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J H Dean

Publications and source records attributed to J H Dean.

At least 37 records · Page 2Linked to original sources
PubMed1989

Molecular mechanism of 7,12-dimethylbenz[a]anthracene-induced immunosuppression: evidence for action via the interleukin-2 pathway.

Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene results in suppression of both humoral and cell-mediated immunity. This suppression is unaccompanied by any significant alteration in splenic lymphocyte subpopulation composition, suggesting that the immune deficit was due to a modulation of lymphocyte function. Additional studies implicated the T helper lymphocyte as the probable target for 7,12-dimethylbenz[a]anthracene-induced immunosuppression, apparently through an inhibition of interleukin 2 production. The purpose of the present study was to examine the mechanism of 7,12-dimethylbenz[a]anthracene-induced T lymphocyte dysfunction at the molecular level and to determine the consequences of 7,12-dimethylbenz[a]anthracene exposure on the interleukin 2 pathway. In vitro exposure of Con A-activated splenocytes to 7,12-dimethylbenz[a]anthracene resulted in suppression of the mitogenic response, suppressed interleukin 2 production, and reduced the expression of the high affinity receptor for interleukin 2. In contrast, expression of the low affinity interleukin 2 receptor was not affected. In addition, interleukin 2-dependent lymphoblasts and long term cultured splenocytes exhibited a dose-dependent decrease in proliferation following in vitro exposure to 7,12-dimethylbenz[a]anthracene. These results suggest that 7,12-dimethylbenz[a]anthracene-induced immunosuppression may be mediated, at least in part, through the interleukin 2/interleukin 2 receptor pathway.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Trypanosoma musculi: characterization of the T-lymphocyte dependency of immunity by selective immunomodulation of the mouse, Mus musculus.

Trypanosoma musculi is a hemoflagellate parasite producing a characteristic course of infection in the mouse, terminating in elimination of the parasite from the vascular system with permanent immunity to reinfection. While this elimination is known to require functional T lymphocytes, the role of these cells has remained undefined. The current study examined the role of T-lymphocyte dependency by the selective in vivo depletion of T-lymphocyte subsets by monoclonal antibodies or immunosuppressive pharmacologic agents. In the former approach, monoclonal antibodies specific for the murine T-lymphocyte surface antigens Thy 1.2, Lyt 2, or L3T4 were administered to mice, resulting in functional depletion of either all T lymphocytes or the T-helper or T-cytotoxic subsets. Subsequent infection with T. musculi revealed that elimination of the T-helper, but not the T-cytotoxic, phenotype resulted in a prolonged and elevated parasitemia. This enhancement of parasitemia was similar to that produced with depletion of all T lymphocytes (i.e., Thy 1.2+ cells), suggesting that the T-helper cell was most important in parasite elimination. In the latter approach, pharmacologic agents displaying selective immunosuppressive activity were employed to inactivate, rather than destroy, T-lymphocyte subpopulations. In vivo inactivation of T-helper lymphocytes by the fungal metabolite cyclosporin-A enhanced the level of parasitemia in treated animals and resulted in a protracted duration of infection. In contrast, treatment with the highly substituted anthracenedione AEAD, which has been demonstrated to selectively inactivate T-cytotoxic cells, had no appreciable effect on the kinetics of infection. These results strongly suggest that the T-lymphocyte dependency of Trypanosoma musculi elimination is due predominantly to the action of the T-helper, rather than T-cytotoxic, lymphocyte.

Animals↗
PubMed1988

Suppression of splenic lymphocyte function by 7,12-dimethylbenz[a]anthracene (DMBA) in vitro.

The effects of the immunosuppressive polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA) were studied directly by in vitro exposure of splenic lymphocytes. On the basis of evidence from prior studies that DMBA immunotoxicity in vivo may not be dependent upon induction of the Ah locus in mice, splenocytes from Ah-responsive B6C3F1, Ah-nonresponsive DBA/2N, and in C57BL/6J Ah-congenic mice (responsive B6-Ah(b)Ah(d) and nonresponsive B6-Ah(d)Ah(d) were exposed to xenobiotic in culture. For some experiments, B6C3F1 mice were pretreated with 200 nmol 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) to induce Ah-associated enzymatic activity prior to in vitro splenocyte exposure to DMBA. Humoral immunity assessed as splenic antibody plaque-forming cells measured after a 5-day in vitro immunization to sheep erythrocytes (SRBC) was suppressed up to 99% by continuous exposure to 20 microM DMBA, and was comparable between control mice having basal levels of hepatic monooxygenase activity and Ah-induced mice (TCDD-treated) having elevated enzyme activity. Similarly, cytotoxic T-lymphocyte generation against P815 target cells was suppressed up to 88 and 86% in 40 microM DMBA-exposed splenocytes from Ah-induced and noninduced mice, respectively. The mixed lymphocyte responsiveness (MLR) of B6C3F1, DBA/2N, B6-Ah(b)Ah(d), and B6-Ah(d)Ah(d) splenocytes exposed in vitro to 40 microM DMBA was suppressed 54, 72, 51, and 29%, respectively. However, the degree of suppression was not significantly different between the strains. The secretion of interleukin 2 (IL2) was also suppressed in splenocytes from both strains exposed to 40 microM DMBA in vitro. Studies which included benzo[a]pyrene (BaP) as a control xenobiotic known to demonstrate Ah dependence showed that the MLR of splenic lymphocytes from Ah-congenic mice was comparably suppressed following 40 microM DMBA exposure, whereas exposure to 40 microM BaP resulted in suppression of the MLR only in B6-Ah(b)Ah(d) splenocytes. In addition, mitogen-stimulated proliferation was inhibited in both B6C3F1 and DBA/2N splenocytes exposed to 40 microM DMBA, whereas 40 microM BaP inhibited only B6C3F1 splenocyte proliferation to LPS. These data suggest that DMBA may act on immunocytes by mechanisms largely independent of the Ah locus and associated metabolic processes.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Effects of 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and cyclosporin A on murine cytomegalovirus infection: studies of resistance mechanisms.

Susceptibility to murine cytomegalovirus (MCMV) was enhanced by treating B6C3F1 and CD-1 mice subcutaneously with 100 mg 7,12-dimethyl-benz[a]anthracene (DMBA)/kg fractionated over a 2 week period prior to sub-lethal infection. Virus-augmented natural killer cell (NKC) activity was depressed in B6C3F1 mice treated with 100 mg DMBA/kg, while serum interferon (IFN) levels were unaffected. Treatment with 50 mg DMBA/kg had no effect on susceptibility to virus or virus-augmented NKC activity. Susceptibility to MCMV was not affected by treating mice with 400 mg benzo[a]pyrene (B[a]P)/kg using the same exposure regimen. Virus-augmented NKC activity was suppressed in B[a]P-treated mice, but the magnitude of the suppression (18%) was much less than that for DMBA-treated mice (39%). Susceptibility to MCMV, virus-augmented NKC and IFN induction were not affected in mice treated intraperitoneally with 50 mg cyclosporin A (CSA)/kg/day for 5 days and infected on the 5th day of treatment. In contrast, enhanced susceptibility to MCMV and depressed NKC activity were observed in mice treated by the same exposure regimen on days 1-5 post infection. Susceptibility was not affected by CSA given on days 5-9 post infection. The data are useful not only because they show that DMBA and appropriately-timed CSA treatments suppress virus augmented NKC and enhance susceptibility to MCMV, but also because they help to define the relative importance of certain immune responses in defending against the infection, thus improving the usefulness of MCMV as a host resistance model for immunotoxicity testing. The data suggest that chemicals which depress NKC are likely to enhance susceptibility to MCMV, and conversely that effects on NKC should be suspected when chemical exposure enhances susceptibility to MCMV.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Persistent suppression of humoral immunity produced by 7,12-dimethylbenz(A)anthracene (DMBA) in B6C3F1 mice: correlation with changes in spleen cell surface markers detected by flow cytometry.

The purpose of these studies was to examine the effects of DMBA on subpopulations of splenocytes obtained from B6C3F1 mice, using cell surface markers defined by monoclonal antibodies and multiparameter flow cytometry. Changes were correlated with alterations in humoral immune function assessed in vitro. Mice were treated for 10 days during a 2 week period by subcutaneous (s.c.) injections of DMBA in corn oil at doses of 0.5, 5 and 10 micrograms/g/day (5-100 micrograms/g total dose). Four mice from each exposure group and an additional corn oil control group of mice were studied at 4 and 8 weeks following the last injection with DMBA. These studies demonstrated a dose-dependent decrease in the total number and percentage of spleen cells expressing B-cell markers (mu heavy chain, kappa light chain and 14.8 antigen) as well as T-cell markers (Thy 1.2, Lyt-1 and Lyt-2). The percentage of splenocytes expressing Mac-1 was increased by DMBA. Helper T-cells appeared to be a very sensitive population of spleen cells to DMBA exposure, as suggested by a decrease in the number and percentage of Lyt-1 positive cells recovered from the spleen 4 weeks after exposure to DMBA. DMBA produced a dose-dependent suppression of the in vitro primary humoral immune responses to SRBC, TNP-Ficoll and TNP-LPS. The fact that a functional suppression of humoral immunity was accompanied by a decrease in the number of mature B-cells and T-cells in the spleen suggests that cell surface markers may be useful indicators of immunotoxicity in animals receiving DMBA in sub-chronic studies.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Evaluation of the immunotoxicity of beta-hexachlorocyclohexane (beta-HCH).

beta-HCH, an isomeric contaminant formed during the manufacture of the insecticide lindane, is a persistent environmental and food chain pollutant which has been reported to exhibit estrogenic activity in rodents and in fish. To investigate potential toxic effects on the reproductive and immune systems, beta-HCH was fed to female B6C3F1 mice for 30 days. Mice exposed to 0, 100, or 300 mg of beta-HCH/kg of diet were evaluated for changes in ovarian and uterine histology, body weight, lymphoid organ weight and histology, splenic cellularity, antigen-specific IgM and IgG plaque-forming cells (PFC), proliferative responses to mitogens, natural killer (NK) cell activity, and induction of cytolytic T lymphocytes. The ovaries and endometrial epithelium exhibited normal architecture. No alterations were observed in body weight, lymphoid organ weight and histology, or splenic cellularity whereas significant changes were found in several immune functions at the 300 mg/kg dose. Proliferation of splenocytes to the mitogens LPS, PHA, and Con A was decreased by 39, 43, and 57%, respectively. T-lymphocyte-mediated cytolysis of tumor targets was decreased by 25% with a concurrent reduction of 45% in NK activity. There was no significant reduction in the number of IgM or IgG PFC in exposed animals. These data indicate that beta-HCH causes nonestrogenic immune function changes in the adult mouse without gross changes in lymphoid organ weight, histology, or cellularity.

Animals↗
PubMed1988

Comparison of a radioisotopic incorporation method and the mouse ear swelling test (MEST) for contact sensitivity to weak sensitizers.

A radioisotopic incorporation assay utilizing [125I]iododeoxyuridine was compared to the standard mouse ear swelling test (MEST) for the strong sensitizers dinitrofluorobenzene and oxazolone, and for the three weak sensitizers ethylenediamine (EDA), glutaraldehyde, and nickel sulfate. Mice were sensitized epicutaneously on the abdomen for 4 consecutive days prior to challenging the left ear with the test agent and the right ear with the vehicle. A comparison of the mean difference between the test and the control ears showed that measuring reactivity 48 hr postchallenge on Day 7 is the most sensitive time period in the radioisotopic incorporation method. Both the isotopic and MEST assays gave positive results with the potent sensitizers, although the response detected by isotopic labeling of emigrating cells was up to 1000-fold greater than that determined by ear swelling measurements. No response was detected to the moderate to weak sensitizer EDA in either assay. Reactivity to glutaraldehyde was not detected by the radioisotopic assay but was minimally responsive and significant by the MEST. The opposite was true for nickel sulfate where minimal but significant reactivity was seen in the isotopic assay but not in the MEST. Although the radioisotopic assay had the advantages of being more quantitative and of having improved sensitivity, it was of no greater value than the MEST for detecting weak sensitizers. It was concluded that the mouse was not a suitable model for routinely detecting reactivity to weak sensitizers regardless of which of the two assays were used.

Animals↗
PubMed1988

Adoptive cell transfer studies to examine the role of T lymphocytes in immunity to Trypanosoma musculi.

Previous studies in this laboratory utilizing monoclonal antibody-induced immunosuppression have demonstrated that the T-helper lymphocyte is primarily responsible for the T lymphocyte dependency of Trypanosoma musculi elimination from the bloodstream of mice, and that T-cytotoxic lymphocytes play a minimal role in this response. In the current study, these findings were extended by examining the effects of adoptive cell transfers on the course of infection with T. musculi using immune splenocytes enriched for T lymphocyte subpopulations. These studies demonstrated that adoptive transfer of immune splenic T lymphocytes resulted in a specific, dose-related enhancement of kinetics of trypanosome elimination. This effect was found to be due to the presence of L3T4+ T-helper cells in the immune splenocyte population. Adoptive transfer of Lyt-2+ T-cytotoxic cells or lymphokine-activated killer (LAK) cells was ineffective in altering the course of infection. In addition, it was found that immune B lymphocytes were equally capable of adoptively transferring immunity to T. musculi, suggesting that the primary role of the T-helper lymphocyte is to provide help in the induction of parasite-specific antibodies.

Animals↗
PubMed1987

The effect of formaldehyde exposure upon the mononuclear phagocyte system of mice.

The vapors of formaldehyde have been reported to represent a potential health hazard, resulting in an increased incidence of carcinomas of the nasal turbinates in experimental animals. To determine the potential role of alterations in the mononuclear phagocyte system (MPS) induced by inhalation of formaldehyde, we studied the systemic effects of exposure upon macrophages. Specifically, we examined the effects of formaldehyde exposure upon development of the MPS by use of an established system of quantitative objective markers, which characterizes and classifies populations of murine macrophages into several developmental stages. Exposure of mice to 15 ppm of formaldehyde for 6 hr daily for 3 weeks did not alter the number or impair the function of resident peritoneal macrophages, although this exposure increased (approximately twofold) competence for release of H2O2 from the macrophages. Furthermore, formaldehyde exposure did not alter the tumoricidal activation or differentiation of macrophages produced by the defined stimulant MVE-2. The data thus indicate that exposure of mice to formaldehyde can induce selective systemic alterations in the function of the MPS for H2O2 production, a change which has been shown in other studies to increase the frequency of mutagenesis.

Acid Phosphatase↗
PubMed1987

Immunosuppression following exposure to 7,12-dimethylbenz[a]anthracene (DMBA) in Ah-responsive and Ah-nonresponsive mice.

Recent reports suggest that the immunotoxicity of certain polycyclic aromatic hydrocarbons is associated with the Ah locus in mice. To test whether immunosuppression mediated by 7,12-dimethylbenz[a]anthracene (DMBA) is regulated by the Ah locus, several endpoints of immune function were measured in Ah-responsive B6C3F1 and Ah-nonresponsive DBA/2N and in Ah-congenic C57BL/6J (responsive B6-AhbAhd and nonresponsive B6-AhdAhd) mice dosed sc with up to 100 micrograms/g DMBA in corn oil. Some groups of B6C3F1 and DBA/2N mice were exposed to 100 micrograms/g benzo[a]pyrene (B(a)P) or 1 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for determination of hepatic microsomal monooxygenase activity. The body weights of all mice were unaffected by DMBA exposure, but thymus weights and spleen cellularity were decreased. Antibody plaque-forming cells (PFC) measured 4 days after iv sheep erythrocyte (SRBC) immunization were suppressed 99% in B6C3F1 and 96% in DBA/2 mice. Antibody PFC after in vitro immunization to SRBC were similarly suppressed 98% in both B6-AhbAhd and B6-AhdAhd Ah-congenic mice exposed to 100 micrograms/g DMBA. Responses to the T-cell mitogens concanavalin A and phytohemagglutinin were significantly suppressed in both B6C3F1 and DBA/2N strains, as was mitogenesis to bacterial lipopolysaccharide. The unidirectional mixed lymphocyte responses of the congenic strains were suppressed 76% in B6-AhbAhd and 85% in B6-AhdAhd, cytotoxic lymphocyte generation was suppressed 68% in B6-AhbAhd and 78% in B6-AhdAhd. The overall differences between immunosuppressive responses in splenocytes from B6-AhbAhd and B6-AhdAhd congenics were not significant. Induction of cytochrome P1-450, a marker of Ah responsiveness, was determined by 7-ethoxycoumarin O-deethylase monooxygenase activity in hepatic microsomes or splenocytes. This monooxygenase activity was not significantly increased in either B6C3F1 or DBA/2 mice exposed to DMBA, whereas B(a)P and TCDD exposure significantly induced enzyme activity in B6C3F1 hepatocytes. These data suggest that DMBA has an immunosuppressive action on murine splenocytes which is independent of the Ah locus and associated induction of cytochrome P1-450 xenobiotic-metabolizing enzymes.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Suppression of T-helper cell function in mice following exposure to the carcinogen 7,12-dimethylbenz[a]anthracene and its restoration by interleukin-2.

Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthrance (DMBA) results in suppression of cell-mediated immunity (CMI), specifically the ability to generate cytotoxic T cells. This is accompanied by an increased susceptibility to challenge with transplantable tumors. Our previous studies have demonstrated no appreciable change in the composition of splenic lymphocyte populations following exposure to DMBA, suggesting a modulation of lymphocyte function, probably at the level of the T lymphocyte. The purpose of this study was to examine the mechanism of DMBA-induced T lymphocyte dysfunction following DMBA exposure, and to determine whether CTL function could be reconstituted by the addition of untreated lymphocytes or lymphokines. Exposure to DMBA in vivo at doses of 50 and 100 micrograms/g and in vitro at doses of 20 and 40 microM suppressed the ability of splenic lymphocytes to generate cytotoxic T-lymphocytes (CTL). CTL-mediated lysis of allogeneic tumor target cells could be restored by the addition of 20% T cell-enriched naive lymphocytes and by 10% T-helper cell-enriched lymphocytes. DMBA suppressed splenocyte production of the lymphokine interleukin-2 (IL-2) in response to mitogenic or allogeneic stimulation by greater than 70% following in vitro exposure and greater than 45% following in vivo exposure. Although DMBA-exposed lymphocytes were impaired in their ability to produce IL-2, CTL responsiveness could be reconstituted by the addition of exogenous IL-2 (purified or recombinant DNA-produced). Complete restoration of CTL responsiveness by the addition of exogenous IL-2 suggests that the T-helper cell, rather than the T-cytotoxic cell, is the target for the DMBA-induced CMI lesion.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Induction of ethylenediamine hypersensitivity in the guinea pig and the development of ELISA and lymphocyte blastogenesis techniques for its characterization.

Ethylenediamine (EDA) is reported to be a poorly characterized iatrogenic and occupational contact sensitizer. To better characterize EDA hypersensitivity, a guinea pig model was employed in which the animals were exposed epicutaneously to simulate conditions of human exposure, and selected immune parameters were measured. Induction of hypersensitivity was by the Buehler occluded patch method (6 hr application/day, once a week for 3 consecutive weeks) to 10, 20, 30, or 40% EDA, using either an ethanol or acetone/corn oil vehicle. Fourteen days after the last induction, guinea pigs were challenged by patch application of 2% EDA (nonirritating). The incidence of responders for erythema in the 10% EDA (ethanol) treatment group was 83 and 50% at 24 and 48 hr, respectively. In the 10% EDA (acetone/corn oil) group the corresponding values were 50 and 17%. For 20, 30, and 40% EDA, in either vehicle, the incidence of erythema was 83 to 100%. Severity grades (scale = 0-3) for cutaneous reactions to increasing concentrations of EDA in ethanol ranged from 0.8 to 2.5; those for EDA in acetone/corn oil ranged from 0.6 to 2.8. Using an enzyme-linked immunosorbent assay developed to detect the predominant serum antibodies to EDA, it was shown that guinea pigs treated by patch application did not produce the main allergic antibody IgG specific for EDA. However, intradermal administration of an EDA-guinea pig serum albumin conjugate (EDA-GSA) to guinea pigs presensitized by patch application resulted in antibody production by 39 and 86% of the animals, at the initial and second dosing, respectively. An in vitro blastogenesis assay, using peripheral blood lymphocytes from EDA-sensitized guinea pigs, was developed to identify specific chemical allergens implicated in vivo sensitization. Maximum tritiated thymidine ([3H]TdR) incorporation by lymphocytes stimulated in vitro with EDA-GSA was observed on Day 7. Optimal antigen concentration for maximum lymphocyte proliferation ranged from 5 to 50 micrograms/ml, the major variation being attributable to interanimal differences. These results indicate that epicutaneous application of EDA in the guinea pig induces a Type IV delayed hypersensitivity; immunological memory to the hapten is maintained in cultured lymphocytes, suggesting the potential usefulness of the lymphocyte transformation test for in vitro diagnosis of chemically induced hypersensitivity in humans.

Animals↗
PubMed1987

Immunotoxicology: an overview.

It is now known that chemicals and drugs may induce selective toxicity which may alter the interactions between immunocompetent cells, especially if the toxicity occurs during proliferation and differentiation. Hence, a flexible panel of sensitive in vivo and in vitro assays has been developed and validated to assess the immunotoxicity or immunopharmacology of suspect agents in rodents. The combined use of such sequential analysis methods with host resistance assays can effectively define immunomodulation following exposure to xenobiotics. Methods development, refinement and validation will be an ongoing requirement because of our rapidly expanding knowledge of the cell biology of the immune system. Classic studies of the comparative preclinical toxicology of several immunosuppressive drugs have substantiated species similarities and have contributed significantly to the development of predictive rodent models for extrapolation to humans. Studies of immunopharmacology and immunotoxicity of cyclosporin A, for example, produced both the desired pharmacology and the undesired toxicity at similar doses in both rodents and humans. When species differences are observed during toxicology studies they are most probably due to differences in absorption, disposition, metabolism, excretion, or delivered dose at the target tissue, rather than major species differences in cellular targets or cell physiology. This assumption is the basis for using rodent species to predict the toxicity of chemicals and drugs under development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: a model of aberrant macrophage development.

Administration of the synthetic estrogen diethylstilbestrol (DES) lowers the systemic resistance of mice to challenge with either tumor cells or the facultative intracellular parasite Listeria monocytogenes. To assess the potential role of impaired mononuclear phagocyte system (MPS) function in this depression of host resistance, we addressed the question of systemic perturbations of the MPS induced by administration of DES. A panel of objective quantitative markers which have been previously shown to identify and characterize macrophages in the several stages of development of activation was employed. DES perturbed the resident population of peritoneal macrophages by increasing their number approximately twofold and by enhancing their competence for phagocytosis, cytostasis of tumor cells, and secretion of plasminogen activator. When we examined the competence of the MPS in DES-treated mice to respond to challenge with activating stimuli, we found that DES systemically suppressed the development of macrophages, in response to either pyran copolymer or BCG, to develop tumoricidal function and to gain competence for secretion of reactive oxygen intermediates such as H2O2. Since these data suggested that DES inhibited the development of macrophages from a precursor stage (i.e., responsive macrophages) to activated macrophages in vivo, we tested this possibility directly by applying known activating signals in vitro to responsive macrophages. Responsive macrophages from DES-treated mice did not become activated in response to the application of two known potent activating signals (i.e., MAF + LPS). Taken together, the data indicate that DES systemically perturbs the MPS and does so by enhancing development of the early stages of maturation and suppressing subsequent development.

Animals↗
PubMed1986

Effect of short-term inhalation exposure to 1,3-butadiene on murine immune functions.

Interest in 1,3-butadiene (BD) as a potential immunomodulator was prompted by reports of an increased incidence of neoplasia in humans exposed to BD during the manufacture of styrene-butadiene synthetic rubber, and by a recent study which demonstrated a high incidence of thymic lymphomas in B6C3F1 mice. B6C3F1 mice were exposed to 1250 ppm BD by inhalation 6 hr per day, 5 days per week, for 6 or 12 weeks. Immune function assays were selected to evaluate specific humoral and cell-mediated immunity and spontaneous cytotoxicity; lymphoid organ histopathology was also evaluated. A slight decrease in antibody plaque-forming cells (PFC) per spleen was observed in exposed mice, although PFC per 10(6) splenic lymphocytes was normal. Significant extramedullary hematopoiesis and erythroid hyperplasia was observed in spleens from exposed mice, and correlated with a twofold increase in thymidine incorporation in spontaneously proliferating splenocytes. No differences in proliferation to alloantigens were demonstrable between control and BD-exposed splenocytes. Mitogenesis by phytohemagglutinin, Concanavalin A, and lipo polysaccharide was suppressed in splenocytes from exposed mice, but may have been due to the cellular dilution effect of hematopoietic activity. Cytotoxic T-lymphocyte generation was suppressed after a 6-week exposure to BD, but was comparable to controls after 12 weeks of exposure. No differences in spontaneous cytotoxicity were observed between control and exposed mice. Overall, no persistent immunological defects were detectable after inhalation exposure to this tumorigenic agent.

Administration, Inhalation↗
PubMed1986

Immunosuppression following 7,12-dimethylbenz[a]anthracene exposure in B6C3F1 mice--II. Altered cell-mediated immunity and tumor resistance.

We have previously demonstrated that the polycyclic aromatic hydrocarbons benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) produce a marked decrease in spleen weight, spleen and bone marrow cellularity and the number of IgM plaque forming cells generated in response to a T-dependent antigen. Exposure to DMBA, but not B[a]P, increased susceptibility to challenge with PYB6 tumor cells and Listeria monocytogenes suggesting that DMBA produces immune impairment involving cell-mediated immunity (CMI) and tumor resistance mechanisms. In this study, female B6C3F1 mice received total doses of 5, 50 and 100 micrograms DMBA/g of body weight in ten subcutaneous injections of 0.5, 5, or 10 micrograms/g over a 2 week period and CMI and tumoricidal functions were examined 3-5 days following the final injection of DMBA. DMBA exposed mice exhibited suppressed splenic cellularity (decreased 62%) and decreased numbers of resident peritoneal cells (down to 47% of control), although the proportion of T cell and T cell subsets, B cells and macrophages in spleens from exposed mice was not altered. Lymphocyte blastogenesis in response to mitogens was suppressed up to 49% with PHA, 48% with Con A and 76% with LPS. The response to alloantigens in unidirectional mixed lymphocyte culture was depressed as much as 73% following exposure to DMBA. Tumor cytolysis mediated by cytotoxic T cells (CTL) was impaired at doses of 50 and 100 micrograms DMBA/g body weight (88-95% suppressed respectively) as was natural killer cell (NK)-mediated tumor cytolysis (24% and 55% suppressed). Antibody-dependent cytotoxicity was significantly depressed in the highest exposure group. Peritoneal macrophage accumulation was decreased in DMBA-treated mice, but the macrophages present were pushed towards activation. The ability of DMBA-exposed mice to eliminate intravenously injected B16F10 tumor cells from the lungs was not impaired. Since NK- and M phi-mediated tumor cytotoxicity are thought to be primarily responsible for pulmonary elimination of B16F10 melanoma cells, the extent of NK suppression observed following DMBA exposure appeared to be insufficient to alter in vivo B16F10 pulmonary elimination. In contrast, the loss of the CTL tumoricidal response correlated with an increased frequency of tumors following challenge with PYB6 tumor cells.

9,10-Dimethyl-1,2-benzanthracene↗