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Biomedical subjects

S D Holladay

Publications and source records attributed to S D Holladay.

At least 37 records · Page 2Linked to original sources
PubMed2000

Fate and the biochemical effects of 2,4,6-trinitrotoluene exposure to tiger salamanders (Ambystoma tigrinum).

Biotransformation, metabolic enzyme profiles, and the glutathione antioxidant system in tiger salamanders (Ambystoma tigrinum) from a 14-day exposure to 2,4,6-trinitrotoluene (TNT) in situ were examined. Concentrations of parent compound and metabolites were measured in skin, kidney, and liver tissue. In addition, cytochrome P450 (P450) and cytochrome b5 content and their dependent isozyme activities, ethoxyresorufin O-dealkylation, pentoxyresorufin O-dealkylation, and the glutathione antioxidant system in the skin, liver, lung, kidneys, and blood were evaluated. Considerable differences were found in relative concentrations of TNT and its metabolites in the skin, relative to the liver and kidney. Trace amounts of TNT were detected only in the skin and liver of exposed animals while one of the secondary reduction metabolites, 2,6-diaminonitrotoluene, was found only in liver and kidney. Differences in the metabolite concentrations between systemic organs (liver, kidneys) and the skin suggest that the skin may be important in the primary reduction of TNT. In addition, measurable levels of these basal enzyme indicators were detected; yet of those evaluated only hepatic P450 content was affected by TNT exposure. The qualitative and quantitative differences in TNT and its metabolites in tissues suggest the fate and metabolism of the TNT in salamanders. Furthermore, results indicate that tiger salamanders possess considerable levels of xenobiotic metabolizing and antioxidant enzymes in these tissues but are not sensitive indicators of TNT exposure.

Ambystoma↗
PubMed2000

Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

Fetal and early postnatal life represent critical periods in vertebrate immune system development. Disruption of such development by perinatal immunotoxic chemical exposure has been widely described in experimental animal models. The resultant inhibited postnatal immune responses in such animals are often more dramatic and persistent than those after exposure during adult life. Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate postnatal aberrant immune responses (e.g., hypersensitivity disorders and autoimmune disease) in genetically predisposed rodents. Limited information is available regarding the possibility of inhibited postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The multifactorial nature of hypersensitivity and autoimmune responses will further complicate the elucidation of possible relationships between chemical exposure during ontogeny of the human immune system and immune-mediated disease later in life. Taken together, however, the available animal data suggest the potential for altered postnatal immune function in humans exposed to immunotoxicants (e.g., environmental chemicals and therapeutic agents) during fetal and/or early postnatal life.

Adult↗
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↗
PubMed2000

Induced minor malformations in the neocortex of normal mice do not alter immunological functions.

The interactive relationship between the CNS and the immune system is well established. Major lesions in the brain have been shown to affect immune response. However, whether minor, focal lesions (ectopias), as seen in autoimmune mice, may induce alterations in the immune system is unknown. To address this point, ectopic lesions in the neocortex were induced in neonatal DBA/2 mice (Induced minor malformations; IMM) and their immune capabilities were assessed at adulthood. Serum was collected from each animal and analyzed for the presence of autoantibodies. In addition, splenic lymphocytes and thymocytes were collected to ascertain proliferative capabilities and to assess for possible phenotypic changes in lymphocyte subsets. Mice with IMM did not manifest IgG autoantibodies against cardiolipin, dsDNA or brain membrane antigens. Total lymphocyte cellularity was not affected. The induction of cerebrocortical ectopias did not impair the ability of splenic and thymic lymphocytes to proliferate in response to anti-CD3 antibodies or Concanavalin-A (Con-A) as determined by non-radioactive (Alamar Blue) and radioactive (3H-thymidine) assays. Moreover, no difference in proliferation of unstimulated and anti-CD3-stimulated splenic lymphocytes exposed to rIL-2 or rIL-7 was observed. Flow cytomeric analysis of a variety of cell surface antigens, indicated that there was no difference in lymphocyte subsets between control and IMM groups. Therefore, we conclude that induced IMM lesions in the CNS of normal DBA/2 mice do not alter immune functions.

Animals↗
PubMed1999

Tilapia (Oreochromis niloticus) dosed with azathioprine display immune effects similar to those seen in mammals, including apoptosis.

Azathioprine, an anti-neoplastic drug and therapeutic immunosuppressant, was administered intraperitoneally at 10.0 and 50.0 mg/kg to 3-6-month-old tilapia (Oreochromis niloticus). Consistent alterations in immune cellular parameters of the blood, pronephros (hematopoietic kidney) and spleen were observed. Peripheral blood total cellularity decreased as the azathioprine dose increased, to approximately half that of the control. Differential analysis of white blood cells indicated a decline in lymphocyte number, in particular, with increased dosage of azathioprine. Pronephric total cellularity was depressed in fish receiving the 10.0 or 50.0 mg/kg dose. In contrast, both splenic weight and splenic total cellularity increased proportionately with the increase in the drug dosage. Histopathologic examination of the spleens showed normal patterns for both control and 10.0 mg/kg dose groups. At 50.0 mg/kg, spleens were characterized by marked expansion of the white pulp, although lymphocytes were rare. Melanomacrophage centers at the higher dose were also larger and more numerous than in the control group. Evaluation of splenic and pronephric leukocytes with apoptotic markers showed an increase in apoptotic cells in the pronephros with increasing drug dose. These changes in fish are consistent with those seen in humans and laboratory rodents dosed with azathioprine, suggesting that fish may be potentially useful as preliminary models for detecting immunosuppressive compounds.

Animals↗
PubMed1999

Prenatal immunotoxicant exposure and postnatal autoimmune disease.

Reports in humans and rodents indicate that immune development may be altered following perinatal exposure to immunotoxic compounds, including chemotherapeutics, corticosteroids, polycyclic hydrocarbons, and polyhalogenated hydrocarbons. Effects from such exposure may be more dramatic or persistent than following exposure during adult life. For example, prenatal exposure to the insecticide chlordane or to the polycyclic aromatic hydrocarbon benzo[(italic)a(/italic)]pyrene produces what appears to be lifelong immunosuppression in mice. Whether prenatal immunotoxicant exposure may predispose the organism to postnatal autoimmune disease remains largely unknown. In this regard, the therapeutic immunosuppressant cyclosporin A (CsA) crosses the placenta poorly. However, lethally irradiated rodents exposed to CsA postsyngeneic bone marrow transplant (i.e., during re-establishment of the immune system) develop T-cell-mediated autoimmune disease, suggesting this drug may produce a fundamental disruption in development of self-tolerance by T cells. The environmental contaminant 2,3,7, 8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD) crosses the placenta and produces fetal thymic effects (italic)in vivo(/italic) similar to effects of CsA in fetal thymic organ culture, including inhibited thymocyte maturation and reduced expression of thymic major histocompatability complex class II molecules. These observations led to the suggestion that gestational exposure to TCDD may interfere with normal development of self-tolerance. Possibly supporting this hypothesis, when mice predisposed to development of autoimmune disease were treated with TCDD during gestation, postnatal autoimmunity was exacerbated. Similar results have been reported for mice exposed to diethylstilbestrol during development. These reports suggest that prenatal exposure to certain immunotoxicants may play a role in postnatal expression of autoimmunity.

Adult↗
PubMed1999

Tilapia (Oreochromis niloticus) and rodents exhibit similar patterns of inhibited antibody production following exposure to immunotoxic chemicals.

The hemolytic plaque forming cell assay (PFC), a measure of ability to produce specific antibodies following challenge with antigen, is a powerful predictor of immunosuppression in chemical-exposed rodents. The efficacy of this assay for predicting humoral immunosuppression in non-rodent species remains unknown. In the present report, tilapia (Oreochromis niloticus) were exposed to 9 chemical agents known to inhibit antibody production in mice (benzo[a]pyrene, 7,12-dimethylbenzanthracene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, dimethyl nitrosamine, cadmium chloride, azathioprine, hexachlorocyclohexane, T2 mycotoxin and toluene) and 5 chemical agents which do not inhibit this response (oxymethalone, acetonitrile, diethylstilbesterol, t-butylhydroquinone and formaldehyde). Eight of 9 agents which inhibit antibody production in rodents caused decreased PFC responses in fish. All 5 compounds with negative humoral effects in rodents were also negative in fish. Thus, 13/14 chemical agents tested gave similar results in tilapia as reported in rodents, suggesting a comparable pattern of humoral immunosuppression in chemical-exposed tilapia to that seen in laboratory rodent models.

Animals↗
PubMed1998

Benzo[a]pyrene-induced hypocellularity of the pronephros in tilapia (Oreochromis niloticus) is accompanied by alterations in stromal and parenchymal cells and by enhanced immune cell apoptosis.

Numerous reports indicate that carcinogenic polycyclic aromatic hydrocarbons (PAH) are mammalian immunotoxicants. These environmental contaminants are widely distributed in both freshwater and costal marine ecosystems where they have been found to bioaccumulate in aquatic species, yet limited information exists regarding potential adverse effects of specific PAH on fish immune function. In the present report, Oreochromis niloticus fish (tilapia) were exposed by intraperitoneal injection to 5, 25, or 50 mg/kg of the PAH, benzo[a]pyrene (B[a]P). Histopathologic evaluation of the primary hematopoietic compartment of fish, the pronephros, demonstrated increased vacuolation of both stromal and parenchymal cells, reduction of lymphoid elements, and immune cell apoptosis. Total pronephros cell counts were diminished in a dose-dependent manner by the chemical exposure. The oxidative metabolic burst in phorbol myristate acetate (PMA)-simulated macrophages isolated from the pronephros was significantly inhibited by B[a]P, but only at the highest dose level employed. The phagocytic capacity of pronephros macrophages was not altered by the chemical treatment.

Animals↗
PubMed1998

In vitro effects of the extracellular protein of Renibacterium salmoninarum on phagocyte function in brook trout (Salvelinus fontinalis).

Renibacterium salmoninarum is a facultative intracellular pathogen often found in host phagocytes where it appears to successfully avoid the host fish's immunological defenses. The objective of this investigation was to determine if soluble extracellular protein (ECP) produced by R. salmoninarum may contribute to the immunomodulation in bacterial kidney disease (BKD) via inhibition of phagocyte respiratory burst and/or phagocytosis mechanisms. Splenic cells from adult brook trout (Salvelinus fontinalis) were incubated with two different concentrations of ECP (0.1 mg/ml and 1.0 mg/ml) and viable R. salmoninarum. Splenic cell cultures were evaluated for respiratory burst activity via flow cytometry with the dichlorofluorescin diacetate (DCF-DA) assay and for phagocytosis via light microscopic assessment of microsphere engulfment. Respiratory burst activity was significantly inhibited in all treatment groups as compared to untreated fish, while no differences were noted in phagocytic activity.

Animals↗
PubMed1997

Exposure of tilapian fish to the pesticide lindane results in hypocellularity of the primary hematopoietic organ (pronephros) and the spleen without altering activity of phagocytic cells in these organs.

Tilapia were dosed by intraperitoneal injection for 5 consecutive days with either 20 or 40 mg/kg of the environmental contaminant hexachlorocyclohexane (lindane). The effects of this organochlorine pesticide on morphology and total cellularity of the spleen and pronephros were examined on the second day following termination of dosing. The functional capacity of phagocytic cells isolated from both spleen and pronephros was also evaluated as possible additional indicators of chemical-induced immunotoxicity. A dose-related reduction was found in spleen and pronephros total white blood cell counts in the fish exposed to lindane. In addition, hypocellularity of lymphoid regions in the spleen and pronephros was evident in chemical-exposed animals upon histopathological examination. However, phagocytosis of fluorescent microspheres by phagocytic cells isolated from the spleen and pronephros was not inhibited by the exposure to lindane. Similarly, no decrease in phorbolmyristate acetate (PMA)-stimulated hydrogen peroxide production was observed in phagocytic cells collected from lindane-exposed fish. These results suggest that cellular depletion in tilapia spleen and pronephros may represent a more sensitive indicator of lindane exposure than does the functional capacity of phagocytic cells isolated from these hematopoietic organs. Ultrastructural observations support this hypothesis and, further, suggest that lymphocytic cells may be targeted at the present exposure levels.

Animals↗
PubMed1996

Alterations in equine guttural pouch morphology with head position: observations using a new technique for producing accurate casts.

BACKGROUND: An improved technique for preparing casts of the equine guttural pouch is described. The new technique is simplified and inexpensive in comparison to previous techniques and produces highly accurate anatomic models which are both durable and flexible. METHODS: Silicone rubber bathtub caulk was injected into the guttural pouches of horse cadavers. The silicone was allowed to cure overnight, and casts were removed by dissection. The new technique was then used to evaluate changes in the shape of the guttural pouch with changes in head position. RESULTS: With flexion of the atlanto-occipital joint, the lateral compartment of the guttural pouch in particular was found to change considerably in size in shape. The angle of inclination of the ventral border of this pouch increased with flexion, as did the depth of the impression made by the rostral portion of the stylohyoid bone. In addition, the lateral compartment diminished in thickness rostrally in casts from flexed animals. CONCLUSIONS: The viscous silicone caulk resulted in superior casts of the equine guttural pouch. Observations of changed pouch shape with head position agree well with previous reports of increased difficulty in draining the lateral compartment of the horse's guttural pouch when the head is held in the flexed position.

Animals↗
PubMed1996

Alterations in fetal thymic and liver hematopoietic cells as indicators of exposure to developmental immunotoxicants.

Recent studies indicate that immune development in humans and other species may be altered after perinatal exposure to immunotoxic environmental contaminants. However, limited information is available regarding appropriate tests that may adequately detect developmental immunotoxic compounds. Experiments in which pregnant laboratory rodents were exposed to a variety of immunotoxic environmental agents indicate that fetal thymus and liver immune cells may be quantitatively and qualitatively altered by immunotoxicant exposure and, thus, may serve as sensitive markers of developmental immunotoxicant exposure. In particular, depression of fetal thymic cell counts appears to be a common event following gestational exposure to immunotoxicants that produce this response in adult animals. Total hematopoietic cell counts in fetal liver, however, may be a poor indicator of immunotoxicant exposure. Altered marker expression in both fetal thymus and liver appears to be a highly sensitive indicator of gestational immunotoxicant exposure. Together, these reports suggest that immune tests with high predictability for immunosuppression in adults may also be appropriate for the detection of developmental immunotoxic agents.

Animals↗
PubMed1995

Topical exposure to chlordane reduces the contact hypersensitivity response to oxazolone in BALB/c mice.

Previous studies have shown that prenatal exposure to the organochlorine pesticide chlordane significantly decreases the ear swelling response to the contact allergen oxazolone in BALB/c mice. Alterations of macrophage function in the efferent arm of the contact hypersensitivity response have also been reported. In the current study, chlordane was applied topically and the effects of oxazolone-induced contact hypersensitivity were determined. Initially, the reduction in oxazolone-induced ear swelling in topically-exposed female BALB/c mice was compared to 30-day-old BALB/c female mice exposed prenatally to chlordane. Prenatal chlordane exposure induced a 36% reduction in ear swelling compared to a 60% reduction following topical treatment at the challenge phase. Topically-applied chlordane also reduced the oxazolone-induced ear swelling by 40% when applied at sensitization. When applied at both sensitization and challenge, ear swelling was reduced by 71%. In a time-course study, it was determined that chlordane must be applied at the time of sensitization, challenge or both or within 1 h post-challenge to significantly reduce ear swelling. A dose-response study showed that the lowest concentration of chlordane resulting in a significantly reduced ear swelling response was 20 micrograms per ear.

Administration, Topical↗
PubMed1995

Patella of selected bats: patterns of occurrence or absence and associated modifications of the quadriceps femoris tendon.

BACKGROUND: Having observed the apparent absence of a bony patella in a Madagascar flying fox (Pteropus sp.), other species from the two suborders of bats (Megachiroptera and Microchiroptera) were examined to determine the presence or absence of a bony patella and the distribution of this feature among bats. METHODS: Gross, radiographic, and histologic examination of seven megachiropteran species representing four genera, as well as six microchiropteran species representing six genera, was performed. RESULTS: A bony patella was observed in all six microchiropteran and in three megachiropteran species. The tendon of the quadriceps femoris muscle in Microchiropteran species was composed mainly of dense regular connective tissue. The quadriceps tendon in Megachiropteran species with a patella contained an abundance of fibrocartilage and hyaline cartilage, unlike the quadriceps femoris tendon of the Microchiroptera or a laboratory mouse examined for comparison. CONCLUSIONS: Four species of the megachiropteran genus Pteropus lacking a bony patella displayed a similar occurrence and distribution of fibrocartilage and hyaline cartilage within the quadriceps tendon as seen in the other bats. In reference to this singular feature, Pteropus is unique among the representatives of megachiropteran and microchiropteran genera examined here.

Animals↗
PubMed1995

Alterations in murine fetal thymus and liver hematopoietic cell populations following developmental exposure to 7,12-dimethylbenz[a]anthracene.

Gestational exposure of ICR mice to the environmental contaminant 7,12-dimethylbenz[a]anthracene (DMBA) was used (i) to study the developmental immunotoxicity of this chemical agent and (ii) to evaluate potential hematopoietic cellular targets in a sensitive developmental model which may be involved in immunosuppression induced by this carcinogenic polycyclic aromatic hydrocarbon (PAH). DMBA produced a dose-dependent hypocellularity in both fetal mouse thymus and liver. Resident hematopoietic cell subpopulations in fetal liver, identified by CD44, CD45R, and Mac-1 monoclonal antibody binding, were reduced by the gestational DMBA treatment. In particular, the total number of CD45R+ B-lineage lymphocytic cells in fetal liver was reduced to 20% of control levels by DMBA. Unlike previous reports with related PAH, DMBA did not inhibit thymocyte differentiation, as indicated by unaltered thymocyte expression of CD4, CD8, and heat-stable antigens. These data may indicate that production of thymic atrophy and impairment of thymocyte differentiation by PAH involve separate mechanisms of action. Results of the present study additionally identify changes in immune cell populations that correlate well with inhibition of cell- and humoral-mediated immunity in experimental animals treated with DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

B lymphocyte precursor cells represent sensitive targets of T2 mycotoxin exposure.

Exposure of experimental animals and humans to the Fusarium trichothecene metabolite, T2 toxin, has been associated with a variety of immunosuppressive effects, including altered parameters of humoral-mediated immunity. Although T2 toxin is cytotoxic in vitro to lymphocytic cells, limited information is presently available regarding the contribution of such a mechanism to immunosuppression in vivo, or to potential immune cell targets. In the present report, subchronic T2 toxin treatment of timed-pregnant B6C3F1 mice resulted in significant and selective depletion of fetal liver cells expressing low levels of surface CD44 and CD45 antigens, suggestive of possible lymphoid progenitor cell sensitivity to this agent. Evaluation of CD45R antigen expression in fetal liver supported such a hypothesis, demonstrating a significant reduction in fetal liver B lymphocytic cells in animals exposed to T2 toxin. Subsequent in vitro T2 toxin exposure of fetal liver cells enriched for prolymphocytes by differential density gradient centrifugation demonstrated the presence of a highly sensitive subpopulation of cells that was eliminated in a selective, and near-complete, manner by T2 toxin exposure. This sensitive cell population was observed to have light-scatter characteristics of CD45R+ B-lineage lymphocytes. Additional studies in adult mice demonstrated a reduction in CD44lo and CD45R+ bone marrow cells similar to that seen in fetal liver, indicating that T2 toxin may also target immature B lymphocytes in this hematopoietic compartment. Taken together, these data suggest that the precursors of B cells may represent, for unknown reasons, highly sensitive targets of T2 toxin exposure.

Animals↗
PubMed1995

Role of proinflammatory cytokines in acetaminophen hepatotoxicity.

Acetaminophen (APAP) intoxication has been shown to activate Kupffer cells. Kupffer cell activation is also associated with the release of proinflammatory cytokines which can induce a variety of pathophysiological responses. These studies examined whether proinflammatory cytokines are produced in response to a hepatotoxic dose of APAP, and if so, the role they play in the observed pathological response. Female B6C3F1 mice received 500 mg APAP/kg in the presence and absence of antibodies against tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha (IL-1 alpha), and IL-1 receptor antagonist (IL-1ra). Serum TNF-alpha, IL-1 alpha, and liver-associated enzyme levels were measured. In addition, the levels of mRNA transcripts for IL-1 alpha, IL-6, and TNF-alpha from livers of treated mice were examined by reverse transcription-polymerase chain reaction (RT-PCR). Administration of APAP resulted in an immediate reduction in body temperature as well as elevated serum levels of IL-1 alpha and TNF-alpha that reached a peak at 12 and 16 hr, respectively. The reduction in body temperature was partially blocked by injection of antibodies against TNF-alpha or IL-1 alpha. Furthermore, neutralization of TNF-alpha delayed the increase in serum IL-1 alpha and liver enzyme levels. In contrast, pretreatment with IL-1ra antisera exacerbated the effect of APAP on body temperature and increased the release of liver enzymes. These data suggest that TNF-alpha and IL-1 alpha are released in response to APAP intoxication and are responsible for certain pathological manifestations of APAP-induced hepatotoxicity.

Acetaminophen↗