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D R Germolec

Publications and source records attributed to D R Germolec.

At least 19 recordsLinked to original sources
PubMed2005

Modulation of immune response following dietary genistein exposure in F0 and F1 generations of C57BL/6 mice: evidence of thymic regulation.

To further determine whether genistein (GEN) modulation of the immune responses was related to its endocrine-disrupting properties and time of exposure, pregnant C57BL/6 mice were exposed to GEN at 0-1250 ppm in feed starting on day 14 of gestation. The C57BL/6 offspring were exposed to GEN in utero and lactationally, and through feed after weaning until postnatal day 42. In dams, exposure to GEN increased the terminal body weight (250 and 1250 ppm), the number of splenic T cells and NK cells (250 ppm), and the activity of NK cells (250 ppm). In F(1) males, GEN increased the terminal body and spleen weights (25 and 250 ppm), the number of CD4(+)CD8(+) and CD4(-)CD8(+) thymocytes (25 ppm), and the number of splenic T cell subsets and NK cells (25 and 250 ppm). Moreover, splenic NK cell activity and anti-CD3-mediated splenocyte proliferation were increased in all treatment groups. In F(1) females, the percentages of CD4(-)CD8(+) and CD4(-)CD8(-) thymocytes (25 and 250 ppm), and CD4(+)CD8(-) and CD4(+)CD8(+) splenocytes (25 and 250 ppm) were increased. In contrast, the percentage and number of CD4(+)CD8(+) thymocytes were decreased (250 ppm). Exposure to GEN decreased the percentages of splenic NK cells in all treatment groups, and decreased the activity of splenic NK cells at the 25 ppm concentration. Additionally, evaluation of CD25(+) and CD44(+) expression by thymocytes indicated that the decrease in the percentage of CD44(+)CD25(+) thymocytes was at least partially responsible for the decrease in the percentage of CD4(-)CD8(-) thymocytes in F(1) male mice. Overall, the results demonstrate that GEN can modulate the immune system in both adult and developing C57BL/6 mice in a dose-specific manner. The gender-specific effects of GEN on the immune responses in F(1) mice suggest that GEN may modulate the immune system by functioning as either an estrogen agonist or antagonist. The differential effects of GEN on thymocytes in F(1) male and female mice indicate that GEN immunomodulation might be related to its effect on thymus.

Animals↗
PubMed2005

Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolin- or ethinyl estradiol-exposed F1 generations of Sprague-Dawley rats following developmental and adult exposures.

The myelotoxicity of five endocrine active chemicals was evaluated in F1 generation of Sprague-Dawley rats following developmental and adult exposures at three concentration levels. Rats were exposed to genistein (GEN: 25, 250 and 1250 ppm), nonylphenol (NPH: 25, 500 and 2000 ppm), methoxychlor (MXC: 10, 100 and 1000 ppm), vinclozolin (VCZ: 10, 150 and 750 ppm) and ethinyl estradiol (EE2: 5, 25 and 200 ppb) gestationally and lactationally through dams from day 7 of gestation and through feed after weaning on postnatal day (PND) 22 to PND 64. The parameters examined included the number of recovered bone marrow cells, DNA synthesis, and colony forming units (CFU) in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin. Except for the EE2, the concentrations of other individual chemicals in the diet were in an approximate range that allowed for a comparison to be made in terms of myelotoxic potency. Decreases in the DNA synthesis, CFU-GM and CFU-M seemed to be the common findings among the alterations induced by these compounds. Using the numbers of alterations induced by each chemical in the parameters examined as criteria for comparison, the order of myelotoxic potency in F(1) males was: GEN>MXC>NPH>VCZ; the order in females: GEN>NPH>VCZ. Additionally, some of the functional changes induced by these compounds were gender-specific or dimorphic. Overall, the results demonstrated that developmental and adult exposures of F1 rats to these endocrine active chemicals at the concentrations tested had varied degrees of myelotoxicity with GEN being the most potent. Furthermore, the sex-specific effects of these chemicals in F1 male and female rats suggest that there may be interactions between these compounds and sex hormone in modulating these responses.

Animals↗
PubMed2005

Oral exposure to atrazine modulates cell-mediated immune function and decreases host resistance to the B16F10 tumor model in female B6C3F1 mice.

Atrazine (ATZ) is used throughout North America to control annual broadleaf weeds and grasses in various crops including; corn, sorghum, and sugar cane. Unfortunately, contamination of surface and ground water has occurred as a result of ATZ's chemical and physical properties, and its widespread use throughout the U.S. Midwest. A study of ATZ's immunomodulatory properties was conducted using female B6C3F1 mice and a panel of immune assays and host resistance models designed to evaluate cell-mediated and antibody-mediated immunity. Mice were administered ATZ by gavage (0, 24, 250, and 500 mg/kg/day) for 14 days then evaluated for immune responsiveness. ATZ treatment significantly increased the number of splenic CD8+ T cells, cytotoxic T cell and mixed leukocyte responses, and dose-dependently reduced host resistance to B16F10 melanoma. Thymus and spleen weights, total spleen cell numbers and fixed macrophage function was also reduced in mice that were exposed to ATZ. These results demonstrate that oral ATZ exposure is sufficient to alter cell-mediated immune function and disease resistance in female B6C3F1 mice.

Administration, Oral↗
PubMed2005

Dietary methoxychlor exposure modulates splenic natural killer cell activity, antibody-forming cell response and phenotypic marker expression in F0 and F1 generations of Sprague Dawley rats.

Methoxychlor, a chlorinated hydrocarbon pesticide, is a persistent environmental contaminant that has been identified in human reproductive tissues. Methoxychlor has been shown to be estrogenic in both in vivo and in vitro studies. As an endocrine disrupter, it may have the potential to adversely affect endocrine, reproductive, and immune systems in animals. The present study evaluated methoxychlor's immunotoxic potential in F0 (dams) and F1 generations of Sprague Dawley rats exposed to an isoflavone-free diet containing methoxychlor at concentrations of 10, 100, and 1000 ppm. In dams, exposure to methoxychlor from gestation day 7 to postpartum day 51 (65 days total exposure) produced a significant increase in the NK activity (1000 ppm) and the percentages of T cells (1000 ppm), helper T cells (1000 ppm) and macrophages (100 and 1000 ppm). In contrast, a decrease in the numbers of splenocytes and B cells was observed at the 100 and 1000 ppm concentrations. In F1 males, exposure to methoxychlor gestationally, lactationally and through feed from postnatal day 22-64 (78 days total exposure) produced an increase in the spleen IgM antibody-forming cell response to sheep red blood cells (100 and 1000 ppm) and the activity of NK cells (1000 ppm). However, there was a decrease in the terminal body weight (1000 ppm), spleen weight (1000 ppm), thymus weight (100 and 1000 ppm), and the numbers of splenocytes (1000 ppm), B cells (100 and 1000 ppm), cytotoxic T cells (1000 ppm) and NK cells (100 and 1000 ppm). In F1 females, exposure to methoxychlor produced a decrease in the terminal body weight (1000 ppm) and the percentages of cytotoxic T cells (10, 100 and 1000 ppm). These results demonstrate that developmental and adult dietary exposure to methoxychlor modulates immune responses in Sprague Dawley rats. Immunological changes were more pronounced in the F1 generation male rats that were exposed during gestation and postpartum, when compared to the F0 and F1 generation females. Increases in antibody-forming cell response and NK cell activity, and altered spleen cell subpopulation numbers were observed in the F1 generation male rats, without similar changes to the F1 generation females.

Animals↗
PubMed2004

The accuracy of extended histopathology to detect immunotoxic chemicals.

The accuracy of extended histopathology to detect immunotoxic chemicals in female B6C3F1 mice was evaluated under the auspices of the National Toxicology Program (NTP). A workgroup was formed consisting of four pathologists who conducted extended histopathological evaluation of lymphoid tissues obtained from a subset of NTP toxicology studies, in which previously detailed immunotoxicity assessment was performed. In addition, a positive control data set of three known immunosuppressive agents, one negative control data set, and an additional negative control group composed of the vehicle only treated groups were included. Data obtained from extended histopathology evaluations were compared to more traditional immune test results (both functional and nonfunctional) from previously conducted immunotoxicity assessments. Analyses of the data indicated that the ability to identify immunotoxic chemicals using histological endpoints decreased linearly as the level of stringency used to determine significant histopathological changes increased. A relatively high (80%) accuracy level was achieved when histological changes were considered in toto (i.e., any histological abnormality in the three tissues examined), using minimal or mild criteria for scoring. When minimal or mild histological changes were considered significant for a specific tissue, a 60% level of accuracy in identifying immunotoxic chemicals was obtained as compared to a 90% accuracy level that was achieved with this data set using the antibody plaque forming cell response, considered to represent the most predictive functional test. A minimal classification was obtained in the analyses of the negative control groups, suggesting that use of the minimal classification for hazard identification is inappropriate as it will likely result in a high incidence of false positives. This was not the case when mild classifications were used as an indicator of significance, which in most instances allowed the successful identification of negatives. When moderate to marked histopathological changes were used to identify immunotoxic chemicals, the level of accuracy that could be achieved was poor. A considerably higher level of accuracy was obtained for the positive control data set than the test chemical data set suggesting that the ability to detect an immunotoxic agent histologically is proportional to the potency of the immunotoxic agent. Comparison of immune function test results and histopathological results obtained from the high-dose treatment groups and the lower-dose treatment group did not reveal any significant differences between the two endpoints to predict immunotoxicity as a function of dose. Of the three lymphoid organs examined, (i.e., lymph node, thymus, and spleen), the most consistent and discernible histological lesions were observed in the thymus cortical region. These lesions correlated with thymus: body weight ratios and to a slightly lesser extent, the antibody plaque forming cell response. Addition of general toxicological endpoints such as body weight and leukocyte counts did not significantly improve the sensitivity of extended histopathology for this data set. Taken together, these data suggest that, while not as sensitive as functional analyses, extended histopathology may provide a reasonable level of accuracy as a screening test to identify immunotoxic chemicals, provided the level of stringency used to score histological lesions is carefully considered to allow for detection of immunotoxic agents while limiting false positives.

Animals↗
PubMed2004

Sensitivity and predictivity in immunotoxicity testing: immune endpoints and disease resistance.

In spite of extensive laboratory data on the effects of chemicals and drugs on immunologic parameters in laboratory animals, and a well established correlation between suppression of immune function and increased incidence and/or severity of certain infectious and neoplastic diseases, interpreting data from experimental immunotoxicology studies for risk assessment purposes has proved challenging. This is particularly true when the immunological effects are minimal-to-moderate in nature, as might be expected from inadvertent chemical exposures. This review examines the methods used to evaluate immune responses in laboratory rodents and their utility to predict disease outcomes. The available data suggest that if a large enough population is exposed and that the challenge dose or virulence of pathogenic organisms or tumor cells is sufficient, small changes in immune surveillance could increase the background incidence and burden of disease in the human population.

Animals↗
PubMed2004

Micromolar concentrations of sodium arsenite induce cyclooxygenase-2 expression and stimulate p42/44 mitogen-activated protein kinase phosphorylation in normal human epidermal keratinocytes.

Based on evidence that arsenic modulates proinflammatory events that are involved in skin carcinogenecity, we hypothesized that in normal human epidermal keratinocytes (NHEK) arsenic increases expression of the procarcinogenic enzyme cyclooxygenase-2 (COX-2) and that this occurs via specific mitogen and stress signaling pathways. To test this hypothesis, NHEK were exposed to sodium arsenite, and COX-2 expression, prostaglandin E2 (PGE(2)) secretion, mitogen-activated protein kinase (MAPK) phosphorylation, and DNA synthesis were quantified. Inhibitors of p42/44 and p38 MAPKs were used to evaluate the contribution of mitogen and stress signaling to the modulation of COX-2. Our results demonstrate that arsenite (0.005-5 microM) elevates COX-2 expression, PGE(2) secretion (2.5-5 microM), and DNA synthesis (1-5 microM). Arsenite stimulated p42/44 but not p38 MAPK phosphorylation (2.5 microM), responses different than those produced by epidermal growth factor. Inhibition of mitogen-activated protein kinase kinase (MAPKK) and p38 MAPK using PD98059 (20 microM) and SB202190 (5 microM), respectively, attenuated the elevation of COX-2 protein induced by arsenite, whereas physiological concentrations of three COX-2 inhibitors (e.g., NS-398, piroxicam, and aspirin) reduced arsenite-stimulated DNA synthesis. These data indicate that arsenite elevates COX-2 in NHEK at the transcriptional and translational levels as well as increases PGE(2) secretion. Compounds that inhibit COX-2 expression and activity may be useful in the scientific study, prevention, and treatment of arsenic skin carcinogenesis and deserve further investigation.

Arsenites↗
PubMed2004

Nonylphenol alters the activity of splenic NK cells and the numbers of leukocyte subpopulations in Sprague-Dawley rats: a two-generation feeding study.

Nonylphenol (NP) has been identified at low levels in surface waters throughout North America. This industrial chemical is primarily used for the production of certain non-ionic surfactants, and has been reported to have weak estrogen-like activity. As estrogen has immunoregulatory properties and is crucial for normal fetal development, it was hypothesized that adult and developmental exposures to NP had the potential to adversely affect the immune system. Furthermore, developmental exposure to NP might also produce differential immunomodulation in F(1) male and female rats. Thus, a two-generation feeding study was conducted to evaluate the potential for NP to modulate certain immune parameters. Pregnant female Sprague-Dawley rats were exposed to NP (0, 25, 500, and 2000 ppm) in their feed for 65 days, beginning 7 days into gestation. The F(1) generation male and female offspring were exposed in utero at the respective treatment levels, commencing the 7th day of gestation, and continuing through to 64 days of age. Changes in splenic antibody-forming cell response, natural killer cell activity, and leukocyte numbers were used to evaluate NP immunotoxicity. The results from the present study indicate that dietary exposure to NP can increase splenic natural killer (NK) cell activity and splenocyte subpopulation numbers in the F(1) generation rats, without similar changes to the F(0) generation. The immunological changes that were observed in the F(1) generation also appeared to be gender-specific.

Animals↗
PubMed2003

Extended histopathology in immunotoxicity testing: interlaboratory validation studies.

There has been considerable interest in the use of expanded histopathology as a primary screen for immunotoxicity assessment. To determine the utility of a semiquantitative histopathology approach for examining specific structural and architectural changes in lymphoid tissues, a validation effort was initiated. This study addresses the interlaboratory reproducibility of extended histopathology, using tissues from studies of ten test chemicals and both negative and positive controls from the National Toxicology Program's immunotoxicology testing program. We examined the consistency between experienced toxicologic pathologists, who had varied expertise in immunohistopathology in identifying lesions in immune tissues, and in the sensitivity of the individual and combined histopathological endpoints to detect chemical effects and dose response. Factor analysis was used to estimate the association of each pathologist with a so-called "common factor" and analysis-of-variance methods were used to evaluate biases. Agreement between pathologists was highest in the thymus, in particular, when evaluating cortical cellularity of the thymus; good in spleen follicular cellularity and in spleen and lymph node-germinal center development; and poorest in spleen red-pulp changes. In addition, the ability to identify histopathological change in lymphoid tissues was dependent upon the experience/training that the individual pathologist possessed in examining lymphoid tissue and the apparent severity of the specific lesion.

Allergy and Immunology↗
PubMed2003

Thalidomide modulation of the immune response in female B6C3F1 mice: a host resistance study.

Previously, we have reported that thalidomide (Thd) treatment can modulate the immune responses in female B6C3F1 mice. The present study was designed to evaluate whether or not these immunomodulatory responses were of sufficient magnitude to alter host resistances in a number of pathogen and tumor models. B6C3F1 mice were treated intraperitoneally with Thd (30-150 mg/kg) for 14 or 28 days, then inoculated with either Plasmodium yeolii, PYB6 fibrosarcoma tumor cells, B16F10 melanoma tumor cells, Listeria monocytogenes, or Streptococcus pneumoniae. Significant dose-dependent protection against B16F10 and L. monocytogenes was observed in mice that were treated with Thd. Furthermore, time course study using bacterial colony-forming units per spleen and liver as the endpoints indicated that the protective effect of Thd on host resistance to L. monocytogenes was time-dependent. In contrast, Thd treatment did not affect host resistance to P. yeolii, S. pneumoniae and PYB6 tumor. Additionally, the effect of Thd on the phagocytic function of the mononuclear phagocyte system (MPS) was evaluated following intravenous injection of 51Cr-labeled sRBCs. The overall phagocytic activity of MPS was not significantly altered by Thd treatment. In conclusion, these results demonstrate that Thd immunomodulation altered host resistance to B16F10 and L. monocytogenes; and selective modulation of Thd on the immune system may be responsible for the pathogen or tumor-specific effect of this compound.

Adjuvants, Immunologic↗
PubMed2002

Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F(0) and F(1) generations of Sprague-Dawley rats.

The potential effects of the phytoestrogen genistein (GEN) on the immune system were evaluated in both F(0) (dams) and F(1) generations of Sprague-Dawley rats exposed to a soy-free diet containing low (L: 25 ppm), middle (M: 250 ppm), and high (H: 1250 ppm) levels of GEN. In dams, exposure to GEN from Gestation Day 7 to Postpartum Day 51 (totally 65 days) produced a significant increase in NK cell activity (M and H), while a decrease in the percentage of helper T cells (H). In F(1) males, exposure to GEN gestationally, lactationally, and through feed from Postnatal Days 22 to 64 (total 78 days) produced an increase in the relative weights (% body) of spleen (L and H) and thymus (L). Furthermore, exposure to GEN increased the number of splenic B cells (H), T cells (L, M, and H), and T-cell subsets (L, M, and H). Although GEN decreased the percentages of splenic NK cells (L, M, and H), no effect on the activity of NK cells was observed. In F(1) females, exposure to GEN produced a decrease in terminal body weight (H), with an increase in the relative weight of spleen (L, M, and H). Exposure to GEN also increased the number of splenic B cells (L), macrophages (L and M), T cells (H), helper T cells (L and H), and cytotoxic T cells (M and H). Additionally, exposure to GEN increased the percentages of T cells (M and H), helper T cells (H), and cytotoxic T cells (M and H). Moreover, the spleen IgM antibody-forming cell response to sheep red blood cells was enhanced (H), although the percentages of B cells were decreased (M and H). No effect on the activity of NK cells was observed; however, the percentages of splenic NK cells were decreased by GEN (L and H). In conclusion, these results demonstrate that exposure to GEN can modulate the immune responses in Sprague-Dawley rats. Furthermore, the sexual dimorphic effects of GEN in F(1) male and female rats suggest that there may be interactions between GEN and the responses modulated by sex hormones.

Animals↗
PubMed2002

Sodium metasilicate hypersensitivity in BALB/c mice.

BACKGROUND: Sodium metasilicate (SMS) is a key ingredient for a number of industrial and consumer products. Although little is known about potential for this chemical to cause allergic reactions, a similar silicate compound, sodium silicate, was reported to elicit IgE-mediated contact urticaria. OBJECTIVE: The aim of this study was to evaluate the potential for sodium metasilicate to elicit an allergic response in female BALB/c mice after dermal exposure. METHODS: The primary irritancy assay (IA), local lymph node assay (LLNA), and a mouse ear swelling test (MEST) were used to evaluate the hypersensitivity response elicited by SMS exposure. An evaluation of lymph node subpopulations, cytokine mRNA expression, and serum IgE levels was also conducted. RESULTS: SMS caused significant dermal irritation at concentrations >or=6% and an allergic response after mice were sensitized with 4% SMS then challenged with 6% SMS in the MEST. Lymph node cell proliferation was not observed in the LLNA after treatment with SMS (2% to 6% SMS). Increases in lymph node cellularity, the percentage of B cells, and the expression of certain cytokine mRNAs were observed in mice treated with SMS. Changes in the concentration of serum IgE after SMS treatment, however, were not observed. CONCLUSIONS: SMS appears to elicit a chemical hypersensitivity response in mice, as indicated by the MEST, but not by the LLNA. Increases in auricular lymph node cellularity, the percentage of B cells, and certain cytokine mRNAs support classifying SMS as a weak chemical allergen.

Allergens↗
PubMed2001

Gadolinium chloride-induced hepatocyte proliferation is prevented by antibodies to tumor necrosis factor alpha.

Gadolinium chloride (GdCl(3)) destroys large Kupffer cells and has been used extensively in mechanistic studies in a number of disease and toxicity processes; however, it cannot be used to study hepatocyte turnover since it increases cell proliferation itself. The mechanism by which GdCl(3) activates cell turnover in liver is unknown, but several possibilities exist. Here it was demonstrated that a direct mitogenic action on hepatocytes is unlikely since GdCl(3) did not stimulate the growth of primary rat hepatocyte in vitro. Therefore, it was hypothesized that GdCl(3) acts indirectly through mitogenic cytokines of nonparenchymal cell origin. Antibodies to tumor necrosis factor alpha (TNFalpha) were used to evaluate if TNFalpha is causally responsible for GdCl(3)-induced cell proliferation. GdCl(3) treatment of rats in vivo increased hepatocyte replication 5-fold in 24 h and 3-fold in 48 h. Pretreatment with specific anti-TNFalpha antibodies completely prevented these effects. However, when antibody treatment was delayed until 24 h after GdCl(3), increased cell proliferation was not prevented, suggesting that TNFalpha production during the first 24 h after treatment is responsible for activation of a signaling cascade involving other mitogens that sustain hepatocyte replication at 48 h. Twenty-four hours after treatment with GdCl(3), TNFalpha mRNA transcripts were increased 2-fold over control, an effect that was prevented by pretreatment with anti-TNFalpha antibody. NFkappaB, which is known to be involved in TNFalpha transcription, was activated by GdCl(3) about 4.5-fold over control 8 h after treatment in vivo, an increase not observed when antibodies to TNFalpha were present. When GdCl(3) was added to macrophages in culture, TNFalpha was nearly doubled 4 h after treatment. Additionally, conditioned media harvested from macrophages treated with GdCl(3) for 2 to 8 h stimulated the growth of HepG2 cells in culture about 2-fold, while antibodies to TNFalpha completely prevented this effect. Taken together, these data are consistent with the hypothesis that TNFalpha released from Kupffer cells at early time points prior to their destruction is causally responsible for triggering a cascade of events responsible for GdCl(3)-induced cell proliferation.

Animals↗
PubMed2001

Dermal exposure to cinnamaldehyde alters lymphocyte subpopulations, number of interferon-gamma-producing cells, and expression of B7 costimulatory molecules and cytokine messenger RNAs in auricular lymph nodes of B6C3F1 mice.

BACKGROUND: Although the Murine Local Lymph Node Assay (LLNA) is efficient in identifying chemicals with sensitizing potential, there is increasing need for alternative end points. Cinnamaldehyde (CIN) was chosen for evaluation based on its moderate potency and extensive use in fragrance materials. OBJECTIVES: The purpose of the present studies is to incorporate some alternative end points, such as phenotypic analysis and cytokine production, into a modified LLNA/irritancy assay (IA) to evaluate the sensitization of female B6C3F1 mice to CIN. METHODS: Several nontraditional end points, including the analysis of lymphocyte subpopulations, B7 costimulatory molecule and cytokine messenger RNA (mRNA) expression, and intracellular interferon-gamma (IFN-gamma) levels, were incorporated into a modified murine local lymph node (LLNA)/irritancy assay (IA) to evaluate the sensitization of female B6C3F1 mice to cinnamaldehyde (CIN). RESULTS: The alternate end points used in these studies support the classification of CIN as a moderately potent sensitizer. Dermal treatment with CIN resulted in an increase in the percentage of B cells in the auricular lymph nodes (ALNs) and expression of the costimulatory molecule, B7-2, on B cells. Lymph node cells also showed increased transforming growth factor-beta1, migration-inhibition factor, and mild increases in IFN-gamma and interleukin-2 cytokine mRNA expression. Although the increase in IFN-gamma mRNA expression did not translate into increased intracellular IFN-gamma levels, the absolute number of T cells producing IFN-gamma in the ALNs increased. Conversely, the MEST did not classify CIN as a contact allergen. CONCLUSION: The nontraditional end points used in the LLNA/IA were not as sensitive as the traditional radioisotope method used to assess cell proliferation. However, they may help identify compounds inappropriately classified as sensitizers or nonsensitizers by the LLNA and MEST.

Acrolein↗
PubMed2001

Immunotoxicity of sodium bromate in female B6C3F1 mice: a 28-day drinking water study.

Bromate is one of the water disinfection by-products (DBPs) produced during the process of ozonation. The purpose of this study was to evaluate the immunotoxic potential of sodium bromate (SB) in female B6C3F1 mice. SB was administered in the drinking water for 28 days at doses of 80-800 mg/l. There was no difference in drinking water consumption between the animals exposed to SB and the tap water controls. Exposure to SB did not produce any signs of overt toxicity. Furthermore, no significant differences were observed in body weight, body weight gain, or the weights of thymus, liver, kidneys or lungs. No gross pathological lesions were observed in SB-treated animals. However, animals exposed to SB had a significant increase in absolute (28%) and relative (26%) spleen weights. The erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), platelet count, total leukocyte count, and counts of differential leukocytes were unaffected by SB. A dose-related increase in reticulocytes was observed following exposure to SB with the greatest increase (78%) observed at the highest dose level. Overall, there were no changes in the absolute number of total T cells, CD4+CD8- T cells, CD4-CD8+ T cells, natural killer (NK) cells and macrophages. Exposure to SB did not affect the percentage of B cells, although a slight increase in absolute number of B cells at the dose of 600 mg/l was observed. There was no alteration in IgM antibody-forming cell (AFC) response, mixed leukocyte reaction (MLR) and NK cell activity after exposure to SB. When the activity of peritoneal macrophages, unstimulated or stimulated with IFN-gamma and LPS, was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of macrophages on the proliferation of B16F10 tumor cells was decreased after exposure to SB. In conclusion, SB, when administered in the drinking water at doses from 80 mg/l to 800 mg/l, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice.

Animals↗
PubMed2001

Evaluation of the immunomodulatory effects of the macrolide antibiotic, clarithromycin, in female B6C3F1 mice: a 28-day oral gavage study.

The macrolide antibiotic, clarithromycin, is used extensively to treat bacterial infections associated with pneumonia, duodenal ulcers, and the advanced stages of human immunodeficiency viral (HIV) infection. In addition to its antimicrobial properties, several studies have indicated that clarithromycin also has anti-inflammatory and immunomodulatory properties. In this study, clarithromycin's immunomodulatory properties were evaluated using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate, and acquired cellular and humoral immune responses. Female B6C3F1 mice were treated daily by gavage with clarithromycin (0, 125, 250, and 500 mg/kg) for 28 days then evaluated for immunomodulation. Minimal immunological changes were observed after 28 days of treatment. A slight increase in the number of spleen antibody-forming cells was observed at the 250 mg/kg treatment level, but not at other doses. Serum IgM levels were unaffected by the clarithromycin treatment. A significant increase in the number of splenic macrophages was also observed in mice treated with 125 mg/kg of clarithromycin, but this increase was not observed at the other treatment levels. Innate and cell-mediated immunity, as measured by natural killer cell activity, and mixed leukocyte and cytotoxic T cell response, respectively, were unchanged following treatment with clarithromycin. These results suggest that the immune system is not a target for clarithromycin at doses of 500 mg/kg or below.

Adjuvants, Immunologic↗
PubMed2001

Evaluation of the immunomodulatory effects of the disinfection by-product, sodium chlorite, in female B6C3F1 mice: a drinking water study.

Sodium chlorite is an inorganic by-product of chlorine dioxide formed during the chlorination of drinking water. Relatively little is known about the adverse health effects of exposure to sodium chlorite in drinking water. In this study, we evaluated sodium chlorite's immunomodulatory properties using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate and acquired cellular and humoral immune responses. Female B6C3F1 mice were exposed to sodium chlorite in their drinking water (0, 0.1, 1, 5, 15, and 30 mg/L) for 28 days, and then evaluated for immunomodulation. Overall, minimal toxicological and immunological changes were observed after exposure to sodium chlorite. Increases in the percentages of blood reticulocytes, and the relative spleen weights were both observed at different sodium chlorite treatment levels; however, these increases were not dose-dependent. An increasing trend in the number of spleen antibody-forming cells was observed over the range of sodium chlorite concentrations. This increase was not, however, significant at any individual treatment level, and was not reflected by changes in serum IgM levels. A significant increase (26%) in the total number of splenic CD8+ cells was observed in mice treated with 30 mg/L of sodium chlorite, but not at the other concentrations. Splenic mixed leukocyte response and peritoneal macrophage activity were unaffected by sodium chlorite. Lastly, exposure to sodium chlorite did not affect natural killer cell activity, although a decrease in augmented natural killer cell activity (42%) was observed at the lowest sodium chlorite treatment level. These results suggest that sodium chlorite, within the range 0.1-30 mg/L, produces minimal immunotoxicity in mice.

Adjuvants, Immunologic↗
PubMed2001

Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice.

The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels in soy products that has been associated with decreased incidences of breast and prostate cancers. The potential effects of genistein on the immune system were evaluated in adult female B6C3F1 mice. Groups of mice were exposed to vehicle or genistein by gavage for 28 d. The doses of genistein used were 2, 6 and 20 mg/kg body. Consistent with the chemopreventive effect of genistein, exposure to this compound significantly increased host resistance to B16F10 tumor as reflected by a decrease in the number of lung tumor nodules after tumor cell injection at the middle and high dose levels. Inhibition of B16F10 tumor formation was not due to a direct effect of serum genistein and/or its metabolites on the proliferation of B16F10 tumor cells. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed in genistein-treated mice with significant changes observed at the middle and high dose levels. Furthermore, in vitro interleukin (IL)-2-stimulated natural killer (NK) cell activity was significantly enhanced in the high genistein dose group, although the basal NK cell activity was not affected. Although no affect on the mixed lymphocyte responses and anti-CD3 antibody-mediated splenocyte proliferation was observed, exposure to genistein significantly increased basal splenocyte proliferation. Exposure to genistein did not alter the activity of the mononuclear phagocyte system and the cytotoxic/cytostatic function of thioglycollate-recruited peritoneal cells on B16F10 tumor cells. Finally, exposure to genistein did not produce biologically meaningful changes in spleen immunoglobulin (Ig)M and IgG antibody-forming cell responses. In conclusion, genistein enhanced host resistance as evaluated in the B16F10 tumor model, which may be related to the increases in the activities of cytotoxic T cells and NK cells.

Animals↗