T L Bunn

Cornell University, Итак, New York, United States

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Publications (9)16.2 Total impact

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    ABSTRACT: The goals of this project were to determine the conditions for optimal immune assessment following in utero exposure to lead (Pb) and to evaluate the roles of age of assessment, gender, and genetic strain of rat on the observed immunotoxicologic outcomes following exposure. A combined delayed-type hypersensitivity response (DHR) to keyhole limpet hemocyanin (KLH) and anti-KLH IgG antibody were assessed as potential biomarkers for developmental immunotoxicity with age, gender, site of antigenic challenge, and strain as variables. Studies were conducted using both male and female Crl:CD (SD)BR or Fisher 344 rats. The heavy metal, Pb, was used as a known developmental immunotoxin. IgG antibody against KLH antigen was measured using an enzyme linked immunosorbant assay (ELISA). Following sensitization with KLH, animals received a challenge injection in either the earlobe or footpad with KLH and the DTH measured 24 hours later using a spring-loaded caliper. Sprague-Dawley (CD) weanlings produced lower levels of antibody and a decreased DHR compared with adults; only adult males had a significantly increased DHR while both male and female adults produced higher levels of antibody than both genders of weanlings. The DHR was greater in young animals when challenged in the footpad vs. the earlobe. Females had optimum antibody levels with a DHR challenge in the earlobe whereas males had optimum levels when challenged in the footpad. In a strain comparison between weanlings exposed in utero to control or 250 ppm Pb acetate in drinking water and rats examined at five weeks of age, the CD vs. F344 rats had higher antibody responses; in contrast, F344 rats exhibited an elevated DHR. Pb exposure in utero via the pregnant dams produced differential gender effects in the juveniles of both strains. Females had a significantly decreased Pb-induced DHR (p
    No preview · Article · Jan 2015
  • Rodney R Dietert · Terry L Bunn · Ji-Eun Lee
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    ABSTRACT: The delayed-type hypersensitivity (DTH) assay has a lengthy history in immunotoxicity testing since it was one of the original functional assays included in the National Toxicology Program (NTP) immunotoxicology test panel. Based on NTP data analysis, the DTH assay is among the most predictive immunotoxicity tests when included with at least two other immune parameters. The DTH assay has the advantage of being: (1) a useful measure of cell-mediated immunity, (2) an in vivo assay where there is less opportunity for ex vivo confounders and (3) a clinically significant human correlate to the tuberculin test. Disadvantages of the DTH assay are that it is potentially labor-intensive to perform, it is somewhat resistant to automation and, when compared with the cyctotoxic T lymphocyte (CTL) assay, it is a relatively crude measurement. However, some groups have been attempting to address the limitations of the DTH assays (see Note 1). The assay is related to the contact hypersensitivity response (CHR), which is covered in another chapter. The DTH response has been used as an indicator of cell-mediated immune status and is dependent upon both T helper 1(Th1)-driven responses as well as cell recruitment and chemotaxis to a local site. As a result, the DTH functional response may be influenced by disruption of either Th1-driven, antigen-dependent T cell development or mobilization of sensitized T cells to a local site. The present chapter describes four common protocols with consideration restricted to protein and xenogeneic cell immunogens.
    No preview · Article · Jan 2010 · Methods in molecular biology (Clifton, N.J.)
  • R R Dietert · J E Lee · T L Bunn
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    ABSTRACT: While the history of immunotoxicology research involving experimental animals of immature ages dates back over several decades, there exist remarkably little data, to date, directly comparing the impact of developmental status on immunotoxicological risk. Given the size of the nonadult human population and the potential for differential vulnerability among the various ages, this represents a serious gap of knowledge in efforts to minimize environmentally linked health risks. This article frames the issues surrounding developmental immunotoxicological evaluations. In particular, the issues introduced include those of potential animal models, strain/genotype selection, gender, age of exposure, and age of assessment. Recent research results involving early exposure to lead (Pb) and other chemicals are discussed to highlight the nature of the decisions that are available and the potential cost-benefit associated with various approaches to evaluation.
    No preview · Article · Sep 2002 · Human & Experimental Toxicology
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    T L Bunn · P J Parsons · E Kao · R R Dietert
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    ABSTRACT: Previous rat studies with lead (Pb) have shown that exposure throughout the full gestational period results in persistent immunotoxicity detectable in both juvenile and adult offspring. Gender differences are also evident. However, little is known about the persistent immunotoxic effects of Pb when administered during specific stages of embryonic development. Adult Sprague-Dawley female rats were administered Pb acetate (or control acetate) in their drinking water early in gestation (days 3-9) or late in gestation (days 15-21). Significantly depressed delayed type hypersensitivity (DTH) responses as well as elevated IL-10 production, relative monocyte numbers, and increased relative thymic weights were observed in late-gestation Pb-exposed female offspring assessed as adults. In contrast, late-gestation Pb-treated male offspring had significantly increased IL-12 production and decreased IL-10 production, while the DTH response, relative monocyte numbers and thymic weights were unchanged. With early exposure, the primary alteration was decreased nitric oxide production in Pb-treated males, whereas in Pb-treated females nitrite production was unaltered. These results suggest that at the Pb dosage employed, the embryo may be more sensitive to the full range of Pb-induced immunotoxic effects with late gestational Pb exposure, and the effects of Pb on DTH function are more pronounced in females. The data also indicate that adherent splenocytes (probably macrophages) and T lymphocytes are the primary immune cells affected during fetal Pb exposure, and that gender may influence the impact of Pb exposure on these cells. Therefore, additional developmental immunotoxicity studies are needed to examine critical windows of immune development for immunotoxicity and differential susceptibility based on gender.
    Full-text · Article · Dec 2001 · Toxicological Sciences
  • T L Bunn · P J Parsons · E Kao · R R Dietert
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    ABSTRACT: Gender-based differences in immunotoxicity induced by the heavy metal lead (Pb) have been observed both in the juvenile chicken and the adult rat following low-level exposure during embryonic development. To better define the gender-based differences, as related to dose following in utero exposure to Pb, potential differential sensitivities were examined after exposure of F344 rats to low concentrations of Pb (0, 50, 100, or 250 ppm Pb) ad libitum throughout gestation. Immune assessment was performed in juveniles (5 wk old) and young adults (13 wk old). At the highest (250 ppm) Pb concentration examined, the delayed-type hypersensitivity (DTH) response was depressed in females relative to gender-matched controls at both ages; relative spleen weights and relative neutrophil numbers were increased while relative and absolute monocyte numbers and relative basophil numbers were decreased at 13 but not 5 wk of age. In contrast, 250 ppm Pb-treated males did not differ in these endpoints. With in utero exposure to 100 ppm Pb, 13-wk-old females again had decreased relative and absolute monocyte numbers and increased relative neutrophil numbers, although the DTH response was unchanged. Males (with 100 ppm Pb) had increased relative neutrophil numbers, decreased relative lymphocytes, and transiently increased nitrite production seen at 5, but not 13, wk of age. After gestational exposure to 50 ppm Pb, minimal immunotoxic effects were observed in either males or females at either developmental age assessed. These results suggest that differential gender-based immunotoxicity profiles exist after gestational Pb exposure depending on the concentration of Pb administered to the dam. In utero exposure of dams to 250 ppm Pb results in more profound immunotoxicity in females than males. Males arenot more sensitive to lower concentrations of Pb than females. Since the 50 ppm exposure produced minimal changes, these data may provide information to establish a no-observed-adverse-effect level (NOAEL) for in utero exposure to Pb. Additionally, while most effects were evident at both juvenile and adult ages, some changes were not fully evident until measured in the adult. Most changes were persistent with only one exception (male nitrite levels at 100 ppm).
    No preview · Article · Nov 2001 · Journal of Toxicology and Environmental Health Part A
  • T L Bunn · JA Marsh · R R Dietert
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    ABSTRACT: Lead has been shown previously to induce immunotoxic effects on macrophage and T-cell-associated functions after full-gestational exposure. To gain a better understanding of a single developmental exposure and the potential role of gender in immunotoxic responses to low levels of lead, 5-d-old avian embryos were injected once with lead acetate (5 or 10 microg). As juveniles (4 wk of age), animals were immunized with a foreign antigen, bovine serum albumin (BSA). At 6 and 8 wk, animals were sensitized with a self antigen, thyroglobulin (Tg). Immune parameters were examined at 6 and 10 wk of age. In males, anti-BSA immunoglobulin G (IgG) levels were significantly increased at the highest lead treatment level compared to sodium acetate controls, while female antibody production was unaltered. Similarly, after early exposure to lead, males (which were noninducible for anti-thyroglobulin antibodies in sodium acetate controls) were induced to produce autoanti-thyroglobulin IgG. Lead exposure did not markedly alter autoantibody levels in females, although, unlike males, control females could be induced to produce autoantibody to thyroglobulin. Males differed significantly in total leukocyte counts between treatment groups, whereas females did not. No marked differences were observed in males or females in the delayed-type hypersensitivity response, lymphocytic infiltration of thyroids, or in spleen, thymus, or bursa weights following exposure to lead. These results suggest that there is a differential immunotoxic effect based on gender after a single in ovo exposure to lead. Therefore, when examining the developmental immunotoxic effects of a metal such as lead, gender is a potential risk factor.
    No preview · Article · Jan 2001 · Journal of Toxicology and Environmental Health Part A

  • No preview · Chapter · Jan 2001
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    ABSTRACT: The objective of this research was to determine whether immunotoxicological test procedures optimized to evaluate the immune system of adults could be integrated into studies with younger animals. All studies were conducted using both male and female Crl:CD  (SD)BR rat pups and weanlings. Baseline values for absolute and relative splenic lymphocyte populations were quantified using flow cytometry in unimmunized animals. Baseline values for the primary humoral immune response to sheep red blood cells (SRBC) were established and optimized using either an enzyme linked immunosorbant assay (ELISA) or the plaque forming cell (PFC) assay. The impact of SRBC immunization on the histology of the spleen was also evaluated. Responses for each age group were compared both within and between litters. Analysis by flow cytometry indicated that 10-day-old rat pups have significantly lower B and T cell numbers compared to weanlings and adults. Due to the difficulty in administering SRBC by tail vein injection, rat pups received SRBC intraperitoneally; but were still unable to generate a primary IgM response. Histologically, no germinal centers were observed in rat pups immunized with SRBC. Taken together, the above results suggest that the spleens of rat pups consist predominantly of functionally immature lymphocytes. Analysis by flow cytometry indicated that weanlings have similar levels of B and T cells compared to adults. Results with the ELISA indicated that the SRBC-specific IgM antibody titer for weanlings was considerably less compared to the titer obtained for young adult rats, while results with the PFC assay indicated a response in weanlings which was within the historical range of responses for adult rats. The latter results were consistent with the histological analysis in that prominent germinal centers were observed in weanlings immunized with SRBC. Based on our flow cytometric, ELISA, and PFC assay data, the litter can be used as the unit of comparison for developmental immunotoxicity. Our results with SRBC suggest that it may not be possible to evaluate a humoral immune functional parameter in rat pups due to the apparent immature status of their immune cells; however, additional antigens need to be examined. Results in weanlings suggest that an antibody response of sufficient magnitude to SRBC can be demonstrated with the PFC assay; but that a high background may preclude the use of the SRBC-specific IgM ELISA. This project was a two-year project and is completed. Publication/presentation information:
    Full-text · Article · Oct 2000 · Toxicology Mechanisms and Methods
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    ABSTRACT: Lead has been shown to exert toxic effects during early development. In these in vivo and ex vivo experiments, the effect of lead on the immune system of the developing embryo was assessed. Nine-week-old female Fischer 344 rats were exposed to lead acetate (0, 100, 250, and 500 ppm lead) in their drinking water during breeding and pregnancy (exposure was discontinued at parturition). Offspring received no additional lead treatment after birth. Immune function was assessed in female offspring at 13 weeks of age. Dams in lead-exposed groups were not different from controls with respect to the immune endpoints used in these experiments; however, in the offspring, lead modulated important immune parameters at modest exposure levels. Macrophage cytokine and effector function properties (tumor necrosis factor-alpha and nitric oxide production) were elevated in the 250 ppm group, while cell-mediated immune function was depressed, as shown by a decrease in delayed-type hypersensitivity reactions in the 250 ppm group. Interferon-gamma levels were decreased in the 500 ppm treatment group. Serum levels of IgE were increased in rats exposed to 100 ppm lead. These results indicate that exposure of mothers to moderate levels of lead produces chronic immune modulation in their F344 rat offspring exposed in utero. Since the mothers were not susceptible to chronic immune alterations, a developmental bias to the immunotoxic effects of lead is indicated. The differences observed are consistent with the possibility that lead may bias T helper subset development and/or function, resulting in alterations in the balance among type 1 and type 2 immune responses.
    Full-text · Article · May 1998 · Toxicological Sciences