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Biomedical subjects

B Adkins

Publications and source records attributed to B Adkins.

At least 37 records · Page 2Linked to original sources
PubMed1995

Early changes in sex hormones are not evident in mice exposed to the uterine carcinogens chloroethane or bromoethane.

Chloroethane and bromoethane have been shown to cause a marked uterine tumor response in B6C3F1 mice exposed for 2 years. These chemicals are nearly unique in this regard among the nearly 400 chemicals studied by the National Toxicology Program, and the reasons for this carcinogenic activity are unclear. The possible relationship of changes in blood concentrations of sex hormones to this response was evaluated by examining the estrous cycle of mice prior to and during a 21-day exposure to concentrations of the haloethanes which resulted in the tumorigenic response in the 2-year studies. Serum concentrations of estradiol and progesterone were determined at the termination of the exposures and compared to exposure group and stage of the estrous cycle. No consistent patterns of change were found in estrous cyclicity or in blood concentrations of sex hormones. Thus, the findings suggest that early changes in circulating sex hormones are not important contributing factors in the uterine neoplasia caused by these chemicals.

Animals↗
PubMed1994

Developmental ages of the thymic epithelium and of the T cell precursors together determine the proportions of peripheral CD4+ cells.

In earlier studies on chimeric animals, we found that fetal thymocytes produced peripheral T lymphocyte populations depleted of CD4+ cells. This occurred whether the fetal thymocytes matured in the presence of adult or fetal thymic stromal cells. In contrast, fetal liver cells that differentiated in the adult thymus generated normal proportions of peripheral CD4+ cells. Because fetal liver cells are thought to be the immediate precursors to fetal thymocytes, we proposed that fetal thymic stroma would modulate the differentiation of fetal liver cells; specifically, that fetal liver cells maturing in the fetal thymus would resemble fetal thymocytes and produce low levels of peripheral CD4+ cells. To test this hypothesis, fetal thymic lobes were colonized in vitro with fetal liver cells and subsequently transplanted in vivo to Thy-1 congenic hosts. Under these conditions, fetal liver cells produced reduced proportions of CD4+ peripheral progeny. The under-representation of CD4+ peripheral T cells was apparently governed by the thymic epithelium because similar results were obtained with 2-deoxyguanosine-treated fetal thymuses colonized by fetal liver cells. In contrast, adult bone marrow cells made normal levels of CD4+ peripheral T cells whether maturation occurred in the fetal or the adult thymus. Thus, pre-T cells (fetal liver or adult bone marrow) lose the capacity to respond to fetal thymic stromal cells during development. These results indicate that the proportions of CD4+ cells in peripheral tissues are regulated by a combination of the developmental ages of the T cell precursors and the thymic stromal environment.

Animals↗
PubMed1994

Up-regulation of murine neonatal T helper cell responses by accessory cell factors.

We previously found that lymph node T cells from 4-day-old, naive neonatal mice show diminished Th1-like responses. Neonatal T cells produced low levels of IL-2 and proliferated poorly in response to soluble anti-CD3 stimulation. However, neonatal T cells resembled Th2 cells (or primed adult T cells) in that they produced large amounts of IL-4. Here, we have investigated the importance of accessory cell signals in the diminished Th1-like responses of neonatal T cells. Anti-CD28 mAb greatly augmented IL-2 production by neonatal T cells in response to plate-bound anti-CD3 Ab. In response to soluble anti-CD3 mAb plus accessory cells, exogenous accessory cell-derived cytokines were sufficient to restore neonatal responses to adult-like levels. In the presence of exogenous IL-6, IL-4 production by neonatal T cells was largely unchanged whereas IL-2 production was dramatically increased, reaching the high levels produced by adult T cells. In addition, the presence of exogenous IL-6 enhanced the proliferation of neonatal T cells to adult levels. IL-6 also had marked effects on the capacity of neonatal T cells to respond to secondary stimuli. In the absence of exogenous IL-6, neonatal T cells responded poorly to secondary stimulation. This lack of responsiveness was not overcome by the addition of IL-2 or by stimulation with phorbol ester and calcium ionophore. When IL-6 was present during the primary stimulation, neonatal T cells, like adult T cells, produced high levels of IL-4 and proliferated extensively in response to secondary stimuli. Thus, IL-6 was sufficient to restore both the primary and secondary responses of neonatal T cells to mature, adult-like levels. These results imply that neonatal T cells have a greater requirement for accessory cell signals than do adult T cells and may have important bearing in overcoming neonatal T cell immunodeficiencies in vivo.

Animals↗
PubMed1993

Developmental regulation of IL-4, IL-2, and IFN-gamma production by murine peripheral T lymphocytes.

Lymph node T cells from naive, 4-day-old neonatal mice resemble activated adult T cells in that they produce low levels of IL-2 but high levels of IL-4 in response to anti-CD3 stimulation in vitro. Herein, we show that the capacity for high level IL-4 production is rapidly lost in the early postnatal period. A decline is first evident at 5 days postbirth. By 6 days postbirth, T cells secrete IL-4 at low levels, similar to those produced by T cells from naive, adult animals. In contrast, the acquisition of high, adultlike IL-2 or IFN-gamma production does not occur until approximately 6 wk of life. Thus, the loss of high level IL-4 production and the acquisition of high level IL-2 and IFN-gamma production are distinct developmental events, occurring at widely separated intervals. There are two phases in the transition to adultlike IL-2 production. In the early neonatal period, the underproduction of IL-2 appears to be due to a combination of intrinsic nonresponsiveness to CD3-mediated stimulation and the production of a soluble inhibitor of IL-2 production. The inhibitory activity required the presence of IL-4 because neutralizing anti-IL-4 antibody completely eliminated inhibition. Moreover, experiments using rIL-4 showed that IL-4 alone was sufficient to dramatically inhibit IL-2 production by T cells from naive, adult animals in a primary stimulation. Between 4 to 5 days and 6 wk of life, the underproduction of IL-2 and IFN-gamma appears to result solely from a lowered responsiveness of the T cells. Thus, the progression to adultlike lymphokine production involves a combination of changes in the types of lymphokines produced and in the magnitude of the response to activation signals.

Animals↗
PubMed1993

Styrene inhalation toxicity studies in mice. I. Hepatotoxicity in B6C3F1 mice.

Studies were conducted to evaluate the toxic effects of short-term repeated styrene inhalation in B6C3F1 mice. Male and female mice were exposed to 0, 125, 250, or 500 ppm styrene, 6 hr/day, for up to 14 days. Styrene toxicity was characterized by severe centrilobular hepatic necrosis and deaths after one exposure to 500 ppm or two exposures to 250 ppm. Mortality and hepatotoxicity were not increased by additional exposures, and in surviving mice, regeneration and repair of initial hepatic injury occurred in spite of continued exposure for 14 days. A marked sex difference was observed, with male mice significantly more susceptible to styrene toxicity than females. A nonlinear dose response was observed where mortality in male and female mice was greater in the 250 ppm dose group than that in the 500 ppm dose group. Severe congestion and necrosis of the liver was present in moribund mice; hepatic congestion and serum alanine aminotransferase and sorbitol dehydrogenase were significantly greater in moribund animals.

Administration, Inhalation↗
PubMed1993

Styrene inhalation toxicity studies in mice. II. Sex differences in susceptibility of B6C3F1 mice.

Styrene is a commercially important chemical used in the production of plastics and resins. In initial short-term styrene inhalation studies, toxicity was significantly greater in male B6C3F1 mice than in females, suggesting that males may metabolize styrene more extensively and/or may be less able to detoxify reactive metabolites. In addition, a nonlinear dose-response was observed where toxicity and mortality were greater in mice exposed to 250 ppm than in those exposed to 500 ppm. These studies were conducted to investigate potential mechanism(s) for sex differences and the nonlinear dose-response in styrene toxicity by evaluating the effects of repeated styrene exposure on styrene oxide production, hepatic GSH availability, and hepatotoxicity in male and female B6C3F1 mice. Mice (36/sex/dose) were exposed to 0, 125, 250, or 500 ppm styrene 6 hr/day for up to 3 days. Styrene exposure caused increased mortality and hepatotoxicity (centrilobular necrosis, increased serum liver enzymes) in males and females after one or two exposures to 250 and 500 ppm. Hepatic GSH levels were decreased in a dose-dependent manner in males and females. After one exposure, GSH levels in males rebounded above controls in all dose groups. After three exposures to 125 or 250 ppm males appeared to maintain GSH levels; GSH was still decreased in the 500 ppm group. GSH levels in females were decreased after each exposure in all dose groups to lower levels than in males, and did not rebound above controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Styrene inhalation toxicity studies in mice. III. Strain differences in susceptibility.

Inhalation toxicity studies were conducted to evaluate mouse strain differences in the susceptibility to styrene vapors. Male and female B6C3F1, C57BL/6, Swiss, and DBA/2 mice (8 weeks old) were exposed to 0, 125, 250, or 500 ppm styrene 6 hr/day, for 4 days (20/sex/dose). Histopathological changes and changes in liver weights were evaluated as a measure of hepatotoxicity. Styrene uptake and styrene-7,8-oxide (SO) formation were estimated by measuring levels of styrene and SO in blood. An estimate of SO detoxification by conjugation with GSH was obtained by measuring hepatic GSH depletion. In general, mortality, increased liver weights, and hepatocellular necrosis were observed in the 250 and 500 ppm dose groups for all strains and both sexes. Considerable sex and strain differences were observed. Mortality, increased liver weights, and hepatocellular necrosis were greatest in B6C3F1 and C57BL/6 mice in the 250 ppm dose group and in males; hepatotoxicity was similar in both strains. Swiss mice exhibited dose-dependent increases in mortality, liver weights, and in hepatocellular necrosis, with only slight sex differences at early time points. Hepatotoxicity in DBA/2, B6C3F1, and C57BL/6 strains was greater at 250 than 500 ppm; however, toxicity was less severe in DBA/2 than in other strains based on absence of mortality in either sex and less extensive liver necrosis at both 250 and 500 ppm. Blood styrene and SO levels did not correlate well with strain differences in toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1992

Freshly isolated, murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation.

In previous studies of chimeric animals, we found that fetal intrathymic T cell precursors give rise to phenotypically abnormal peripheral T cell populations. Because most peripheral T lymphocytes in newborn mice are the progeny of fetal T cell precursors, this result led to the hypothesis that neonatal and adult T cells differ in their functional capacities. To investigate this issue, the responses of neonatal and adult T cells to anti-CD3 antibody and TCR-independent stimulation were compared. When stimulated with soluble anti-CD3 antibody in the presence of adult accessory cells, neonatal T cell proliferation was markedly decreased compared with that of adult T cells. This reduction in proliferation was associated with both quantitative and qualitative differences in lymphokine production. At 48 h of stimulation with anti-CD3 antibody, neonatal T cells produced at least 10-fold less IL-2 than adult T cells. This apparently accounted for their reduced proliferation because the addition of exogenous IL-2 restored their proliferation to the levels achieved by adult T cells. In striking contrast to adult T cells, neonatal T cells secreted large amounts of IL-4 upon primary stimulation in vitro. The differences between neonatal and adult T cells in proliferation and lymphokine production were shown to be specific for CD3-mediated stimulation. In the presence of phorbol ester and calcium ionophore, neonatal and adult T cells showed equivalent proliferation and IL-2 production. Under these conditions, IL-4 production by neonatal or adult T cells was essentially undetectable. Thus, in response to TCR-independent stimulation, freshly isolated neonatal and adult T cells show similar functional responses. However, when stimulation occurs via the CD3 components of the TCR, the responses of neonatal T cells resemble those of primed T cells from adult animals.

Animals↗
PubMed1991

Thymic irradiation inhibits the rapid recovery of TH1 but not TH2-like functions of CD4+ T cells after total lymphoid irradiation.

Four to six weeks after total lymphoid irradiation (TLI), there is a selective deficit in the CD4+ T cells which secrete IL-2, proliferate in the MLR, and induce GVHD (Th1-like functions). A similar deficit in CD4+ T cells which secrete IL-4 and help antibody responses (Th2-like functions) is not observed. In the present study, shielding of the thymus with lead during TLI increased the Th1-like functions of CD4+ cells. Mice without thymus shields showed a marked selective reduction in the medullary stromal cells identified with the monoclonal antibody, MD1, and the severe reduction was prevented with thymus shields. Thus, shielding the thymus prevents the depletion of thymic medullary stromal cells and allows for a rapid recovery of Th1-like functions in the mouse spleen after TLI. Th2-like functions recover rapidly after TLI whether or not the thymus is irradiated.

Animals↗
PubMed1991

Developmental regulation of the intrathymic T cell precursor population.

The maturation potential of CD4-8- thymocytes purified from mice of different developmental ages was examined in vivo after intrathymic injection. As previously reported, 14-day fetal CD4-8- thymocytes produced fewer CD4+ than CD8+ progeny in peripheral lymphoid tissues, resulting in a CD4+:CD8+ ratio of less than or equal to 1.0. In contrast, adult CD4-8- thymocytes generated CD4+ or CD8+ peripheral progeny in the proportions found in the normal adult animal (CD4+:CD8+ = 2 to 3). Here we have shown that CD4-8- precursor cells from the 17-day fetal thymus also produced peripheral lymphocytes with low CD4+:CD8+ ratios. Precursors from full term fetuses produced slightly higher CD4+:CD8+ ratios (1.1-1.6) and precursors from animals three to 4 days post-birth achieved CD4+:CD8+ ratios intermediate between those produced by fetal and adult CD4-8- thymocytes. Parallel changes in the production of alpha beta TCR+ peripheral progeny were observed. Fetal CD4-8- thymocytes generated fewer alpha beta TCR+ progeny than did adult CD4-8- thymocytes. However, peripheral lymphocytes arising from either fetal or adult thymic precursors showed similar proportions of gamma delta TCR+ cells. The same pattern of progeny was observed when fetal CD4-8- thymocytes matured in an adult or in a fetal thymic stromal environment. In contrast to fetal thymic precursors, fetal liver T cell precursors resembled adult CD4-8- thymocytes by all parameters measured. These results suggest that fetal thymic precursors are intrinsically different from both adult CD4-8- thymocytes and fetal liver T cell precursors. Moreover, they lead to the hypothesis that the composition of the peripheral T cell compartment is developmentally regulated by the types of precursors found in the thymus. A model is proposed in which migration of adult-like precursors from the fetal liver to the thymus approximately at birth triggers a transition from the fetal to the adult stages of intrathymic T cell differentiation.

Animals↗
PubMed1990

B cell infiltration of the thymic medulla in New Zealand black, New Zealand white, and (New Zealand black x New Zealand white)F1 mice. Effect of total lymphoid irradiation.

Thymuses from female (New Zealand black x New Zealand white)F1 [( NZB x NZW]F1), New Zealand black, and New Zealand white mice of different ages were examined by immunohistochemical and flow cytometric analysis. Two-and-a-half-month-old (NZB x NZW)F1 mice showed infiltration of the thymus with B cells, and by 6-8 months of age, showed a disruption of the entire medullary area. More than 80% of the thymic B cells had the phenotypic characteristics of conventional B cells (IgM+, IgD+, Ly-1-). Total lymphoid irradiation induced a marked depletion of medullary B cells and a restoration of the thymic architecture.

Animals↗
PubMed1989

Developmental potential of CD4-8- thymocytes. Peripheral progeny include mature CD4-8- T cells bearing alpha beta T cell receptor.

We have used the intra-thymic transfer system to investigate the population dynamics of thymocyte and mature T cell subsets in the absence of continuing precursor input from the bone marrow. We have followed the development and life span of CD4+ and CD8+ thymocyte subsets and mature peripheral T cells from intra-thymically injected adult or fetal CD4-8- thymic precursors. Both precursor types proliferated, differentiated, and exported to peripheral lymphoid tissues alpha beta-TCR+CD4+8- and CD4-8+ progeny which formed a stable, long-lived component of the peripheral T cell pool. The production of phenotypically mature thymocytes and peripheral T cells occurred more rapidly from fetal CD4-8- precursors. CD4+8-:CD4-8+ ratios among peripheral progeny of intra-thymically-injected CD4-8- precursors were initially normal, but they steadily declined among progeny of the fetal precursors. Thus, there appear to be differences in the life span and/or proliferative capacity of mature T cells derived from embryonic vs adult progenitors. In addition to the predominant CD4+8- and CD4-8+ subsets of peripheral T cells, a minor (1 to 20%) population of Thy-1+CD3+4-8- T cells was identified among peripheral progeny of intra-thymically-injected CD4-8- thymocytes, as well as in lymph nodes of unmanipulated animals. A total of 20 to 34% of this subset expressed V beta 8+ TCR and the majority were CD5hi, Pgp-1+, and J11d-. The function and specificity of this newly identified population of thymically derived peripheral T cells remains to be investigated.

Aging↗
PubMed1989

Intrathymic maturation of murine T lymphocytes from CD8+ precursors.

The CD4-8- thymocyte subset contains immature precursors for phenotypically and functionally mature CD4+8- and CD4-8+ thymocytes and peripheral T cells, as well as nonmature CD4+8+ thymocytes, most of which die in situ. The intrathymic death of most thymocytes is probably related to selective influences that ensure that only those precursors bearing self-major histocompatibility complex (MHC)-restricted and self-tolerant T-cell antigen receptors (TCR) survive to complete the maturation process. Interactions between surface molecules on thymocytes (TCR, CD4, and CD8) and thymic stromal cells (MHC proteins) are critical to repertoire selection. To understand this process, the lineage relationships among immature, nonmature, and mature thymocytes must be defined. We have examined directly the precursor-progeny relationships among CD4+8-, CD4-8+, and CD4+8+ murine thymocyte subsets by assessing their short-term (less than 5 days) developmental potentials following intrathymic injection into Thy-1 congenic, unirradiated host mice. Our results identify TCR-/lo CD4-8+ and TCRlo CD4+8+ blast cells as sequential intermediates in the development of mature TCRhi CD4+8- and TCRhi CD4-8+ thymocytes from CD4-8- precursors, thus defining at least one intrathymic maturation pathway for T lymphocytes.

Animals↗
PubMed1988

Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells.

Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.

Animals↗
PubMed1988

Normal thymic cortical epithelial cells developmentally regulate the expression of a B-lineage transformation-associated antigen.

Nonlymphoid, stromal cells in the mouse thymus are believed to be important in T cell maturation and have been proposed to play a central role in the acquisition of major histocompatibility complex (MHC) restriction and self-tolerance by maturing thymocytes. Both cortical and medullary epithelial cells in the thymus express high levels of class II (A) major histocompatibility antigens (MHC Ags). We show here that a specific subset of these A+ epithelial cells express a transformation-associated antigen (6C3Ag) found previously on the surfaces of Abelson murine leukemia virus-transformed pre-B cells and on those bone marrow-derived stromal cell clones which support normal and preneoplastic pre-B cell proliferation. Among solid lymphoid organs, only the thymus contains 6C3Ag+ cells and within the thymus, this antigen is found exclusively on A+ epithelial cells in cortical regions. It is striking that the expression of the 6C3Ag on thymic epithelium is developmentally regulated, suggesting a role for this lymphostromal antigen in the maturation of the thymic microenvironment.

Abelson murine leukemia virus↗
PubMed1987

Inhalation exposure technology used for varying exposure modes and profiles in toxicology studies.

Current technology used in inhalation toxicology studies employs various exposure modes and concentration profiles. Inhalation exposure modes typically utilize wholebody techniques, whereas other exposure modes include nose- and head-only exposure systems and, in some cases, whole- or partial-lung exposure systems. The latter two conditions are utilized when safety considerations are warranted by the hazardous nature of the chemical or agent being tested, the test substance may be dermally adsorbed, and/or the costs of the chemical used are of concern. Inhalation exposure studies may span several minutes to 24 h of continuous exposure and from one day to the full life span of the animal being tested. Time-varying profile exposures, on the other hand, are typically used to mimic human exposures to chemical agents and, in some cases, to more accurately extrapolate animal toxicity data in assessing human risk. Automation of inhalation exposure systems has expedited the timely operation of both accurate and repeatable profiles, and it has allowed for reexamination of classical time-weighted average concentration information relating to human health concerns. The toxicological assessment of potential health effects resulting from exposure to airborne substances typically involves thorough characterizing of the test agent via acute, subchronic, and chronic toxicity testing.

Administration, Inhalation↗
PubMed1987

The toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. II. Repeated exposure and recovery studies.

F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3 ppm exposures, and mice died after exposures to 6 ppm. Deaths appeared to be related to severe respiratory distress. Survivors in high dose groups lost weight initially, then gained weight at rates equal to controls throughout a 91-day recovery period. Lung weights increased significantly in male and female rats exposed to 3 ppm, but no persistent changes in brain, kidney, thymus, spleen, liver, or testis weights were seen in either mice or rats. Blood and serum from male and female rats were taken for clinical pathology and hematology assessments on day 7 of postexposure, the day prior to the first observed deaths of these animals. No changes or only slight changes were seen in measures of serum alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, or in blood and brain cholinesterase activities. However, serum creatine kinase increased with dose in both males and females. Blood urea nitrogen, creatinine, and methemoglobin were unchanged. No changes were seen in counts of red blood cells or platelets, or in red cell indices. Hemoglobin concentrations and hematocrits were slightly elevated. No changes were noted in absolute leukocyte counts, but counts of segmented neutrophils increased and lymphocytes decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗