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R R Dietert

Publications and source records attributed to R R Dietert.

At least 19 recordsLinked to original sources
PubMed2001

Gender-based profiles of developmental immunotoxicity to lead in the rat: assessment in juveniles and adults.

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).

Aging↗
PubMed2001

Developmental windows of differential lead-induced immunotoxicity in chickens.

The developing immune system of rodents has been shown to exhibit increased sensitivity to lead-induced immunotoxicity compared with that of adults. However, little is known about potential windows of increased vulnerability during discrete periods of embryonic development. To investigate differential embryonic sensitivity to lead-induced immunotoxicity, sublethal doses of lead ranging from 5 to 400 microg/egg were introduced into fertilized Cornell K Strain White Leghorn chicken eggs via the air sac at one of four different stages of embryonic development (5, 7, 9, and 12 days of incubation, designated as E5, E7, E9, and E12, respectively). Lead levels of blood and bone were determined at hatching and lead-induced immunotoxicity was evaluated in 5-6 week old young chickens using a delayed-type hypersensitivity (DTH) reaction against bovine serum albumin (BSA), macrophage production of nitric oxide, and interferon-gamma (IFN-gamma) production by splenic lymphocytes as immune indicators. Splenic lymphocyte production of IFN-gamma was significantly suppressed (measured for E7 and E9 exposures only, P<0.05) among lead treated groups when compared with controls. Macrophage production of nitric oxide (measured as nitrite production) was significantly depressed (P<0.05) following E5, E7, and E9 lead exposures but not following E12 lead exposure. In contrast with this pattern, DTH function was unaltered following the E5, E7, and E9 exposures, but was significantly depressed (P<0.05) after E12 exposure to lead. Since the same lead dose (200 microg/egg) given at E9 and E12 produced the same blood and bone lead levels and resulted in a different outcome regarding DTH function, the capacity of lead to influence DTH function appeared to emerge between days 9 and 12 of in ovo development. Based on these results, it is hypothesized that lead exposure during different windows of embryonic development is likely to result in different immunotoxic outcomes in the juvenile.

Animals↗
PubMed2001

Exposure to lead during critical windows of embryonic development: differential immunotoxic outcome based on stage of exposure and gender.

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.

Adjuvants, Immunologic↗
PubMed2000

Gender differences in developmental immunotoxicity to lead in the chicken: analysis following a single early low-level exposure in ovo.

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.

Animals↗
PubMed2000

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

Child↗
PubMed1999

Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (DMSA) on immune function and lead-induced immunotoxicity.

Meso-2,3-dimercaptosuccinic acid (DMSA) is a drug currently employed for cheltion therapy in lead poisoning; however, little is known about its potential effects on the immune system. To examine the effect of DMSA and its capacity to reverse immunotoxicity resulting from exposure to lead in utero, female Fischer 344 rats were administered lead acetate in drinking water from 2 weeks prior to mating until parturition; DMSA was given by gavage on days 6-21 of gestation. The immune function of the female offspring was tested at 13 weeks of age. The results showed that lead (250 ppm) suppressed Th1-type responses (delayed-type hypersensitivity (DTH), interferon gamma (IFN gamma) production), enhanced a Th2-type response (interleukin-4 (IL-4) production), and increased tumor necrosis factor alpha (TNF alpha) production from macrophages. DMSA treatment (60 mg/kg per day) during pregnancy significantly lowered the blood lead levels of both the embryos and the lactating dams as well as the milk lead level of lactating dams. The chelation treatment also reversed the lead-induced alterations in pup body weight, relative spleen weight, TNF alpha, and IL-4 production. But in utero exposure to DMSA alone resulted in decreased DTH response in adult offspring. This was likely due to a reduced cell recruitment, since plasma monocyte chemoattractant protein-1 (MCP-1) levels were decreased. The DMSA-exposed offspring also demonstrated increased interleukin-2 (IL-2) production. These results suggest that DMSA reverses some of the lead-induced immunotoxicity; however, this treatment itself during embryonic development produces subsequent adult immunomodulation.

Animals↗
PubMed1999

Influence of dietary arginine concentration on lymphoid organ growth in chickens.

In vivo effects of graded dietary levels of arginine on the body and lymphoid organs were investigated using Cornell K strain chickens of the B15/B15 haplotype. Two-week-old birds were fed an arginine-deficient basal diet (0.53% arginine) supplemented with additional arginine (up to 1.0% L-arginine to the diet). At four weeks of age, body weight, lymphoid organ weight, and concentrations of amino acids in plasma were measured. Arginine supplementation produced significant increases in plasma arginine (from 200 nM in chicks fed the basal diet to 2,000 nM in chicks receiving the 1.5% arginine diet) and ornithine concentrations (from 17 nM in chicks fed the basal diet to 500 nM in chicks receiving the 1.5% arginine diet). The arginine-deficient diet reduced body weight gain (P < 0.0001) and thymus, spleen, and bursa of Fabricius weights (P < 0.05). In contrast to the bursa weight, the thymus and spleen weights, as percentages of body weight, were also decreased (P < 0.05). This study suggests that arginine markedly influences lymphoid organ development, with a more pronounced effect on the thymus and spleen than on the bursa of Fabricius.

Amino Acids↗
PubMed1998

Developmental exposure to lead causes persistent immunotoxicity in Fischer 344 rats.

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.

Animals↗
PubMed1998

Avian macrophage metabolism.

This review considers the role of avian macrophages as a source of immune effector and immunoregulatory metabolites. Although considerable attention has been given to the importance of leukocytic cytokines, particularly the monokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta), metabolites produced by macrophages appear to be of equal importance in determining the progression of immune responses. The three metabolite categories that have received the greatest attention are the reactive oxygen species (ROS), the reactive nitrogen intermediates (RNI), and the eicosanoids. Additionally, the xenobiotic metabolites produced via cytochrome P450 activity mediate some immune-environmental interactions. Each of these four metabolite categories is subject to different requirements for metabolite production, and each has distinct effector functions. An understanding of macrophage metabolite regulation could allow improvements in avian health management and production via the effective control of metabolite production. The present review considers prior and recent information on the production of the metabolites by avian macrophages. Additionally, the potential ramifications of metabolite production and regulation are discussed.

Animals↗
PubMed1998

Chemical sensitivity and the immune system: a paradigm to approach potential immune involvement.

This paper approaches the issue of chemical sensitivity and the immune system though a consideration of established environmentally-induced immune alterations which have particular relevance to the broader topic of chemical sensitivity. Additionally, the report discusses the potential problems associated with prior narrow evaluation strategies for the assessment of environmentally-induced inflammation. A combined approach to assessment drawing upon biomarkers of both the immune and neurological systems is suggested. Such an approach recognizes the key roles which mediators of these two systems play in facilitating host inflammatory responses. The paper concludes with a discussion of the types of specific immune alterations which, from a mechanistic perspective, are likely to be involved with any linkage of chemical sensitivity to the immune system.

Environmental Exposure↗
PubMed1997

Characterization of leukotriene production in vivo and in vitro in resident and elicited peritoneal macrophages in chickens and mice.

Previously, we reported differences in arachidonic acid metabolism in elicited chicken peritoneal macrophages when compared with murine resident and elicited peritoneal macrophages. We now describe leukotriene (LT) production in the same systems, using resident (murine) and inflammatory macrophages (from both species). Inflammatory (4- or 42-g Sephadex-elicited) peritoneal macrophages from chickens lacked the capacity to produce LT in vivo (following opsonized zymosan [OZ] stimulation) or in vitro, in response to A23187. In addition, chicken macrophages were unable to metabolize exogenously added LTC4 or LTD4 in vitro. In contrast, resident murine peritoneal macrophages produced measurable quantities of LTs (in vivo) within 5 min with an 8-fold increase after 45 min. LTC4 was effectively converted to LTE4 in vivo in a time-dependent manner (65% LTC4/35% LTE4 after 5 min stimulation with OZ and 6% LTC4/94% LTE4 after 60 min stimulation), but no in vitro. The lack of LTC4 metabolism to LTE4 in vitro could not be explained by cell-cell interaction between adherent and nonadherent cells. LTD4 was not detected under any experimental condition. Murine peritoneal cells incubated with LTD4 (with or without agonist) produced LTE4 in a time-dependent fashion. Addition of L-cysteine (a dipeptidase inhibitor) did not explain the lack of detectable levels of LTD4 following intraperitoneal stimulation with OZ. These results suggest that elicited chicken peritoneal macrophages are incapable of producing LTs compared to murine peritoneal macrophages. In addition, these studies fail to explain the different product profiles with in vivo stimulation of murine peritoneal macrophages as compared to in vitro stimulation.

Animals↗
PubMed1996

Inhibition of nitric oxide synthase gene expression in vivo and in vitro by repeated doses of endotoxin.

We have examined the effects of repeated endotoxin administration in vivo and in vitro on the induction of nitric oxide synthase (NOS). In vivo, hepatic NOS activity and mRNA were increased markedly by the administration of Escherichia coli lipopolysaccharide (LPS). The change in hepatic NOS activity coincided with a marked accumulation of hepatic citrulline. Both enzyme activity and citrulline concentration returned to normal by 12 h after LPS administration. At this time, a subsequent administration of endotoxin caused no change in either NOS mRNA, NOS activity, or citrulline concentration, and thus an endotoxin-refractory state for nitric oxide (NO) synthesis was established. Normal sensitivity was reestablished by 24 h after the initial dose. In vitro studies using both a macrophage cell line (HD11) and primary macrophages indicated that LPS pretreatment caused cells in culture to become completely refractory to subsequent stimulation by LPS. Finally, we tested the hypothesis that NO may be involved in the development of the refractory state. Various inhibitors blocked the initial synthesis of NO by > 90% but failed to influence the development of the refractory state. Our study demonstrates both in vivo and in vitro that NO synthesis is completely blocked after repeated exposure to endotoxin by a mechanism that appears to be pretranslational. This model of early endotoxin tolerance may provide insight into the molecular mechanisms that regulate expression of the NOS gene.

Animals↗
PubMed1996

Toxicological considerations in evaluating indoor air quality and human health: impact of new carpet emissions.

This review article considers evidence regarding the toxicological impact of new carpet emissions on indoor air quality and human health. It compares emissions data from several studies and describes the dominant compounds found in those emissions. The toxicity of each these compounds is assessed for animal and human data, with a focus on inhalation exposure. Data for acute and chronic exposures are presented, and synergistic effects are considered. Differences and similarities between health responses caused by toxicity and/or by immunological reactions are discussed. Possible neurogenic pathways and associations between these and immune changes are considered as they might relate to inflammatory-based human reactions. Additionally, factors affecting human odor responses are described. The roles that a variety of psychological factors may also play in the etiology of potentially related phenomena, such as the sick building syndrome, pathogenic illness, and multiple chemical sensitivity, are considered. Gaps in the literature are identified within the article and suggestions for future research are offered. In particular, it is noted that few, if any, prior studies have evaluated both neurogenic and immune-mediated inflammation status within the same study. Based on the present information available, it is concluded that under normal environmental circumstances, VOC emissions from new carpets are sufficiently low such that they should not adversely affect indoor air quality or pose significant health risk to people.

Air Pollutants↗
PubMed1994

Nitric oxide (.NO)-induced mitochondrial injury among chicken .NO-generating and target leukocytes.

In an analysis of nitric oxide (.NO) production and toxicity, chicken macrophage-generated .NO inhibited mitochondrial activity in both .NO-producing macrophages themselves and lymphoid tumor targets. However, differences in targeting of mitochondrial toxicity were observed among these cells. Two chicken macrophage cell lines, HD11 and MQ-NCSU, produced .NO (measured as nitrite) dependent upon concentrations of L-arginine and bacterial endotoxin (lipopolysaccharide). Mitochondrial activity was negatively correlated with the amount of .NO produced. Using a modified MTT assay, .NO induced suppression in two mitochondrial complexes. Mitochondrial activity was significantly suppressed among HD11 cells receiving LPS alone (complex I, 63.0 +/- 5.5% suppression; complex II, 27.9 +/- 5.2%). In contrast, mitochondrial activities in samples receiving LPS plus inhibitor, NG-nitro-L-arginine methyl ester (NAME; 5 mM) or 2,4-diamino-6-hydroxypyrimidine (DAHP; 5 mM), were not significantly different from control values. When HD11 macrophages were cocultured with lymphoblastoid tumor targets, RECC-CU60 (T cell) or LSCC-RP9 (B cell), adding LPS (1 microgram/ml), tumor cell mitochondrial activity was significantly suppressed. In the generator macrophages, complex I was more suppressed than complex II, whereas in lymphoid targets no such difference was observed. These results indicate that .NO inhibits complex I and II mitochondrial activity but that differential targeting can occur among chicken leukocyte populations.

Animals↗
PubMed1994

2,4-Diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, suppresses nitric oxide production by chicken macrophages.

Biosynthesis of nitric oxide (.NO) from L-arginine by nitric oxide synthase (NOS) represents a major cytotoxic effector function of macrophages. It has been shown that most mammalian NOS requires tetrahydrobiopterin (BH4) as a cofactor and that inhibition of BH4 synthesis results in suppressed .NO production. Chicken L-arginine metabolism differs from that of mammals in that chickens cannot synthesize L-arginine de novo. Therefore, it is important to examine whether chicken macrophage .NO synthesis is also BH4-dependent. 2,4-diamino-6-hydroxypyrimidine (DAHP), a specific inhibitor for GTP cyclohydrolase I (GTP-CH; EC 3.5.4.16), the rate-limiting enzyme in de novo pterin synthesis, was used to block synthesis of BH4. Both chicken peritoneal macrophages (PECs) and the avian MC29 virus-transformed macrophage cell line, HD11, exhibited a dose-dependent reduction in .NO production (measured as nitrite accumulation) relative to DAHP concentration. Authentic BH4 and a substrate for pterin salvage pathway of BH4 synthesis, sepiapterin, were both capable of restoring the production of .NO in DAHP-treated PECs and HD11 macrophages. These results suggest that chicken macrophages require active synthesis of BH4 to produce .NO and that chemicals interfering with BH4 synthesis may result in suppressed .NO production and, hence, .NO-mediated immune function.

Animals↗
PubMed1994

Effect of dietary vitamin E and selenium deficiency on chicken splenocyte proliferation and cell surface marker expression.

Beginning at hatching, chicks were fed a Basal diet, without vitamin E or selenium (Se) or the same diet supplemented with vitamin E (100 IU/kg) and Se (0.2 ppm). The effect of these treatments on the expression of cell surface markers (CT-1a, CD3, CD4, CD8, sIgs, and Ia) defining specific thymocyte and peripheral blood leukocyte (PBL) subpopulations were examined using flow cytometric analyses. In parallel studies the effect of the dietary deficiencies on splenocyte proliferative responses to ConA or PHA stimulation was examined. The mean expression of CD3 and CT-1a per cell was increased while CD8 and CD4 expression was decreased on thymocytes from chicks fed the Basal diet. The proportion of double negative (CD4-, CD8-) thymocytes and single positive CD8+ thymocytes was significantly decreased while single positive CD4+ and double positive (CD4+, CD8+) thymocytes were significantly increased by the dietary vitamin E and Se deficiencies. The dietary deficiencies resulted in a decreased proportion of peripheral T cells and specifically decreased the number of CD4+ PBL. The proliferative response to both ConA and PHA was impaired by the vitamin E and Se dietary deficiencies. The proliferative response could be fully reconstituted but only after vitamin E and Se supplementation for periods longer than 1 week. Plasma SeGSHpx and alpha-tocopherol levels paralleled the mitogen responsiveness observed. These results support the conclusion that vitamin E and Se deficiencies may affect both the maturation of specific lymphocyte subpopulations and the functional and proliferative capabilities of the peripheral lymphocytes.

Animals↗
PubMed1994

Profiles of chicken macrophage effector functions.

In contrast to the mammalian system, avian species lack the so-called "resident" or "harvestable" macrophage population in the abdominal exudate. However, macrophages can be recruited into the chicken's abdominal cavity (presumably from the blood monocyte pool) if an inflammatory agent such as Sephadex is injected. The kinetics of inflammatory cell recruitment in terms of time, cell type, and state of activation to perform a particular effector function is currently an active area of research. This report will provide information on several chicken macrophage effector functions, including in vivo chemotaxis, phagocytosis, bacterial uptake and killing, biosynthesis of nitric oxide and various enzymes, and monokines such as interleukin-1 and granulocyte colony-stimulating factor.

Acid Phosphatase↗