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Rodney R Dietert

Publications and source records attributed to Rodney R Dietert.

13 recordsLinked to original sources
PubMed2007

Methodologies for developmental immunotoxicity (DIT) testing.

Developmental immunotoxicity has gained increasing recognition as a significant factor influencing the risk of later life disease. Based on the data collected thus far on different chemicals and drugs, the developing immune system can be significantly more sensitive than the adult immune system to xenobiotic-induced insult. There are distinct differences between the immune system surrounding birth and that in the mature adult as well as differences in the nature of immunotoxic changes based on age. Immunosuppresssion is not the only concern. Immunotoxic changes that increase the risk for allergic or autoimmune responses should also be considered. Therefore, one should not assume that immunotoxicity assays validated for adult exposure assessment are inherently the most predictive for developmental immunotoxicology (DIT) evaluation. Many of those adult-based protocols were developed solely to detect immunosuppression, whereas DIT concerns include shifts in immune balance. For this reason, it is useful to examine the various immune endpoints that have been employed in recent perinatal immunotoxicity studies, compare those against routine adult immunotoxicity evaluation protocols, and consider the options that are available for effective DIT testing. The results published on several chemicals and drugs in recent years suggest that functional tests are a front-line priority for perinatal immunotoxicity detection and that a combination of at least two functional tests (such as a multi-isotype T-dependent antibody response (TDARs), and a cell-mediated immune response assay such as the delayed-type hypersensitivity assay and/or T cell or NK cytotoxicity assays) should be paired with immune cell populations and histopathological analysis. Cytokine production measurements offer outstanding promise and may eventually be able to be substituted for other more laborious procedures. However, multi-cytokine analysis needs to be standardized in terms of optimum source for analysis and protocol.

Animals↗
PubMed2006

Lead and immune function.

The heavy metal lead is a widely deposited environmental toxicant known to impact numerous physiological systems, including the reproductive, neurological, hepatic, renal, and immune systems. Studies illustrating the capacity of lead to impair immune function and/or host resistance to disease date back to at least the 1960s. However, it has only been in recent years that lead has been recognized among a new category of immunotoxicants-those that dramatically shift immune functional capacity while producing only modest changes to immune cell populations and lymphoid organs. These relatively noncytotoxic immunomodulating chemicals and drugs represent the immunotoxic hazards most difficult to identify and problematic for risk assessment using historic approaches. As a result, such environmental factors are also among the most likely to contribute to chronic immune-related disease at relevant exposure levels. This review considers the animal and human evidence that lead exposure can produce a stark shift in immune functional capacity with a skewing predicted to elevate the risk of atopic and certain autoimmune diseases. At the same time, host defenses against infectious agents and cancer may be reduced. Age-based exposure studies also suggest that levels of blood lead previously thought to be safe, that is, below 10 microg/dl, may be associated with later life immune alterations.

Animals↗
PubMed2006

Induction of asthma and the environment: what we know and need to know.

The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop "Environmental Influences on the Induction and Incidence of Asthma" to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment.

Adolescent↗
PubMed2006

Perinatal immunotoxicity: why adult exposure assessment fails to predict risk.

Recent research has pointed to the developing immune system as a remarkably sensitive toxicologic target for environmental chemicals and drugs. In fact, the perinatal period before and just after birth is replete with dynamic immune changes, many of which do not occur in adults. These include not only the basic maturation and distribution of immune cell types and selection against autoreactive lymphocytes but also changes designed specifically to protect the pregnancy against immune-mediated miscarriage. The newborn is then faced with critical immune maturational adjustments to achieve an immune balance necessary to combat myriad childhood and later-life diseases. All these processes set the fetus and neonate completely apart from the adult regarding immunotoxicologic risk. Yet for decades, safety evaluation has relied almost exclusively upon exposure of the adult immune system to predict perinatal immune risk. Recent workshops and forums have suggested a benefit in employing alternative exposures that include exposure throughout early life stages. However, issues remain concerning when and where such applications might be required. In this review we discuss the reasons why immunotoxic assessment is important for current childhood diseases and why adult exposure assessment cannot predict the effect of xenobiotics on the developing immune system. It also provides examples of developmental immunotoxicants where age-based risk appears to differ. Finally, it stresses the need to replace adult exposure assessment for immune evaluation with protocols that can protect the developing immune system.

Adult↗
PubMed2005

Impact of in ovo-administered lead and testosterone on developing female thymocytes.

The developing immune system is particularly sensitive to lead-induced immunotoxicity, but in some models, genders can differ in lead-induced immunotoxicity. Using an avian in ovo model of lead-induced T-helper disruption, the ability of in ovo administered lead and testosterone to alter thymocyte maturation among female embryos was investigated. On embryonic day (E) 8, Cornell K-strain embryos were given either testosterone (12.5 microg/egg in ethanol) or 15% ethanol in 100 microl volume. The groups then received either lead acetate (200 microg/egg) or sodium acetate (control) on E 12 of incubation. On E 20, thymocytes from 4-5 female embryos per group were analyzed by flow cytometry for cell surface markers CD3, CD4, CD8, TCR1, and TCR2. Lead alone did not induce any appreciable changes among the cell populations measured in this study. However, when testosterone treatment was followed by lead (testosterone + lead), there was a significant increase in CD4+CD8+ double-positive cells compared with either control or lead treatment groups. Testosterone, either by itself or in combination with lead, significantly reduced the percentage of cells with the CD4+CD8- phenotype when compared to the lead alone group. No change was detected with respect to the CD4-CD8+, CD4-CD8-, TCR1+, and TCR2+ phenotypes following any treatment. Therefore, sex hormonal balance in early life appears to influence the manner in which the developing thymus responds to the heavy metal lead.

Animals↗
PubMed2005

Developmental immunotoxicity of cyclosporin-A in rats: age-associated differential effects.

Cyclosporin-A (CYP-A) is a widely used immunosuppressive drug. Yet, information on the long-term impact of embryonic exposure is relatively scarce. The effects of CYP-A on reproductive and immunologic parameters in CD strain female offspring exposed in utero at doses of 0, 0.2, 2, 10, or 20 mg/kg/day (from gestational day 6 to 21) were compared against identically dosed CD adult rats. Embryotoxicity was seen at the two highest doses. CYP-A was acutely immunotoxic in adults (tested at 20 mg/kg/day dose) but with minimum long-term effects. In contrast, the offspring experienced relatively persistent alterations. CYP-A exposure increased ano-genital distance in the neonates. In the 5-week-old offspring, the delayed type hypersensitivity (DTH) response and splenic B cell number (determined by flow cytometry) were both decreased at the 2 mg dose level. IL-4 level was reduced and blood monocytes were increased at both exposure doses. All other parameters were unchanged. In the adult offspring (13-week-old), no difference was seen in either the DTH response or B cell ratios, but IL-4 level was increased at 2 mg/kg/day, and anti-KLH IgG titer decreased at both doses. In exposed non-pregnant adults, changes were minimal following a 13-week recovery period. Blood neutrophils were increased at all doses of the drug and flow cytometry data suggested some perturbation in CD4(+)CD8(+) cells, macrophages, and B-cells. All other parameters were unchanged. In conclusion, the adult rodent immune system largely recovers from CYP-A exposure given sufficient time. However, embryonic exposure appears to produce a series of immune perturbations including functional impairment during postnatal maturation.

Animals↗
PubMed2004

Symposium summary: children's health risk--what's so special about the developing immune system?

In recent years, there has been increasing regulatory pressure to protect the health of children, with the basic tenet being that children differ significantly from adults in their biological or physiological responses to chemical exposures. In a regulatory context, this has been translated to mean a requirement for an additional 10-fold safety factor for environmental contaminants, specialized tests, or both. Much of the initial focus has been on the developing endocrine and nervous systems; but increasingly, the developing immune system has been identified as a potential target organ for chemically mediated toxicity. More recently, the question has been raised regarding whether the current state of science supports the creation of developmental immunotoxicology (DIT) test guidelines. What is needed is a risk-based evaluation of the biology associated with the proposed differential sensitivity between children and adults and the impact of that assessment on additional regulatory measures to protect children in risk assessment analyses. Additionally, an understanding of whether the developing immune system shows greater susceptibility, either qualitatively or quantitatively, to chemical perturbation is critical. To address the question "What's so special about the developing immune system?" a symposium was organized for the 2003 Society of Toxicology annual meeting that brought together risk assessors, clinicians, immunologists, and toxicologists.

Adolescent↗
PubMed2004

Developmental immunotoxicology of lead.

The heavy metal, lead, is a known developmental immunotoxicant that has been shown to produce immune alterations in humans as well as other species. Unlike many compounds that exert adverse immune effects, lead exposure at low to moderate levels does not produce widespread loss of immune cells. In contrast, changes resulting from lead exposure are subtle at the immune cell population level but, nevertheless, can be functionally dramatic. A hallmark of lead-induced immunotoxicity is a pronounced shift in the balance in T helper cell function toward T helper 2 responses at the expense of T helper 1 functions. This bias alters the nature and range of immune responses that can be produced thereby influencing host susceptibility to various diseases. Immunotoxic responses to lead appear to differ across life stages not only quantitatively with regard to dose response, but also qualitatively in terms of the spectrum of immune alterations. Experimental studies in several lab animal species suggest the latter stages of gestation are a period of considerable sensitivity for lead-induced immunotoxicity. This review describes the basic characteristics of lead-induced immunotoxicity emphasizing experimental animal results. It also provides a framework for the consideration of toxicant exposure effects across life stages. The existence of and probable basis for developmental windows of immune hyper-susceptibility are presented. Finally, the potential for lead to serve as a perinatal risk factor for childhood asthma as well as other diseases is considered.

Aging↗
PubMed2003

Developmental immunotoxicity of dexamethasone: comparison of fetal versus adult exposures.

Dexamethasone-21 phosphate was administered (s.c.) to pregnant CD rats at days 6-21 of gestation (0, 0.0625, 0.125, 0.25, and 0.5 mg/kg/day) with identical exposure of non-pregnant adult females. Some reproductive (anogenital distance) and growth (body weight) measures of pups were altered. In the juvenile (5 weeks), the delayed type hypersensitivity response to KLH was significantly reduced at all doses examined and this pattern continued into adulthood (13 weeks). In contrast, the DTH response of adults exposed to DEX was unaltered even at the highest dose. Few DEX-induced changes were seen in offspring or adult blood parameters or in splenocytes analyzed for cell surface makers (by flow cytometry). The thymus of both exposed pups (both ages) and adults showed a marked reduction in the medulla/lobe area beginning with the 0.125 mg/kg/day DEX exposure level. Macrophage production of TNF and NO was only marginally affected as was splenocyte production of IL-4 and IFN-gamma. In contrast, pups assessed as juveniles were significantly depressed in splenic IL-2 and IL-10 production. DEX exposure altered serum antibody levels across age groups with an increase of KLH-specific IgG (beginning with the 0.0125 mg/kg/day dose) while total IgE was reduced. These results suggest that while DEX exposure produces some common alterations following in utero versus adult exposure, fetal exposure (even at the lowest doses tested) produces marked and persistent functional loss (DTH) not evident in exposed adults. Furthermore, there was no apparent advantage in delaying immune assessment until the offspring reached adulthood.

Animals↗
PubMed2003

Developmental immunotoxicity of lead: impact on thymic function.

BACKGROUND: Since the potential effects of early exposure to lead on thymic functions have not been fully characterized, in this study we evaluated the capacity of lead to alter thymic function in juvenile chickens following embryonic exposure. METHODS: Cornell K strain White Leghorn chicken eggs were administered lead acetate (400 microg/egg) or sodium acetate (control) on embryonic development (E12) with and without thymulin supplementation. Ex vivo production of interferon-gamma (IFN-gamma)-like cytokine by thymocytes and a delayed-type hypersensitivity (DTH) reaction were measured in the juvenile. Additionally, the effects of in vitro exposure to lead on both thymocytes and thymic stromal cells (TSCs) were evaluated. RESULTS: Following E12 exposure to lead, ex vivo production of IFN-gamma-like cytokine by juvenile-derived thymocytes decreased significantly compared to the control. The same effect was observed when thymocytes were directly exposed to lead in vitro and stimulated with thymic stromal supernatant. In contrast, when TSCs were exposed to lead in vitro, no change was seen in their functional capacity for promoting cytokine production. In ovo supplementation with thymulin partially reversed lead-induced DTH depression without any change in IFN-gamma-like cytokine production. Embryonic exposure to thymulin alone partially depressed the DTH response. CONCLUSIONS: These results suggest that lead can directly influence thymocyte function in the absence of the thymic microenvironment. Since thymulin levels may influence lead-induced immunotoxicity, embryonic endocrine status may be an important consideration. Lead exposure appears to alter thymic functions directly; however, indirect effects via endocrine factors are not precluded.

Animals↗
PubMed2002

Embryonic exposure to lead: comparison of immune and cellular responses in unchallenged and virally stressed chickens.

Lead, a ubiquitous environmental contaminant, has been shown to modulate various functions of the immune system and decrease host resistance to infectious disease. However, limited information is available concerning the direct effects of lead on the host immune response to an infectious agent after developmental exposure. The current study utilized chickens to examine the effect of embryonic lead exposure on immune and cellular responses during viral challenge. Sublethal doses of lead were introduced into fertilized Cornell K Strain White Leghorn chicken eggs via the air sac at day 5 or day 12 of embryonic development (designated as E5 and E12, respectively). Four-week-old female chickens were inoculated with infectious bronchitis virus (IBV) strain M41. Antibody titer to IBV, delayed-type hypersensitivity (DTH) response against bovine serum albumin (BSA), the absolute number and percentage of leukocyte subpopulations, and interferon-gamma (IFN-gamma)-like cytokine production by splenocytes were evaluated at 5-6 weeks of age. While antibody response to IBV in juvenile chicks was unaffected by the in ovo lead exposure, IFN-gamma-like cytokine production by splenocytes was significantly depressed following lead exposure at both developmental stages. In contrast with this pattern, the DTH response against BSA was unaffected following E5 exposure, but was significantly decreased after E12 exposure to lead. These changes were similar to those previously reported in chickens not exposed to IBV. While lead exposure at E5 induced significant changes in the percentage of circulating heterophils at 1 day postinfection (dpi), lead did not cause any change in relative leukocyte counts after E12 exposure. At 7 dpi, E5 lead exposure resulted in decreased absolute number and percentage of circulating lymphocytes, while total leukocyte counts, and the absolute number and percentage of circulating monocytes and heterophils were significantly reduced in E12 lead-exposed chickens. These results suggest that low-level exposure to lead has a direct effect on the developing chicken immune system, which is evident even during a postnatal infection. Furthermore, some of the changes were observed only when chicks were stressed by the viral infection. It appears that lead exposure during different stages of embryonic development is likely to result in different immunotoxic outcomes in juveniles.

Animals↗