asthma, atherosclerosis, autoimmune diseases, diabetes, and cancer, and to conditions of aging. Hematology and clinical chemistry data from standard toxicology studies can provide an initial indication of the presence and sometimes location of inflammation in the absence of specific data on the immune tissues. These data may suggest more specific immune function assays are necessary to determine the existence or mechanism(s) of -immunomodulation. Although changes in hematology dynamics, acute phase proteins, complement factors and cytokines are common to virtually all inflammatory conditions and can be measured by a variety of techniques, individual biomarkers have yet to be strongly associated with specific pathologic events. The specific profile in a given inflammatory condition is dependent upon species, mechanisms, severity, chronicity, and capacity of the immune system to respond and adapt.

Poly-and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF 3 (CF 2 ) 8 COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague-Dawley rats were exposed to 0-2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B 6 C 3 F 1 /N mice were exposed once/week to 0-5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26-89%) was observed following exposure to !0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig þ and NK þ cells were decreased (17.6-27%). At ! 1.25 mg PFDA/kg/week the numbers of splenic CD3 þ , CD4 þ , CD8 þ , and Mac3 þ cells were decreased (10.5-39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24-39%) at !0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral-and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.ARTICLE HISTORY

BackgroundDysregulation of positive and negative selection, antigen presentation, or apoptosis in the thymus can lead to immunosuppression or autoimmunity. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide (CPS), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that induce similar immunotoxic effects in the thymus, however, the mechanism of toxicity is purported to be different for each compound.ObjectivesWe hypothesized that genomic analysis of thymus after chemical-induced atrophy would yield transcriptional profiles that suggest pathways of toxicity associated with reduced function.MethodsFemale B6C3F1 mice were exposed to these immunosuppressive agents and changes in gene expression and immune cell subpopulations were evaluated.ResultsAll four chemicals induced thymic atrophy and changes in both the relative proportion and absolute number of CD3+, CD4+/CD8−, CD4−/CD8+, and CD4+/CD8+ thymocytes. The most significant impact of exposure to DEX, DES, and CPS was modulation of gene expression in the T-cell receptor (TCR) complex and TCR and CD28 signaling pathways; this could represent a common mechanism of action and play a pivotal role in lineage commitment and development of T cells. Up-regulation of genes associated with the antigen presentation and dendritic cell maturation pathways was the most distinctive effect of TCDD exposure. These elements, which were also up-regulated by DEX and DES, contribute to positive and negative selection.ConclusionsGenomic analysis revealed gene expression changes in several pathways that are commonly associated with xenobiotic-induced immune system perturbations, particularly those that contribute to the development and maturation of thymic T cells.

Black cohosh extracts (BCE; Actaea racemosa) are being used worldwide as an alternative to hormone replacement therapy for the management of menstrual and menopausal symptoms, yet the effects of BCE on the immune system are largely unknown. Female B6C3F1/N mice were treated daily with BCE (0, 62.5, 125, 250, 500, or 1000 mg/kg) for 28 days by oral gavage. Liver weights were significantly increased (26%–32%) at the 1000 mg/kg dose. Dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin were observed. Decreasing trends were observed in all thymic T cell populations, with the most notable dose-responsive effects on immature thymocytes. In the spleen, dose-related decreases were observed in all cell phenotypes evaluated, reaching the level of statistical significance at the 1000 mg/kg BCE dose. Splenic natural killer (NK) cell numbers were significantly decreased at all BCE doses, with the exception of absolute NK numbers at the 125 mg/kg dose. No effects were observed on T-dependent antibody responses of the humoral immune system, including the antibody-forming cell response to sheep erythrocytes (sRBC) and IgM antibody levels to both sRBC and keyhole limpet hemocyanin. Cytotoxic T cell (TCTL) activity was increased, as was the mixed leukocyte response in one of two studies. Anti-CD3 mediated proliferation and the delayed-type hypersensitivity response were unaffected. No effects were observed on innate immunity or on bone marrow cellularity and colony-forming units. Overall, BCE exposure in B6C3F1/N mice for 28 days at doses up to 1000 mg/kg had minimal immune effects, with the exception of an increased TCTL response.