Thymus förtvining, atrophy, PCB, dioxin, vitaminerThymus atrophy(Thymus förtvining)Thymus atropy and ( PCB or dioxin or vitamin )1 BIOLAN 99465271 9715.AU Kamath-A-B, Xu-H, Nagarkatti-P-S, Nagarkatti-M.TI Evidence for the induction of apoptosis in thymocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vivo.SO Toxicology-and-Applied-Pharmacology 142 (2). 1997. 367-377. ISSN0041-008X.IN Dep Biomedical Sci Pathobiol, VA-MD Regional Coll Vet Med, VirginiaTech, Blacksburg, VA 24061, USA.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for itsimmunotoxic effects particularly on the thymus. The exact mechanismby which TCDD induces thymic atrophy is not clear. In the currentstudy, we investigated whether TCDD triggers apoptosis in thymocytes,when administered in vivo, by using the TdT-mediated FITC -dUTP nickend labeling method and analyzing the cell flow cytometrically.Significant apoptosis was detected at 8-12 hr after the TCDDinjection but not at 24 hr or beyond, up to 120 hr of study.Furthermore, the induction of apoptosis was confirmed using the JAMtest in which thymocytes from TCDD-treated mice, labeled with (3H)thymidine, exhibited increased DNA fragmentation when compared to thecontrols. Similar to TCDD treatment, administration of dexamethasone(5 or 100 mg/kg) into C57BL/6 mice triggered apoptosis that was onlydetected at 12 hr after administration of the drug and notthereafter. When thymocytes from TCDD- or dexamethasone-treated micewere cultured in vitro for 24 hr, they exhibited marked increase inapoptosis when compared to the vehicle-treated controls. However,TCDD, when added to in vitro cultures of thymocytes, failed totrigger apoptosis. Together, our studies demonstrate that TCDD caninduce apoptosis in thymocytes in vivo. This can be detected only atan early stage following TCDD administration, possibly because ofrapid clearance of apoptotic cells by the phagocytic cells in vivo.2 BIOLAN 99436466 9714.AU Nagarkatti-M, Kamath-A, Xu-H.TI 2,3,7,8-Tetrachlorodibenzo-P-dioxin (TCDD) induced thymic atrophy ismediated through apoptosis.SO 4th International Union of Biochemistry and Molecular BiologyConference, Edinburgh, Scotland, UK, July 14-17, 1996. Biochemical-Society-Transactions 24 (4). 1996. 618S. ISSN 0300-5127.IN Dep Biomedical Sciences Pathobiology, VA-MD Reginal Coll VeterinaryMed, Va Tech, Blacksburg, VA 24061, USA.3 BIOLAN 99240131 9645.AU Fernandez-Salguero-P-M, Hilbert-D-M, Rudikoff-S, Ward-J-M, Gonzalez-F-J.TI Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity.SO Toxicology-and-Applied-Pharmacology 140 (1). 1996. 173-179. ISSN0041-008X.IN Lab Mol Carcinogenesis, Natl Cancer Inst, Natl Inst Health, Bethesda,MD 20892, USA.AB Acute exposure of mammals to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a diverse set oftoxicologic and pathologic effects. The mechanism of some of theseeffects has been studied extensively in vitro and correlative studieshave indicated the involvement of a transcription factor known as thearyl hydrocarbon receptor (AHR). However, a definitive association ofthe AHR with TCDD-mediated toxicity has been difficult to establishdue to the diversity of effects and the ubiquitous expression of thisreceptor. In an effort to distinguish AHR-mediated TCDD toxicitiesfrom those resulting from alternative pathways, we have made use ofthe recently described AHR-deficient mouse that was generated bylocus-specific homologous recombination in embryonic stem cells.Present studies demonstrate that AHR-deficient mice are relativelyunaffected by doses of TCDD (2000 mu-g/kg) 10-fold higher than thatfound to induce severe toxic and pathologic effects in littermatepressing a functional AHR. Analyses of liver, thymus, heart,kidney, pancreas, spleen, lymph nodes, and uterus from AHR-deficientmice identified no significant TCDD-induced lesions. The resistanceof AHR-deficient mice to TCDD-induced thymic atrophy appearsrestricted to processes involving AHR since the corticosteroiddexamethasone rapidly and efficiently induced cortical depletion inboth AHR-deficient and normal littermate control mice. Taken togetherthese results suggest that the pathological changes induced by TCDDin the liver and thymus are mediated entirely by the AHR. However, itis important to note that at high doses of TCDD, AHR-deficient micedisplayed limited vasculitis and scattered single cell necrosis intheir lungs and livers, respectively. The mechanism(s) responsiblefor these apparently receptor-independent processes remain unclearbut may involve novel, alternative pathways for TCDD-inducedtoxicity.4 BIOLAN 99063665 9630.AU Rhile-M-J, Nagarkatti-M, Nagarkatti-P-S.TI Role of Fas apoptosis and MHC genes in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity of T cells.SO Toxicology 110 (1-3). 1996. 153-167. ISSN 0300-483X.IN Dep Biol, Virginia Tech, Blacksburg, VA 24061-0406, USA.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for itsimmunotoxic effects particularly on the thymus as well as on T and Blymphocyte functions. Previous studies have suggested that TCDD mayinduce apoptosis in thymocytes although its demonstration in vivo hasmet with limited success. TCDD has also been shown to alter the majorhistocompatiblity complex- (MHC) encoded molecules, however, its rolein immunotoxicity is not clear. In the current study, we investigatedthe role of Fas (CD95), an important molecule involved in theinduction of apoptosis, on TCDD-mediated immunotoxicity using micebearing homozygous lpr mutation which leads to failure of expressionof Fas. When TCDD was administered orally at 0, 0.1, 1.0, or 5.0 mu-g/kg body weight for 11 days, it was found to be less toxic to thethymocytes from C57BL/6 lpr/lpr mice (Ah-responsive, Fas-) whencompared to C57BL/6 +/+ mice (Ah-responsive, Fas+). Similar resultswere obtained when peripheral T cell responsiveness to antigenicchallenge with conalbumin was studied in these mice. When mice thatdiffered only at the MHC were compared for immunotoxic effects ofTCDD, it was noted that B10 cntdot D2 (Ah-responsive, H-2-d) weremore sensitive to TCDD-mediated thymic atrophy and peripheral T celldysfunction when compared to B10 mice (Ah-responsive, H-2-b). In allTCDD-sensitive strains tested, the thymic atrophy was accompanied bya uniform depletion of all four subset of T cells (CD4+, CD4+ CD8+,CD4- CD8-, and CD8+) and the percentage of these subsets was notaltered. Furthermore, in these strains, TCDD suppressed the antigen-specific peripheral T cell responsiveness but not the responsivenessof naive resting T cells to polyclonal mitogens. Lastly, using cell-mixing experiments, it was demonstrated that TCDD directly affectedthe T cells responding to conalbumin but not the antigen presentingcells (APCs). Together, our studies demonstrate that although Ahlocus plays the primary role, determining the toxicity of TCDD on theT cells, there are secondary factors such as expression of Fas or theMHC-phenotype which may play an important role in TCDD-mediatedimmunotoxicity. The role of Fas further suggests that TCDD may inducetoxicity in T cells by triggering apotosis.5 BIOLAN 98789960 9621.AU Mohamed-M-I, Beckman-M-J, Meehan-J, Deluca-H-F.TI Effect of 1,25-dihydroxyvitamin D-3 on mouse thymus: Role ofextracellular calcium.SO Biochimica-et-Biophysica-Acta 1289 (2). 1996. 275-283. ISSN0006-3002.IN Dep Biochem, Univ Wisconsin-Madison, 420 Henry Mall, Madison, WI53706, USA.AB We recently reported that mice treated with 1,25-dihydroxyvitamin D-3(1,25-(OH)-2D-3) or 19-nor-1,25-(OH)-2D-2 experienced a severe lossof their thymocytes and decreased proliferation in response toconcanavalin A mitogen. The present study investigated the effect ofshort-term treatment with 1,25-(OH)-2D-3 on the thymic architectureand thymocyte subsets. Daily treatment with 1,25-dihydroxyvitamin D-3at 20 ng per mouse for 4 days induced significant involution ofthymic tissue. The atrophy was predominantly observed in the corticalcomponent. Flow cytometric analysis of thymocyte subsets showed thatthe CD4+ CD8+ population was the primary target. Since the treatedmice experienced profound hypercalcemia, we studied the effect of1,25-(OH)-2D-3 on animals fed a vitamin D-deficient, low calcium dietor the same diet containing vitamin D for 25 days prior to treatment.The low calcium fed mice showed severe hypocalcemia and slightthinning of thymic cortex. Treatment with 1,25-(OH)-2D-3 moderatelyimproved the hypocalcemia but had no further effect on the thymus ofthese animals. On the other hand, hypercalcemia and thymic atrophywere found in the animals fed the diet containing vitamin D. Overall,the atrophy effect on the thymus caused by 1,25-(OH)-2D-3 treatmentwas prevented by eliminating the hypercalcemia observed in +D+Catreated animals. Thus, thymic atrophy probably resulted fromhypercalcemia and not from 1,25-(OH)-2D-3 itself.6 BIOLAN 98657122 9608.AU De-Heer-C, Van-Driesten-G, Schuurman-H-J, Rozing-J, Van-Loveren-H.TI No evidence for emergence of autoreactive V-beta-6+ T cells in Mls-1-a mice following exposure to a thymotoxic dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin.SO Toxicology 103 (3). 1995. 195-203. ISSN 0300-483X.IN Lab Pathol, Natl Inst Public Health Environmental Protection, PO Box1, 3720 BA, Bilthoven, Netherlands.AB Tolerance to minor lymphocyte stimulatory-1-a (Mls-1-a) antigens isassociated with clonal deletion of cells carrying the T cell receptorvariable region V-beta-6. Thymic epithelial cells may contribute tothe intrathymic negative selection of potentially autoreactive V-beta-6+ cells. Because 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)acts on thymic epithelial cells, we hypothesized that it mayinterfere with intrathymic selection processes. In the present study,this was addressed by exposing Mls-1-a DBA/2 mice to a singlethymotoxic dose of TCDD. The emergence of V-beta-6+ cells in thymus,spleen, and mesenteric lymph nodes was investigated during thesubsequent recovery of TCDD-induced thymic atrophy. In addition. theextrathymic differentiation of T lymphocytes in the liver wasstudied. TCDD exposure resulted in a severe thymic atrophy, and anincrease in hepatic mononuclear cells. However, we were not able todemonstrate any emergence of potentially autoreactive mature V-beta-6+ T cells, that differentiated either intrathymically orextrathymically, in TCDD-exposed DBA/2 mice.7 BIOLAN 99465042 9700.AU Weber-L-W-D, Greim-H.TI The toxicity of brominated and mixed-halogenated dibenzo-p-dioxinsand dibenzofurans: An overview.SO Journal-of-Toxicology-and-Environmental-Health 50 (3). 1997. 195-215.ISSN 0098-4108.IN Dep Pathol Lab Med, Univ Kansas Med Cent, Kansas City, KS 66160-7410,USA.AB Brominated dibenzo-p-dioxins and dibenzofurans can be formed underlaboratory conditions by pyrolysis of flame retardants based onpolybrominated biphenyls and biphenyl ethers. Their occurrence in theenvironment, however, is due to combustion processes such asmunicipal waste incineration and internal combustion engines. Asthese processes generally take place in the presence of an excess ofchlorine, predominantly mixed brominated and chlorinated compoundshave been identified so far in environmental samples. Brominateddibenzo-p-dioxins or dibenzofurans bind to the cytosolic Ah receptorabout as avidly as their chlorinated congeners and induce hepaticmicrosomal enzymes with comparable potency. The same holds true formixed brominated-chlorinated compounds. Gross pathologic symptoms-hypothyroidism, thymic atrophy, wasting of body mass, lethality-alsooccur at doses that, on a molar concentration basis, are virtuallyidentical to those seen with the chlorinated compounds. Their potencyto induce malformations in mice following prenatal exposure isequivalent to that of chlorinated dibenzo-p-dioxins anddibenzofurans. Possible activities as (co)carcinogens and endocrinedisrupters have not been evaluated, but are likely to exist.Considering the overall similarity in action of chlorinated andbrominated dibenzo-p-dioxins and dibenzofurans, environmental andhealth assessments should be based on molar body burdens withoutdiscrimination for the nature of the halogen.8 BIOLAN 98099238 9507.AU De-Heer-C, Schuurman-H-J, Vos-J-G, Van-Loveren-H.TI Lymphodepletion of the thymus cortex in rats after single oralintubation of 2,3,7,8-tetrachlorodibenzo-p-dioxin.SO Chemosphere 29 (9-11). 1994. 2295-2299. ISSN 0045-6535.IN Lab Pathol, National Inst Public Health Environmental Protection, POBox 1, 3720 BA Bilthoven, Netherlands.AB Atrophy of the thymus and thymic lymphodepletion occurs afterexposure to sublethal doses of TCDD. Previous studies using highdoses of TCDD (150 mu-g/kg) have indicated a preferentiallymphodepletion of the thymus cortex on day 4 after a single oralintubation. Here we describe the effects of a single oral intubationof lower dose levels of TCDD (1, 5, and 25 mu-g/kg) on thymic weightsand thymocyte subpopulations in Wistar rats on day 4 after exposure.A single administration of 1 mu-g/kg TCDD induced a significantreduction in the number of immature CD4+CD8+ double-positive (DP)thymocytes. At this time point the numbers of mature medullarythymocytes were not affected at any dose level tested. We concludethat also lower dose CD3-high levels of TCDD induce thymic atrophyvia a preferential lymphodepletion of the thymus cortex.9 BIOLAN 97552962 9448.AU De-Heer-C, De-Waal-E-J, Schuurman-H-J, Vos-J-G, Van-Loveren-H.TI The intrathymic target cell for the thymotoxic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin.SO Experimental-and-Clinical-Immunogenetics 11 (2-3). 1994. 86-93. ISSN0254-9670.IN Lab Pathol, Natl Inst Public Health and Environ Prot, PO Box 1,NL-3720 BA Bilthoven, NET.AB Sublethal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)produces thymic atrophy and thymic lymphodepletion in all speciesinvestigated. Lymphodepletion is first seen in the cortex of thethymus, but also occurs in the medulla at later time points. Thisarticle surveys in vivo and in vitro studies on TCDD-induced thymustoxicity. It is concluded that the first intrathymic target cell forthe action of TCDD is the cortical epithelial cell.10 BIOLAN 97552961 9448.AU Esser-C, Lai-Z, Gleichmann-E.TI Proliferation inhibition and CD4-CD8 thymocyte subset skewing by invivo exposure of C57BL-6 mice to Ah receptor-binding 3,3',4,4'-tetrachlorobiphenyl.SO Experimental-and-Clinical-Immunogenetics 11 (2-3). 1994. 75-85. ISSN0254-9670.IN Med Inst Environ Hygiene, Auf'm Hennekamp 50, D-40225 Duesseldorf,GER.AB 3,3',4,4'-Tetrachlorobiphenyl (TCB) and other Ah receptor-bindingxenobiotics lead to thymus atrophy and immunosuppression, the formerpossibly causing the latter. In order to better understand the TCB-induced events in the murine thymus, we analyzed the effects of TCBon the proliferation capacity and maturation kinetics of differentthymocyte subsets in 2-week-old C57BL/6 mice (i.e. of the Ah-b-1'dioxin-sensitive' genotype). Mice were injected with a single doseof TCB, and the development of thymocytes was followed up for 10 daysusing flow cytometric surface marker analysis combined withmeasurement of DNA content by 7-amino-actinomycin D staining. Already2 days after exposure to TCB, fewer of the more immature thymocytes(CD4-CD8-, CD4CD8+alpha-beta-TCR-) were proliferating than in thymifrom control animals. Eventually this led to a severe decrease inthymus cellularity. Moreover, a shift towards the CD4-CD8+ maturesubpopulation was observed. The effects were reversible, andproliferation and CD4/CD8 subset distribution returned to normallevels within the observation period. The results are in goodagreement with the data obtained previously in vitro with fetalthymus organ cultures.11 BIOLAN 97520688 9446.AU Kurl-R-N.TI An inhibitory factor in rat thymus which interferes with binding ofcytosol Ah receptor to xenobiotic responsive element.SO Biochemistry and Molecular Biology International 34 (1). 1994. 55-66.ISSN *********.IN Dep Med, Graduate Program Pathobiol, Brown Univ Sch Med, Providence,RI 02912, USA.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce arylhydrocarbon hydroxylase in several tissues in the rat. This effect ofTCDD is mediated by the Ah receptor. However, TCDD does notsignificantly enhance aryl hydrocarbon hydroxylase activity in therat thymus. Analysis of 3H-TCDD bound Ah receptor on sucrosegradients revealed the presence of radioactivity sedimenting at 8-9Sand 5-6S in the cytosol and nuclei of thymus respectively. Incubationof rat thymic cytosol with TCDD increased protein kinase C dependentphosphorylation, which reached saturation levels at highconcentrations of TCDD, but the TCDD bound receptor did notappreciably retard 32P-labeled XRE-3 as determined by electrophoreticmobility shift assay. Incubation of rat hepatic cytosol with TCDDalso increased protein kinase C dependent phosphorylation in aconcentration dependent manner as well as retarded the mobility of32P-labeled XRE far more than that observed with thymic cytosol. Theability of the Ah receptor to bind to XRE was temperature dependent.Incubation of thymic cytosol either with okadaic acid or with sodiumfluoride did not increase the binding of the Ah receptor to XRE. Onmixing hepatic cytosol with thymic cytosol prior to theelectrophoretic mobility shift assay, the binding of the hepatic Ahreceptor to XRE was reduced in a concentration-dependent manner. Asimilar effect was observed when renal cytosol was used instead ofhepatic cytosol. Thymic cytosol also reduced the binding of thehepatic glucocorticoid receptor to its cognate responsive element.Thymic cytosol did not alter the topology/integrity of XRE. Thesedata suggest that the thymus contains a factor(s) which interfereswith the binding of AhR to its cognate responsive element.12 BIOLAN 97505492 9444.AU De-Heer-C, Verlaan-A-P-J, Penninks-A-H, Vos-J-G, Schuurman-H-J, Van-Loveren-H.TI Time course of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducedthymic atrophy in the Wistar rat.SO Toxicology-and-Applied-Pharmacology 128 (1). 1994. 97-104. ISSN0041-008X.IN Lab for Pathol, National Inst of Public Health and EnvironmentalProtection, PO Box 1, 3720 BA Bilthoven, NET.AB Exposure to sublethal doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in Wistar rats results in thymic atrophy and reduced thymiccellularity. In a first experiment, rats were once orally intubatedwith 0, 1, 5, 25, 50, and 150 mu-g TCDD/kg body wt and sacrificed atDay 10. The dose that produced one-half of the maximal thymicinvolution was estimated at about 10-20 mu-g/kg. The time course(Days 0-21) of thymic atrophy induced by a single oral intubation of25 mu-g TCDD/kg body wt revealed four phases. In phase 1 (initiationphase, Days 0-2) a decrease in proliferative activity was seen incortical thymocytes, whereas no changes occurred in thymiccellularity. Phase 2 (lymphodepletion phase, Days 2-8) wascharacterized by an initial strong depletion of immature CD4+CD8+double-positive (DP) cells (Day 4), followed by a more gradualdecrease in the number of mature thymocytes (Day 6). On Day 8 thelymphodepletion was maximal. In phase 3 (stationary phase, Days 8-13)no changes occurred in thymic cellularity. Although the first signsof recovery were already seen on Day 6, indicated by a recovery inproliferative activity in the thymus cortex, an increase in thymiccellularity was observed first after Day 13 (phase 4, recovery phase,Day 13 onward). Reversibility of thymic atrophy is therefore observedwithin the estimated half-life of TCDD in the rat thymus ( gt 16days). We conclude that TCDD exerts a rapidly reversible effect on anintrathymic cortical target cell population.13 BIOLAN 97505399 9444.AU Kremer-J, Gleichmann-E, Esser-C.TI Thymic stroma exposed to aryl hydrocarbon receptor-bindingxenobiotics fails to support proliferation of early thymocytes butinduces differentiation.SO Journal-of-Immunology 153 (6). 1994. 2778-2786. ISSN 0022-1767.IN Div Immunol, Med Inst Environ Hygeine, Heinrich Heine UnivDuesseldorf, Auf'm Hennekamp 50, 40225 Duesseldorf, GER.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 3,3',4,4'-tetrachlorobiphenyl (TCB), two ubiquitous environmental pollutants,accelerate thymocyte maturation, and eventually lead to thymusatrophy. These processes are mediated by binding of TCDD or TCB tothe cytosolic arylhydrocarbon receptor (AhR) abundant in the thymus,which acts as a ligand-activated transcription factor. At severalstages of their maturation thymocytes need the interaction withthymus stroma. We tested whether thymocytes themselves or the thymusstroma are targets of AhR-binding compounds for interference withthymocyte maturation. We depleted fetal thymus lobes fromproliferating cells, i.e., thymocytes, by treatment withdeoxyguanosine and recultivated them with immature thymocytes (CD4-CD8-), exposing either the stroma or the thymocytes to TCDD or TCBbefore recultivation. Although CD4-CD8- immature thymocytes coulddifferentiate in TCB-treated stroma, expansion of the cells wasseverely impaired. Selective exposure of thymocytes to AhR-bindingcompounds likewise did not impair the capacity of differentiation ofCD4-CD8- thymocytes. These cells, however, could expand whentransferred into new lobes that had not been exposed to TCDD or TCB.TCB treatment of fetal thymi leads to an accumulation ofphenotypically mature CD4-CD8+ cells. We show here that these cellsdo not belong to the transient CD4-CD8+ thymocytes, as previouslysuggested, because in recultivation experiments they do not give riseto any thymocyte subset further down the maturation pathway.14 BIOLAN 97505252 9444.AU Kaminski-M.TI Processes of cell necrosis: Apoptosis-and their modifications bytoxic substances.SO Medycyna-Pracy 45 (3). 1994. 267-277. ISSN 0465-5893.IN Medykow 20, 40-751 Katowice-Ligota, POL.AB Apoptosis - a programme physiological necrosis of cells is a synonimof a complex multistage process of cell reduction described duringthe 1970s. It occurs during metamorphosis on insects and amphibiansas well as during embryogenesis, intrauterine and extrafetal life ofmammals. It regulates the atrophy of completely developed organs,e.g. thymus, and the hormonal reconstructure of adrenal glands,mammary and prostate glands, ovaries and others. It is a reverse ofproliferation and it guarantees homeostasis of the number, structureand biochemical activity of tissues and organs. It is developed byapoptosis substances and factors represented by protein hormones,peptides, steroid hormones, cytokines and metabolites of vitamin A,antimetabolites, drugs, toxic substances, ionizing radiation,antigens. On the other hand, the development of apoptosis is arrestedby so called "survival factors" -erythropoietin, CSF, NGF, IL-1and2, certain hormones, phenobarbital, ciproteron. The process of aprogrammed necrosis is associated with spectacular "events" ofmorphological, biochemical and macromolecular nature. Steering isprovided by a group of genes, partly recognized, particularly in theNematode of Caenorhabolitis elegans. They are among others killergenes which remove the remnants of decaying cells and genes whichhinder the expression of death genes. Transduction of calcic signalfrom the receptor to the nuclear chromatin releasing a programmednecrosis of cells is also discussed.15 BIOLAN 97426340 9438.AU Esser-C.TI Dioxins and the Immune System: Mechanisms of Interference: A MeetingReport. (Second Duesseldorf Symposium on Immunotoxicology,Duesseldorf, Germany, June 1993).SO International-Archives-of-Allergy-and-Immunology 104 (2). 1994.126-130. ISSN 1018-2438.IN Med Inst Environ Hyg, Auf'm Hennekamp 50, D-40225 Duesseldorf, GER.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin, or simply 'dioxin', is anenvironmental pollutant, infamous for its extremely high toxicity.Dioxin mimicks the unknown natural ligand of the cytosolicarylhydrocarbon receptor which is conspicuously abundant in thethymus, and acts as a transcription factor upon ligand engagement.Thymus atrophy and immunosuppression have long been known to be major effects of dioxin exposure, evident at even very low doses. In ameeting held in Dusseldorf, FRG, the immunotoxicology of dioxin wasdiscussed with respect to the pathomechanisms of dioxins onlymphocyte stem cells, thymus and T cells, cytokine modulation, andother components of the immune system. Such immunological insults mayhave consequences for the risk assessment of chemical compounds likedioxin.16 BIOLAN 97379838 9433.AU Silverstone-A-E, Frazier-D-E-Jr, Fiore-N-C, Soults-J-A, Gasiewicz-T-A.TI Dexamethasone, beta-estradiol, and 2,3,7,8-tetrachlorodibenzo-p-dioxin elicit thymic atrophy through different cellular targets.SO Toxicology-and-Applied-Pharmacology 126 (2). 1994. 248-259. ISSN0041-008X.IN SUNY-Health Sci Cent, Dep Microbiol and Immunol, 750 East Adams,Syracuse, NY 13210, USA.AB The effects of single doses of dexamethasone (DEX), beta-estradiol-17-valerate (E2), and 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on the kinetics of thymic atrophy and related bone marrow andthymocyte phenotype alterations were examined. The results implydifferences in the mechanisms by which these compounds act. Of thethree compounds, DEX induced maximal atrophy by 3 days with completerecovery by Day 12. At the point of maximal atrophy, the RAG-1+TdT+CD4+8+3-int thymocyte population was proportionately the mostdepleted. In contrast, TCDD and E2 caused maximal thymic atrophy byDay 12. E2 treatment, like DEX, resulted in a preferential decreasein the RAG-1+TdT+CD4+8+3-int population, but unlike DEX, thisdecrease persisted. TCDD-induced thymic atrophy resulted from aproportional loss of all classes of thymocytes. There was nosignificant relative reduction of TdT+RAG-+ cells by TCDD in thethymus. A slow and persistent reduction of TdT and RAG-1 in bonemarrow by both TCDD and E2 contrasted with the rapid reduction andquick recovery of these markers in marrow from DEX-treated animals.Additional studies showed that only DEX-induced atrophy wasaccompanied by the induction of thymocyte apoptosis, as detected bymultiple nucleosomal length DNA fragments within the first 24 hr. Thedifferent kinetics and proportions of subsets in the atrophiedthymuses, as well as the distinct patterns of alterations of RAG andTdT expression, and the presence or the absence of apoptosis provideevidence for different mechanisms of thymic atrophy by these agents.The slow induction and longer persistence of thymic atrophy inducedby E2 and TCDD, as well as their effects on bone marrow stem cellmarkers, suggest that bone marrow thymocyte precursors are majortargets for these agents.17 BIOLAN 97379737 9433.AU Frazier-D-E-Jr, Silverstone-A-E, Gasiewicz-T-A.TI 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced thymic atrophy andlymphocyte stem cell alterations by mechanisms independent of theestrogen receptor.SO Biochemical-Pharmacology 47 (11). 1994. 2039-2048. ISSN 0006-2952.IN Dep Environ Med, Box EHSC, Univ Rochester Sch Med, 575 Elmwood Ave,Rochester, NY 14642, USA.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has both agonist andantagonist effects on estrogen-mediated activities and estrogenreceptor (ER) levels in epithelial tissues following exposure. Wepreviously demonstrated that TCDD alters bone marrow lymphocyte stemcells, including prothymocytes, as measured by functional assays andalterations in the lymphocyte stem cell-specific markers terminaldeoxynucleotidyl transferase (TdT) and recombinase activating gene-1(RAG-1). We have also shown that 17-beta-estradiol valerate (EV)affects lymphocyte stem cells by reducing TdT and RAG-1 mRNA. It hasbeen suggested that the effect of TCDD on these lymphocyte stem cellsmay be mediated directly or indirectly through estrogenic action and/or the ER. Studies were designed to evaluate whether endogenousestrogens or the ER mediate TCDD-elicited bone marrow alterations andthymic atrophy. Ovariectomy did not alter the sensitivity of mice toTCDD-induced thymic atrophy or to a reduction in TdT biosynthesis inbone marrow cells compared with either intact or sham-operated mice.The pure estrogen antagonist ICI 164,384 blocked E-2V-induced uterinehypertrophy, thymic atrophy and reductions in lymphocyte stem cellmarkers. However, the antiestrogen failed to protect against TCDD-elicited thymic atrophy or bone marrow alterations in intact animals.The results are consistent with the hypothesis that the effects ofTCDD on the thymus and/or bone marrow are mediated by mechanismsindependent of estrogens or the ER.18 BIOLAN 97182283 9414.AU Frazier-D-E-Jr, Silverstone-A-E, Soults-J-A, Gasiewicz-T-A.TI The thymus does not mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin-elicited alterations in bone marrow lymphocyte stem cells.SO Toxicology-and-Applied-Pharmacology 124 (2). 1994. 242-247. ISSN0041-008X.IN Dep Environmental Med, Environmental Health Sci Center, UnivRochester Sch Med, Rochester, NY 14642, USA.AB Our previous studies have shown that bone marrow lymphocyte stemcells are affected following perinatal or exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These alterations may, in part,be responsible for thymic atrophy that is also observed followingTCDD exposure. However, other investigators have suggested that thethymus or thymic-derived lymphocytes can affect bone marrow stem celldevelopment. The purpose of these studies was to determine whetherthe TCDD-elicited effects that we have observed on lymphocyte stemcells in bone marrow were secondary to the actions of this chemicalon the thymus. A single intraperitoneal dose of TCDD (30 mu-g/ kg) tosham-operated or neonatally thymectomized female BALB/c mice reducedthe levels of mRNA in the bone marrow for the lymphocyte stem cell-specific enzymes terminal deoxynucleotidyl transferase (TdT) andrecombinase activating gene (RAG-1). TdT biosynthesis was alsoreduced by TCDD treatment. Thus, neonatal thymectomy had no effect onthe TCDDelicited reduction of TdT or RAG-1 mRNAs or TdT biosynthesis.Genetically athymic (nu/nu) mice were used to further determine ifthe actions of TCDD on the thymus or long-lived T-cells alteredlymphocyte stem cell development. As observed in BALB/c mice, TCDDtreatment decreased the expression of TdT and RAG-1 mRNAs in bonemarrow from athymic nu/nu and intact nu/+ littermates. We concludethat TCDD-elicited alterations in bone marrow lymphocyte stem cellsare not secondary to any actions, direct or indirect, that TCDD hason the thymus or thymic-derived T-cells.19 BIOLAN 97098001 9408.AU Ivens-I-A, Loeser-E, Rinke-M, Schmidt-U, Mohr-U.TI Subchronic toxicity of 2,3,7,8-tetrabromodibenzo-p-dioxin in rats.SO Toxicology 83 (1-3). 1993. 181-201. ISSN 0300-483X.IN Toxicology, Bayer AG, Friedrich-Ebert-Strasse 217-333, 42096Wuppertal, GER.AB 2,3,7,8-Tetrabromodibenzo-p-dioxin (2,3,7,8-TBDD) was administereddaily to male and female rats for 91 days by gavage. Ten male and 10female rats per group received 0.01, 0.1, 1, 3, or 10 mu-g 2,3,7,8-TBDD/kg body weight per dose per day, solubilized in arachis oil. At1 mu-g/kg per day and above, body weight gain was dose-dependentlyreduced by treatment. Animals in the 3 and 10 mu-g/kg dose groupsshowed symptoms of wasting syndrome. Fifty percent of the animals inthe 3 mu-g/kg dose-group died and all animals of the highest dose (10jug/kg) died or had to be killed in extremis. Hematologicalinvestigations indicated changes - mainly in the 1 and 3 mu-g/kgdose-groups - in hemoglobin content, packed cell volume and number ofthrombocytes. The prothrombin-time was markedly prolonged after 3 mu-g/kg in week 13. Clinical chemistry performed at the end of treatmentrevealed an increase in plasma alkaline phosphatase (APh), aspartateaminotransferase, ASAT and alanine aminotransferase, ALAT (femalesonly) in the highest surviving dose-group (3 mu-g/kg). Marginalchanges of APh and ASAT were seen in rats in the 1 mu-g/kg dose-group. In the same animals, total bilirubin was elevated.Triglycerides were reduced mainly at 1 and 3 mu-g/kg. Serum thyroxinwas reduced, beginning with a marginal change at 0.1 mu-g/kg,triiodothyronine was elevated, starting with a dose of 1 mu-g/kg.Thymus weights were reduced in rats of the 1, 3 and 10 mu-g/kg dose-groups. Histopathological analysis showed atrophy of the lymphatictissue in thymus and spleen. Investigations of the liver indicatedpeliosis hepatis after treatment with 3 or 10 mu-g/kg. Activities ofmicrosomal enzymes (ethoxyresorufin O-deethylase, ethoxycoumarin O-deethylase, aryl hydrocarbon hydroxylase, UDP-glucuronyltransferase)investigated in liver, lung and kidney were dose-dependently elevatedafter 13 weeks of treatment. At a dose of 3.0 mu-g/kg, activitieswere below those of the dose 1.0 mu-g/kg, probably due to livertoxicity. The induction ratio of kidney was generally higher than inliver and lung. No signs of treatment-related toxicity were observedin the 0.01 and 0.1 mu-g/kg groups after the subchronicadministration of 2,3,7,8-TBDD by gavage.21 BIOLAN 97040348 9402.AU De-Waal-E-J, Rademakers-L-H-P-M, Schuurman-H-J, Van-Loveren-H, Vos-J-G.TI Ultrastructure of the cortical epithelium of the rat thymus after invivo exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).SO Archives-of-Toxicology 67 (8). 1993. 558-564. ISSN 0340-5761.IN Natl Inst Public Health and Environ Protection, Lab Med Med Devices,PO Box 1, NL-3720 BA Bilthoven, NET.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known for inducingcortical atrophy in the rat thymus. The present study was conductedto provide ultrastructural evidence for the cortical epithelium to bea target for TCDD in vivo. Juvenile male Wistar rats were orallyintubated once with either 50 or 150 mu-g/kg TCDD and killed 4 or 10days thereafter. Major changes were found in the cortical thymicepithelium. First, a relative shift occurred from "pale" to darkercortical epithelial cell types, as judged by their nuclear andcytoplasmic electron density. This effect was most prominent at 10days after exposure to 150 mu-g/kg TCDD. The increased electrondensity of the cortical epithelium indicates an altered state ofcellular differentiation. Secondly, at the 150 mu-g/kg dose levelfocal epithelial cell aggregates were seen both at day 4 and day 10after administration. This aggregation may either be compound inducedor represent a secondary event to the collapse of the thymic stroma.Thirdly, increased vacuolation of cortical epithelial cells wasapparent. This effect is interpreted as a consequence rather than acause of thymocyte depletion from the cortex. This study indicatesthat TCDD exposure affects the cortical epithelium of the rat thymusat a high dose level. Electron microscopy reveals that thedifferentiation of epithelial cells is altered. In addition,epithelial cell aggregates are formed.22 BIOLAN 96067482 9334.AU GAO-L, XU-D, JIN-H, WANG-Z, XU-Z, GU-C.TI A STUDY ON THE ADEQUATE DOSAGE OF VITAMIN E IN PREVENTION ANDTREATMENT OF VISCERAL INJURY IN BURNED RATS.SO ACTA-NUTR-SIN 14 (4). 1993. 339-344.IN INST HYGIENE, ENIVRONMENTAL MED, TIANJIN 300050, CHINA.AB Forty-two male rats were fed with normal vitamin E(VE) requirementdiet, i.e. 0.2 mg.cntdot.100 gbw.cntdot.-1.cntdot.d-1 for one weekand then thirty-five rats were induced a 3rd degree burn of 20% BSA,another 7 uninjured rats served as normal controls. The burned ratswere divided into 5 subgroups receiving VE at the dosage of 0.2, 1,2, 5, 10 mg. 100gbw-1.cntdot.d-1 respectively for 14 days. Theresults showed that the serum and liver VE contents were lower andthe serum LPO higher significantly in the burned rats as comparedwith the normal control, it was also found that thymus was atrophic,the thymic cortex become thinner thymocytes constricted, and thesplenic corpuscles decreased, the sperm and spermatocytes weremarkedly decreased with testis atrophy. When burned rats were fed VE,as the dosage increased to 2 mg.cntdot. 100gbw-1.cntdot.d-1, theserum and liver VE levels significantly raised and the serum LPOreturned to control level. The histological changes of thymus, spleenand testes were nearly similar to the normal control rats.23 BIOLAN 96040400 9330.AU HALOUZKA-R, JURAJDA-V.TI EFFECTS OF POLYCHLORINATED BIPHENYLS ON THE INFECTION OF CHICKENSWITH NON-ONCOGENIC MAREK'S DISEASE VIRUS STRAINS.SO ACTA-VET-BRNO 61 (4). 1992. 207-217.IN DEP PATHOLOGICAL MORPHOLOGY, UNIV VETERINARY PHARMACEUTICAL SCIENCES,612 42 BRNO, CZECH.AB The report describes the effects of polychlorinated biphenyls (PCB)on Brown Leghorn chickens infected with non-oncogenic strains (M andK) and Marek's disease virus (MDV) and observed during a 5-weekperiod. Two groups of chicks were each infected with MDV isolates Mand K, respectively, in doses of 103 PFU per bird and fed a non-contaminated feed mixture. Two other groups were infected in the sameway and fed the same feed mixture contaminated with PCB at 50 mg perkg feed. Non-infected chickens fed the non-contaminated feed mixturewere used as controls. At weekly intervals the birds were subjectedto serological examination and weighted and their lymphoid organs,skin, nerves and gonads were examined histopathologically. PCBproduced apathy, a reduction in body mass, moulting disorders andwhite discolouration of the feathers. They reduced the production ofactive MD-precipitating antibody and the incidence of microscopic MD-lymphoproliferative lesions, as compared with the data obtained inthe birds only infected. They potentiated cytolytic changes in thelymphoid organs and, at the end of the experiment, caused atrophy ofthe bursa of Fabricius and of the thymus. Morphological signs oflocal cell-mediated immunity in the lymphoid organs were observedvery rarely. The results are helpful to the differentiation ofmorphological immunosuppressive changes of different etiology andcontribute to a better understanding of the causes of reducedimmunological competence in poultry.24 BIOLAN 94091218 9239.AU DE-WAAL-E-J, SCHUURMAN-H-J, LOEBER-J-G, VAN-LOVEREN-H, VOS-J-G.TI ALTERATIONS IN THE CORTICAL THYMIC EPITHELIUM OF RATS AFTER IN-VIVOEXPOSURE TO 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD ANIMMUNOHISTOLOGICAL STUDY.SO TOXICOL-APPL-PHARMACOL 115 (1). 1992. 80-88.IN NATL INST PUBLIC HEALTH EVIRON PROTECTION, LAB MED MED DEVICES, POBOX 1, 3720 BA BILTHOVEN, NETH.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces thymic atrophy inrats. The present study was initiated to provide (immuno)histologicaldata on the mechanism of action. Juvenile male Wistar rats wereorally intubated once with 50 or 150 .mu.g/kg TCDD. They wereeuthanized 4 or 10 days thereafter, or were allowed to stay aliveuntil Day 20 or 26. Growth retardation occurred rapidly in all TCDD-treated animals. Lethality was demonstrated within 20-21 days afteradministration. At Days 4 and 10 after intubation, thymic atrophy wasshown by reduction of thymic weight and cortex/medulla ratio.Staining patterns for T-cell markers in the atrophic thymusescoincided with the reduction of cortical areas. There was no evidenceindicating that the effects were indirectly caused by stress. TCDD-induced thymic atrophy persisted until Day 26 after administration.Immunohistochemical analysis revealed prominent changes in thecortical thymic epithelium at the 150-.mu.g/kg dose level. First, inthe cortex epithelial cell aggregates were observed both at Day 4 andat Day 10 after administration. Apparently, the architecture of theepithelium had changed in these animals. Second, at 10 days afteradministration epithelial cells were found with the simultaneoupression of markers that in the normal uninvoluted thymus onlyoccur either in the subcapsular/medullary area or in the cortex. Thisphenotype points to an unusual stage of differentiation. We concludethat TCDD exposure affects the cortical epithelium of the rat thymusat a high dose level. Apparently, it disturbs the epithelial networkand interferes with the differentiation of epithelial cells.25 BIOLAN 43005204 9224.AU SILVERSTONE-A-E, FIORE-N-C, SOULTS-J-A, CUNNINGHAM-L-M, GASIEWICZ-T-A.TI SHRINKING A THYMUS DIFFERENCES BETWEEN DIOXIN CORTICOSTEROIDS ANDESTROGENS.SO MEETING OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTALBIOLOGY (FASEB) PART II, ANAHEIM, CALIFORNIA, USA, APRIL 5-9, 1992.FASEB-FED-AM-SOC-EXP-BIOL-J 6 (5). 1992. A1701.IN SUNY HEALTH SCI CENT, SYRACUSE, NY 13210.26 BIOLAN 93083448 9211.AU MORRIS-D-L, SNYDER-N-K, GOKANI-V, BLAIR-R-E, HOLSAPPLE-M-P.TI ENHANCED SUPPRESSION OF HUMORAL IMMUNITY IN DBA-2 MICE FOLLOWINGSUBCHRONIC EXPOSURE TO 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD.SO TOXICOL-APPL-PHARMACOL 112 (1). 1992. 128-132.IN DEP PHARMACOL TOXICOL, BOX 613 MCV STATION, MED COLL VIRGINIA/VCU,RICHMOND, VA 23298.AB Previous studies have indicated that mice which differ in their acutesusceptibility to responses mediated by the Ah receptor have apattern of suppression of the antibody response which is consistentwith a role by the putative dioxin receptor. The objective of thepresent investigation was to compare the TCDD-induced suppression ofthe antibody response following acute and subchronic exposures inB6C3F1 mice, an Ah-high-responder strain, and DBA/2 mice, an Ah-low-responder strain. Results of our initial studies demonstrate thatsuppression of humoral immunity can be enhanced in DBA/2 miceapproximately 10-fold following subchronic versus acute exposures tothe same cumulative doses of TCDD. This change in suppression of theantibody response in DBA/2 mice was not accompanied by significantchanges in liver weight (hepatomegaly), as was observed in the B6C3F1strain when exposed under comparable conditions. In contrast, effectson thymus weight (involution) were enhanced in the DBA/2 micefollowing subchronic exposure and demonstrated a higher degree ofatrophy than was seen in the B6C3F1 strain (68 versus 56% decrease inthymic weight at the 42 .mu.g/kg cumulative dose). These findingssuggest that multiple mechanisms may be operating to suppress humoralimmunity in vivo and that the conditions of exposure can alter thetoxic effects of TCDD in the DBA/2, Ah-low responsive, mouse strain.27 BIOLAN 42023691 9200.AU DE-WAAL-E-J, RADEMAKERS-L-H-P-M, SCHUURMAN-H-J, VAN-LOVEREN-H, VOS-J-G.TI ATROPHY OF THE RAT THYMUS EFFECTS OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN ON THE EPITHELIAL MICROENVIRONMENT ASSESSED AT THEULTRASTRUCTURAL LEVEL A COMPARISON WITH BISTRI-N-BUTYLTINOXIDE.SO IMHOF, B. A., S. BERRIH-AKNIN AND S. EZINE (ED.). LYMPHATIC TISSUESAND IN-VIVO IMMUNE RESPONSES; TENTH INTERNATIONAL CONFERENCE ONLYMPHATIC TISSUES AND GERMINAL CENTRES IN IMMUNE REACTIONS,COMPIEGNE, FRANCE, JULY 1-5, 1990. XX+1007P. MARCEL DEKKER, INC.: NEWYORK, NEW YORK, USA; BASEL, SWITZERLAND. ILLUS. ISBN 0-8247-8528-2. 0(0). 1991. 117-122.IN NATL INST PUBLIC HEALTH ENVIRON PROT, BILTHOVEN, NETH.28 BIOLAN 92094523 9139.AU HANIOKA-N, SAEKI-H-K, ISHIDA-C, KOGA-N, YOSHIMURA-H.TI TOXICOLOGICAL ASSESSMENT OF 2 5 2'5' TETRACHLOROBIPHENYL AND ITSMAJOR METABOLITE 3 HYDROXY-2 5 2' 5'-TETRACHLOROBIPHENYL IN RATS.SO FUKUOKA-ACTA-MED 82 (5). 1991. 191-196.IN DEP HYGIENIC FORENSIC CHEM, FACULTY PHARMACEUTICAL SCIENCES, KYUSHUUNIVERSITY 62, FUKUOKA 812.AB We observed previously that piolychlorinated biphenyl (PCB) could beclassified to two groups, 3-methylcholanthrene (MC)-type andphenobarbital (PB)-type, in term of inducibility of the hepaticenzymes. MC-type PCBs such as 3, 4, 3', 4'-tetrachlorobiphenyl (TCB),3,4,5,3',4'-pentachlorobiphenyl (PenCB) and 3, 4,5,3',4',5'-hexachlorobiphenyl (HexCB) exhibited high acute toxicity in parallelwith their induction ability of microsomal benzo(a)pyrene 3-hydroxylase and cytosolic DT-diaphorase. On the contrary, PB-typePCBs such as 2,5,2',5'-TCB and 2,4,5,2',4',5'-HexCB which inducemicrosomal benzphetamine N-demethylase and NADPH-cytochrome P-450reductase activities showed virtually no or very low toxicity. In thepresent study, we examine effects of 2,5,2',5'-TCB and its majormetabolite 3-hydroxy-2,5,2',5'-TCB on body weight gain, organ weightsand activities of hepatic enzymes in rats and assessed acute toxicityof these compounds. As the result, in both 2,5,2',5'-TCB and 3-hydroxy-2,5,2',5'-TCB groups, the body weights were increased duringthe experiment, but the rate of growth was significantly supressedafter 3 days. Significant hypertrophy of the liver and decrease oftotal liver lipid content were observed in 2,5,2',5'-TCB group, butthe atrophy of spleen and thymus was not affected in both groups. Onthe other hand, in 2,5,2',5'-TCB group, benzo(a)pyrne 3-hydroxylaseand benzphetamine N-demethylase activities were increased to 2.4-foldand 1.5-fold, respectively, but were not increased in 3-hydroxy-2,5,2',5'-TCB group. After injection of 2,5,2',5'-TCB 45% ofthe dose was excreted as 3-hydroxy-2,5,2',5'-TCB in feces for 5 days.On the other hand, 40% of unchanged 3-hydroxy-2,5,2',5'-TCB was alsoexcreted after injection of 3-hydroxy 2,5,2',5'-TCB for 2 days. Theseresults suggest that 2,5,2',5'-TCB possesses only low toxicity andits major metabolite, 3-hydroxy-2,5,2',5'-TCB is also an inactivemetabolite.29 BIOLAN 92063350 9134.AU LUNDBERG-K.TI DEXAMETHASONE AND 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN CAN INDUCETHYMIC ATROPHY BY DIFFERENT MECHANISMS IN MICE.SO BIOCHEM-BIOPHYS-RES-COMMUN 178 (1). 1991. 16-23.IN DEP TOXICOL, UPPSALA UNIV, UPPSALA BIOMED CENTER, BOX 594, S-751UPPSALA, SWED.AB The effects of in vivo exposure to dexamethasone (DEX) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymocyte proliferation andthymocyte number were compared. In the thymus of DEX-treated mice (1mg/kg) both proliferation and cell number had decreased by 70% oneday after exposure. This decrease was, however, transient, and valuesreturned to normal within 2 weeks. By contrast, in TCDD exposed mice(50 .mu.g/kg), a reduction in proliferation was not observed untilday 2 after exposure, and the degree of reduction was only about 50%.By this point in time, cell number had only decreased by 20%.Proliferation increased again on day 3 after TCDD administration,whereas cell number continued to decrease and remained low throughoutthe observation period (8 days). DEX had a direct and immediateeffect on cells in all thymocyte subpopulations whereas TCDDinitially only affected the immature double negative (DN) and doublepositive (DP) populations.30 BIOLAN 92041331 9131.AU VAN-LOVEREN-H, SCHUURMAN-H-J, KAMPINGA-J, VOS-J-G.TI REVERSIBILITY OF THYMIC ATROPHY INDUCED BY 2 3 7 8TETRACHLORODIBENZO-P-DIOXIN TCDD AND BIS-TRI-N-BUTYLTINOXIDE TBTO.SO INT-J-IMMUNOPHARMACOL 13 (4). 1991. 369-378.IN LAB PATHOL, NATL INST PUBLIC HEALTH AND ENVIRONMENTAL PROTECTION,BILTHOVEN, NETH.AB We studied the reversibility of thymic atrophy induced by intubationof 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 10 days after a singledose of 50 .mu.g/kg, or bis(tri-n-butyltin)oxide (TBTO), 4 days aftera single dose of 75 mg/kg. This was done by an experimental design inwhich the atrophic thymus was placed in an in vivo situation in whichthe toxic chemical was no longer present, e.g. by transplantation ofatrophic thymic lobes in untreated normal rats with connection to thevasculature of the recipient. At 20 days after the transplantation,the atrophic thymus showed the morphology and architecture of anormal uninvoluted thymus: lymphocyte counts and phenotypicexpression of markers on lymphocytes, epithelium, and macrophages inthe transplanted lobe did not differ from those in untreated donorrats or those in the normal uninvoluted thymus. Considering themechanism of action of the toxic chemicals, TBTO has been claimed toaffect preferentially (passenger) lymphocytes in the thymus: therecovery after transplantation therefore is explained on the mereinflux of newly-recruited precursor cells from the bone marrow. ForTCDD a toxic action on the stationary epithelial component of thethymus has been claimed. We conclude that this epithelial damage isreversible within the 3-week period of the present experiment, withrespect to both the morphology and immunologic phenotype ofepithelium and other cell populations, as well as the recruitment oflymphocytes.31 BIOLAN 91079747 9112.AU ANDERSSON-L, NIKOLAIDIS-E, BRUNSTROM-B, BERGMAN-A, DENCKER-L.TI EFFECTS OF POLYCHLORINATED BIPHENYLS WITH AH RECEPTOR AFFINITY ONLYMPHOID DEVELOPMENTS IN THE THYMUS AND THE BURSA OF FABRICIUS OFCHICK EMBRYOS IN-OVO AND IN MOUSE THYMUS ANLAGEN IN-VITRO.SO TOXICOL-APPL-PHARMACOL 107 (1). 1991. 183-188.IN DEP TOXICOLOGY, UPPSALA UNIV, BOX 594, S-751 24 UPPSALA, SWEDEN.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and its congeners bind tothe Ah receptor and are known to cause thymic atrophy in mostexperimental animal species and also to inhibit lymphoid developmentin the embryonic thymus (T-cells) and in the bursa of Fabricius ofchick embryos (B-cells). The coplanar polychlorinated biphenyls(PCBs) 3,3',4,4'-tetrachlorobiphenyl (TCB), 3,3',4,4',5-pentachlorobiphenyl (PeCB), and 3,3',4,4',5,5'-hexachlorobiphenyl(HBC) (relatively strong Ah receptor ligands) and the mono-ortho-chlorinated analogues of TCB and PeCB (relatively weak Ah receptorligands) were administered to chick embryos by air chamber injectionon Day 13 of incubation. The numbers of lymphoid cells (on Day 19) inthe thymus and the bursa of Fabricius were lower, in a dose-dependentmanner, in embryos treated with the coplanar PCBs compared withcontrols. Approximate ED50 values for inhibition of bursal celldevelopment were 4 .mu.g for PeCB, 50 .mu.g for TCB, and 300 .mu.g/kgegg for HCB. The most immunotoxic of the mono-ortho-chlorinatedanalogues of TCB and PeCB were about 1000 times less potent than PeCB. The in vitro effects of the PCBs were studied in organ culturesof thymi from 15-day-old mouse fetuses. The three coplanarchlorobiphenyls inhibited lymphoid development in this culture systemin a dose-dependent manner. PeCB was only about 10 times less potent(EC50 .apprxeq. 2 .times. 10-9 M) than TCDD (FC50 .apprxeq. 2 .times.10-10 M), whereas HCB and TCB were about 100 times less toxic than PeCB. No inhibition of lymphoid development by the mono-ortho-chlorinated PCBs was observed using concentrations as high as 10-6 M.32 BIOLAN 91079745 9112.AU PUHVEL-S-M, CONNOR-M-J, SAKAMOTO-M.TI VITAMIN A DEFICIENCY AND THE INDUCTION OF CUTANEOUS TOXICITY INMURINE SKIN BY TCDD.SO TOXICOL-APPL-PHARMACOL 107 (1). 1991. 106-116.IN DIV DERMATOLOGY, DEP MED, UCLA SCH MED, LOS ANGELES, CALIF 90024.AB The mechanisms involved in the induction of toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototype for a group of toxicpolyhalogenated aromatic hydrocarbons, are largely unknown. To testthe hypothesis that TCDD-induced toxicity involves the reduction ofvitamin A levels, we investigated the role of vitamin A deficiency inmodulating the cutaneous response of congenic haired (+/+) andhairless (hr/hr) mice to TCDD. Hairless mice are recognized assensitive models for expression of TCDD-induced cutaneous toxicity.Haired mice normally do not develop a cutaneous response to TCDD.Mice raised on a vitamin A-deficient diet, and age- and -matchedcontrols raised on standard chow, were treated topically with TCDDand their cutaneous response monitored histologically. Body weightsand thymus gland weights were monitored as additional parameters oftoxicity. Liver and skin vitamin A levels were determined by HPLC.Vitamin A depletion by itself had no effect on the normal cutaneoushistology of the haired phenotype, nor were any changes in cutaneousmorphology attributable to TCDD toxicity observed in haired, TCDD-treated animals even when they were severely vitamin A depleted. Onthe other hand, in hairless mice, vitamin A deficiency caused adistinct increase in keratinization of dermal epithelial cysts, andan increase in the sensitivity of these cysts to TCDD-inducedhyperkeratinization. TCDD-induced body weight loss and atrophy of thethymus gland were not affected by the vitamin A status of either thehaired or hairless animals. Analysis of vitamin A levels in skin andliver, following topical treatment of mice with TCDD, indicated thatTCDD exposure did not affect cutaneous levels, but did significantlylower liver levels of vitamin A. These experiments suggest thatalthough systemic vitamin A deficiency may potentiate the expressionof TCDD-induced toxicity in skin of hairless mice, expression ofTCDD-induced toxicity probably involves more complex mechanisms thana reduction in vitamin A levels.33 BIOLAN 91011231 9049.AU FINE-J-S, GASIEWICZ-T-A, FIORE-N-C, SILVERSTONE-A-E.TI PROTHYMOCYTE ACTIVITY IS REDUCED BY PERINATAL 2 3 7 8TETRACHLORODIBENZO-P-DIOXIN EXPOSURE.SO J-PHARMACOL-EXP-THER 255 (1). 1990. 128-132.IN BOX EHSC, UNIVERSITY ROCHESTER SCHOOL MEDICINE, 575 ELMWOOD AVE,ROCHESTER, NY 14642.AB The mechanism by which exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces thymic atrophy and cell-mediated immunesuppression in experimental animals is poorly understood. A previousstudy from our laboratory found that terminal deoxynucleotidyltransferase-synthesizing lymphocyte stem cell populations in fetalliver and neonatal bone marrow, but not thymus, were profoundlyaltered after perinatal TCDD exposure, implying that a defect in theprothymocyte population in liver and marrow may play a role in theetiology of thymic atrophy in TCDD-exposed animals. In this report,we present results of experiments designed to directly assess theprothymocyte compartment in mice exposed to TCDD perinatally byexamining the ability of these stem cells to reconstitute anirradiated thymus. Maternal TCDD exposure (15 .mu.g/kg) caused asignificant impairment of both fetal liver and neonatal bone marrowprothymocyte activity. These alterations occurred at tissueconcentrations less than 200 fg of TCDD per mg. TCDD treatment alsoresulted in a mild reduction in colony-forming unit-spleen in theseorgans and a decrease in colony-forming unit-granulocyte-macrophagein fetal and neonatal liver, but not bone marrow. Overall, these dataprovide evidence that alterations to early stages of T-lymphopoiesis,at the level of the prothymocyte, may be involved in the developmentof TCDD-induced thymic atrophy and cell-mediated immunosuppression.34 BIOLAN 90081784 9037.AU BIRNBAUM-L-S, MCDONALD-M-M, BLAIR-P-C, CLARK-A-M, HARRIS-M-W.TI DIFFERENTIAL TOXICITY OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD INC57BL-6J MICE CONGENIC AT THE AH LOCUS.SO FUNDAM-APPL-TOXICOL 15 (1). 1990. 186-200.IN ENVIRONMENTAL TOXICOL DIV, HEALTH EFFECTS RES LAB, US EPA, TRIANGLEPARK, NC 27711, USA.AB The acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) waamined in male C57BL/6J mice differing only at the Ah locus. Wildtype mice (Ahb/b; "b/"b) were treated once with 0, 50, 100, 200,300,and 400 .mu.g TCDD/kg po while congenic mice (Ahd/d, "d/d") receiveda single dose of 0, 400, 800, 1600, 2400, and 3200 .mu.g TCDD/kg.Mice were checked daily, weighed twice a week, and those thatsurvived, killed 35 days post-treatment. The LD50 values were 159 and3351 .mu.g/kg for b/b and d/d mice, respectively. Mean time to deathwas 22 days and was independent of dose and genotype. Decrease inbody weight gain was noted in both strains 5 days after treatment andoccurred at doses .gtoreq. 100 .mu.g/kg in b/b mice and 1600 .mu.g/kgin d/d mice. Dose-related increases in liver weight (both absoluteand relative to body weight) and decreases in thymus, spleen, testes,and epididymal fat pad weights were observed at 8-24-fold higherdoses in d/d than in b/b mice. A dose-related increase in segmentedneutrophils was observed in both strains. Serum chemistry valuesindicated that 8-24 .times. greater doses of TCDD were needed toelevate sorbitol dehydrogenase, alanine aminotransferase, and 5'-nucleotidase and to decrease total and esterified cholesterol in d/dthan in b/b mice. Few effects were seen on total bile acids, serumtriglycerides, glucose, or on esterified cholesterol. In the liver,hepatocellular cytomegaly, fatty change, and bile duct hyperplasiaoccurred in both strains in a dose-related manner, as did thymic andsplenic atrophy. Necrosis of germinal epithelium in the testes andedema in the stomach submucosa occurred at acutely toxic doses. Theselesions also occurred at doses 8-24.times. greater in d/d than in b/bmice. Thus, the spectum of toxicity is independent of the allele atthe Ah locus, but the relative dose needed to bring about variousacute responses is approximately 8-24.times. greater in congenic micehomozygous for the "d" allele than for the wild type animals carryingtwo copies of the "b" gene.35 BIOLAN 89110723 9017.AU LEIGHTON-F-A.TI THE SYSTEMIC TOXICITY OF PRUDHOE BAY CRUDE AND OTHER PETROLEUM OILSTO CD-1 MICE.SO ARCH-ENVIRON-CONTAM-TOXICOL 19 (2). 1990. 257-262.IN DEP VET PATHOLOGY, WESTERN COLL VET MED, UNIV SASKATCHEWAN,SASKATOON, SK S7N OWO CANADA.AB CD-1 mice were given oral doses of 0-16 ml/kg/day for five days ofPrudhoe Bay (PBCO), South Louisiana and Arabian Light crude oils,Bunker C oil (BCO), mineral oil (MO) and corn oil. Minor decreases inpacked cell volume and increases in mean corpuscular hemoglobinconcentration occurred after ingestion of crude oils and BCO. Dietarydepletion of vitamin E and selenium failed to enhance hematologicalchanges. Pronounced liver enlargement and atrophy of thymus andspleen accompanied ingestion of all petroleum oils except MO and wereshown to be dependent on dose of PBCO. Concentration of RNA and totalRNA were increased while total DNA, but not concentration of DNA, wasincreased in enlarged livers. Liver enlargement was attributedprimarily to hyperplasia with an additional contribution due tohypertrophy. The severe hemolytic anemia reported in marine birdsthat ingested PBCO was not reproduce in mice. Liver enlargement andlymphoid tissue atrophy were similar to those reported in otherspecies exposed to petroleum oils.36 BIOLAN 89093818 9016.AU FINE-J-S, SILVERSTONE-A-E, GASIEWICZ-T-A.TI IMPAIRMENT OF PROTHYMOCYTE ACTIVITY BY 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN.SO J-IMMUNOL 144 (4). 1990. 1169-1176.IN ENVIRON HEALTH SCI CENT, BOX EHSC, UNIV ROCHESTER SCH MED, ROCHESTER,NY 14642.AB Exposure of experimental animals to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in severe thymic atrophy and suppression ofcell-mediated and humoral immune functions. However, despite mucheffort the mechanism by which TCDD produces these responses,particularly thymic atrophy, remains unclear. In this report, we haveexamined the effect of acute TCDD exposure on lymphocyte stem cellsin young BALB/c mice to determine whether alterations to eventsearly in T lymphopoiesis contribute to TCDD-induced thymic atrophy.TCDD produced a dose-dependent reduction in thymic weight andcellularity following a single dose of 5 to 120 .mu.g TCDD/kg. Thisthymic atrophy correlated with a dose-dependent suppression of thebiosynthesis and mRNA levels of the lymphocyte stem cell-specific DNApolymerase terminal deoxynucleotidyl transferase in bone marrow andthymus. However, the reduction in thymic terminal deoxynucleotidyltransferase synthesis, on a per cell basis, was less than thatobserved in bone marrow. Intrathymic CD4/CD8 and IL-2R expressiondemonstrated only mild alterations after exposure to 30 .mu.g TCDD/kg. These data suggest that thymocytes are more refractory to TCDDthan are pre-T cells. To assess the possibility directly, bone marrowprothymocytes from TCDD-treated donor mice were examined for theircapacity to reconstitute the thymuses of adoptive, irradiatedrecipients. Our results indicate that prothymocyte activity wasseverely impaired by TCDD exposure and that this effect occurred atlow tissues levels of TCDD. In contrast, we observed no reduction inthe number of colony-forming unit-granulocyte macrophage and amoderate decrease in colony-forming unit-spleen. These data suggestthat TCDD-induced thymic atrophy is the result, at least in part, ofimpaired thymic seeding by prothymocytes.37 BIOLAN 88102985 8910.AU ROBERTS-E-A, VELLA-L-M, GOLAS-C-L, DAFOE-L-A, OKEY-A-B.TI AH RECEPTOR IN SPLEEN OF RODENT AND PRIMATE SPECIES DETECTION BYBINDING OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN.SO CAN-J-PHYSIOL-PHARMACOL 67 (6). 1989. 594-600.IN DIV CLIN PHARMACOL TOXICOL, HOSP SICK CHILD, 555 UNIVERSITY AVE,TORONTO, ONTARIO, CANADA M5G 1X8.AB In many species systemic toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is manifested by a generalized wasting syndromeaccompanied by a variety of specific organ changes including atrophyof the thymus and spleen. TCDD toxicity in most tissues is thought tobe mediated by the Ah receptor. Although the spleen is a prime targetfor TCDD toxicity, the possible presence of Ah receptor in the spleenhas not previously been investigated. Specific binding of (3H)TCDD toAh receptor in spleen cytosols was assessed by velocity sedimentationon sucrose gradients. Ah receptor was detected in spleen cytosolsfrom Rhesus monkeys (mean .+-. SEM, 36 .+-. 8 fmol/mg cytosolprotein), fetal Rhesus monkeys (9 .+-. 6), Sprague-Dawley rats (20.+-. 5), C57BL/6J mice (18 .+-. 2), New Zealand white rabbits (19 .+-. 2), and Hartley guinea pigs (15 .+-. 2). Ah receptor was notdetectable in spleen cytosol from genetically "nonresponsive"DBA/2Jmice or from Golden Syrian hamsters, a species resistant to toxicityof TCDD. Molecular properties of Ah receptor from spleen were similarto those of the receptor from liver of the same species. The high Ahreceptor content in spleen cytosols from those species that are mostsusceptibel to TCDD toxicity is consistent with the view that the Ahreceptor mediates TCDD toxicity in spleen as well as in othertissues.38 BIOLAN 88090925 8909.AU KOGA-N, NAKASHIMA-H, KAMIMURA-H, HOKAMA-Y, YOSHIMURA-H.TI TISSUE DISTRIBUTION INDUCTIVE EFFECT ON LIVER ENZYMES AND ACUTETOXICITY OF 2 3 4 7 8 PENTACHLORODIBENZOFURAN IN GOLDEN SYRIANHAMSTERS.SO FUKUOKA-ACTA-MED 80 (5). 1989. 227-234.IN DEP HYGIENIC FORENSIC CHEM, FAC PHARM SCI, KYUSHU UNIV, FUKUOKA 812.AB The hamsters have been known to be the least sensitive mammalianspecies to the acute toxicity of highly toxic polyhalogenatedhydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. In thepresent study, the tissue distribution, inductive effect of liverenzymes and acute toxicity of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) in male Golden Syrian hamsters were examined. The highestcontent (about 48% of dose) of PenCDF was found in the liver 5 daysafter a single i.p. dose of 1.0 mg/kg. The amount ranging about 5 to10% of dose was also distributed to mesentery, skin and muscle. Inliver, the distribution of PenCDF was just parallel to that ofcytochrome P-450 (P-450), marker enzymes of liver endoplasmicreticulum, suggesting that PenCDF binds to P-450. The mode ofinductive effects of PenCDF in hamsters was 3-methylcholanthrene-typeas reported previously in rats. However, the typical enzymes such asbenzo(a)pyrene 3-hydroxylase and DT-diaphorase were induced to arelatively less extent than did in rats. In hamsters pretreated withPenCDF at a dose of 0.5 mg/kg, the potent atrophy of thymus and the3-fold increase of liver lipid peroxide were observed, whereas thebody weight gain was not suppressed at all. These results suggestthat the induction of liver enzymes and the atrophy of thymus mightnot be the direct cause of PenCDF-induced lethality in hamsters.39 BIOLAN 88076969 8909.AU KONO-K, HAYAKAWA-M, ASAI-K, KUZUYA-F, HARADA-T.TI THE RELATIONSHIP BETWEEN ILLNESS IN THE AGED AND IN INHERENTLYSCORBUTIC RATS ODS RATS.SO JPN-J-GERIATR 25 (5). 1988. 508-514.IN DEP GERIATRICS, NAGOYA UNIV SCH MED.AB A colony of Wistar rats with a hereditary defect in L-ascorbic acid-synthesizing ability was established in 1973. We have examined thepathophysiological findings of this rat mutant (ODS rats) in acuteand chronic vitamin C deficient states. In experiment 1, 0DS ratsaged 63 days showed severe body loss and atrophy of thymus, spleenand bone. In experiment 2, ODS rats aged 285 days showed osteoporoticand emphysematous changes in bone and lung, respectively. Moreover,we found some pathological changes in bone and lung, respectively.Moreover, we found some pathological changes in these rats similar tothose found in elderly people, that is, corneitis and findingssuggesting the presence of immune deficiency due to atrophic changeof T and B-lymphocytes in thymus and spleen. From these findings,vitamin C deficiency might have an etiological relationship with theabove mentioned geriatric diseases.40 BIOLAN 87110224 8905.AU SILKWORTH-J-B, CUTLER-D-S, SACK-G.TI IMMUNOTOXICITY OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN IN A COMPLEXENVIRONMENTAL MIXTURE FROM THE LOVE CANAL NIAGARA FALLS NEW YORK USA.SO FUNDAM-APPL-TOXICOL 12 (2). 1989. 303-312.IN WADSWORTH CENTER LAB RES, NEW YORK STATE DEP HEALTH, ALBANY, NY12201.AB The organic phase of the leachate (OPL) from the Love Canal chemicaldump site contains more than 100 organic compounds including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The immunotoxic potential of OPLwas determined in two mouse strains which differ in their sensitivityto aromatic hydrocarbon (Ah) receptor-mediated toxicity. OPL wasadministered in corn oil in a single oral gavage to male BALB/cByJ(Ahb/Ahb) mice (0.5, 0.8, or 1.1 g/kg) and DBA/2J (Ahd/Ahd) mice(0.6, 0.9, or 1.3 g/kg). TCDD was similarly administered at 0.25,1.0, 4.0, or 16.0 .mu.g/kg. Two days later all mice were immunizedwith sheep erythrocytes (SRBC). The antibody response (PFC) and organweights were evaluated 4 days later. OPL produced thymic atrophy andhepatomegaly in both strains at all dose levels. The PFC/spleen inBALB/cByJ mice was significantly reduced at the three doses to 34,13, and 15%, respectively, of the control response. Serum anti-SRBCantibody levels and relative spleen weights were also reduced. Theonly immune effect in the DBA/2J mice was a decrease of the PFC/spleen to 58% of the control at the highest dose. TCDD decreased therelative thymus and spleen weights only in BALB/cByJ mice. However,TCDD produced hepatomegaly, a decrease in serum antibody, and adecrease in PFC/spleen in both BALB/cByJ and DBA/2J mice to 3 and15%, respectively, at 16 .mu.g/kg. Thus, the TCDD dose required tocause a 50% suppression (ED50) of PFC/spleen for the BALB/cByJ andDBA/2J strains was 1.84 and 3.89 .mu.g/kg, respectively. The ED50 forOPL was 0.24 g/kg in BALB/cByJ mice. The TCDD concentration in theOPL was estimated to be 7.6 ppm, which agrees closely with thechemical analysis (3 ppm). The results suggest that theimmunosuppression caused by OPL in BALB/cByJ mice was primarily dueto TCDD, that the non-TCDD components of OPL diminished the TCDDimmunotoxicity in the DBA/2J strain, and that the thymic atrophy andhepatomegaly were caused primarily by the non-TCDD components of theOPL.41 BIOLAN 87088227 8900.AU FINE-J-S, GASIEWICZ-T-A, SILVERSTONE-A-E.TI LYMPHOCYTE STEM CELL ALTERATIONS FOLLOWING PERINATAL EXPOSURE TO 2 37 8 TETRACHLORODIBENZO-P-DIOXIN.SO MOL-PHARMACOL 35 (1). 1989. 18-25.IN ENVIRONMENTAL HEALTH SCIENCES CENTER, DEP BIOPHYSICS, UNIV ROCHESTERSCH MED, ROCHESTER, NY 14642.AB Perinatal exposure of experimental animals to the environmentalcontaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads tothymic atrophy and a suppression of cell-mediated immunity that ismore severe and persistent than that caused by exposure,suggesting that events involved in the maturation of the immunesystem are particularly sensitive to TCDD. We report here thatperinatal TCDD exposure produces an alteration in the lymphocyte stemcell population in the fetus and neonate, as evidenced by asignificant reduction in the lymphocyte stem cell-specific enzymeterminal deoxynucleotidyl transferase (TdT). After maternal treatmentwith a single dose of TCDD (10 .mu.g/kg of body weight) ongestational day (gd) 14, TdT biosynthesis and TdT-specific mRNA werereduced more than 50% in fetal liver lymphoid cells on gd 18. An evenmore extensive reduction was seen in neonatal bone marrow throughpostnatal day 18. In contrast, thymic TdT synthesis appeared to berelatively unaffected on a per cell basis of perinatal TCDD exposure,although the actual number of TdT-synthesizing thymocytes wasdiminished due to extensive thymic atrophy. These effects occurred atconcentrations of 1-31 fg of TCDD/mg of thymus. Flow cytometricanalysis of thymocyte surface marker expression revealed a slightdecrease in the percentage of Lyt-2+L3T4+ thymocytes on gd 18 andpostnatal day 4. This alteration was no longer apparent by postnatalday 11, when marrow TdT biosynthesis was most suppressed. Theseresults suggest that TCDD-induced thymic atrophy during the perinatalperiod may be due, in part, to an effect on the prothymocyte.42 BIOLAN 87065928 8900.AU GORSKI-J-R, MUZI-G, WEBER-L-W, PEREIRA-D-W, IATROPOULOS-M-J, ROZMAN-K.TI ELEVATED PLASMA CORTICOSTERONE LEVELS AND HISTOPATHOLOGY OF THEADRENALS AND THYMUSES IN 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN-TREATEDRATS.SO TOXICOLOGY 53 (1). 1988. 19-32.IN INST FUER TOXIKOLOGIE DER GESELLSCHAFT FUER STRAHLEN- UNDUMWELTFORSCHUNG MUENCHEN MBM, 8042 NEUHERBERG, WEST GERMANY.AB The relationship between thymic atrophy and plasma corticosteronelevels was examined in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated, pair-fed and ad libitum-fed male Sprague-Dawley rats given ausually lethal (125 .mu.g/kg) or non-lethal (25 .mu.g/kg) dose ofTCDD. At both dosages, corticosterone levels in TCDD-treated animalsbegun to rise as early as day 4 after treatment. At later time pointscorticosterone levels were 5-7 times higher in rats given the non-lethal dose, and 6-10 times higher in rats administered the lethaldose than the levels observed in ad libitum-fed controls.Corticosterone levels in control rats pair-fed to the lethal dosegroup (as a result of the severe reduction in feed intake) weresimilarly elevated as in TCDD-treated rats but this was not the casein pair-fed rats of the non-lethal TCDD dosage (due to an essentiallyunchanged feed intake). At both dosages, relative thymus weights ofTCDD-treated rats started decreasing by day 4 and continued todecline for the most part of the study. Relative thymus weights ofrats pair-fed to the non-lethal TCDD dosage were not different fromad libitum-fed rats. However, the decrease in relative thymus weightsof rats pair-fed to the lethal TCDD dosage paralleled that of TCDD-treated rats with an apparent 8-day lag period. Morphologically, thethymus as well as the adrenal revealed differential changes in TCDD-treated rats from those observable in pair-fed rats. These resultssuggest that either TCDD exerts a direct effect on the thymus and theadrenals or it causes an additional stresss (e.g., a metabolicstress) over and above the starvation stress, which may beresponsible for the differential morphological changes in theseglands.43 BIOLAN 87065884 8900.AU NIKOLAIDIS-E, BRUNSTROM-B, DENCKER-L.TI EFFECTS OF TCDD AND ITS CONGENERS 3 3' 4 4' TETRACHLOROAZOXYBENZENEAND 3 3' 4 4' TETRACHLOROBIPHENYL ON LYMPHOID DEVELOPMENT IN THETHYMUS OF AVIAN EMBRYOS.SO PHARMACOL-TOXICOL 63 (5). 1988. 333-336.IN DEP TOXICOL, UPPSALA UNIV, BOX 594, S-75124 UPPSALA, SWEDEN.AB Thymus anlagen from 11-day-old chick and 14-day-old turkey and duckembryos were cultured in media containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 5 days. The maximal TCDD-induced decrease inlymphoid cell number of chick embryo thymus (to about 60% of thecontrol number) occurred at concentrations of 10-10 M and above. Toproduce the same effect on lymphoid cell number in the cultures ofthymus anlagen from turkey and duck embryos, about a 100-fold higherconcentration of TCDD was needed. The toxicity of the TCDD congeners3,3'4,4'-tetrachloroazoxybenzene (TCAOB) and 3,3',4,4'-tetrachlorobiphenyl (TCB) to embryonic chicken thymus was tested invitro and in ovo. In chick embryo thymus cultures, TCAOB and TCB wereabout two orders of magnitude less toxic than TCDD. Injection ofTCAOB and TCB into chicken eggs preincubated for 11 days resulted ina dose-dependent decrease in thymic lymphoid cell number 5 dayslater, declining to about 14% of the controls at 10 .mu.g TCAOB/kgegg. The ED50 value was estimated to be 3.6 and 60 .mu.g/kg egg forTCAOB and TCB, respectively.44 BIOLAN 86108886 8800.AU BREWSTER-D-W, URAIH-L-C, BIRNBAUM-L-S.TI THE ACUTE TOXICITY OF 2 3 4 7 8 PENTACHLORODIBENZOFURAN 4PECDF IN THEMALE FISCHER RAT.SO FUNDAM-APPL-TOXICOL 11 (2). 1988. 236-249.IN SYSTEMIC TOXICOL BRANCH, NATL INST ENVIRON HEALTH SCI, RESEARCHTRIANGLE PARK, NC 27709.AB Polychlorinated dibenzofurans are ubiquitous environmental pollutantswhich have great potential for human exposure. To characterize thetoxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), male F344rats were administered a single oral dose of 0, 100, 250, 500, 1000,or 2000 .mu.g 4PeCDF/kg. A progressive and dose-dependent loss ofbody weight was evident by 3 days after treatment. Signs of toxicityincluded piloerection, hair loss, hypoactivity, morbidity, and death.Death occurred as soon as 14 days after treatment and continuedthroughout the 35-day observation period. The LD50/35 was estimatedto be 916 .mu.g/kg with a 95% confidence interval of 565-1484 .mu.g/kg. Dose-dependent increases were observed in serum cholesterol,triglyceride, and bile acid concentrations and in sorbitoldehydrogenase and aspartate aminotransferase activities. Thehematocrit, hemoglobin, mean corpuscular volume, and mean corpuscularhemoglobin concentrations were depressed in a dose-dependent fashion.Hepatic ethoxyresorufin-O-deethylase (EROD) activity was increased inall treatment groups approximately 25 times above that of controlanimals. Lymphoid depletion in the thymus and spleen was observed inthe three highest doses and thymic atrophy was present at all doselevels. Absolute liver weight and the liver:body weight ratio weresignificantly increased above controls. Hepatotoxicity was dose-dependent and was characterized by lipid accumulation resulting inhepatocytomegaly. Epithelial hyperplasia and focal ulcerations of theforestomach was observed in animals administered 500 .mu.g 4PeCDF/kg.Spontaneous cardiomyopathy was exacerbated by treatment with 2000.mu.g/kg. Since 4PeCDF and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)produces a similar spectrum of toxic effects, the biochemicalmechanisms(s) of toxicity for these chemicals may be similar.45 BIOLAN 86097960 8800.AU PLUSS-N, POIGER-H, HOHBACH-C, SUTER-M, SCHLATTER-C.TI SUBCHRONIC TOXICITY OF 2 3 4 7 8 PENTACHLORODIBENZOFURAN PECDF INRATS.SO CHEMOSPHERE 17 (6). 1988. 1099-1110.IN INST TOXICOL, FEDERAL INST TECHNOL, UNIV ZURICH, CH-8603SCHWERZENBACH, SWITZ.AB Groups of rats were maintained for 13 weeks on diets containing 2, 20and 200 .mu.g/kg of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) or 0.2,2 and 20 .mu.g/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Thehigh PeCDF diet caused death of all female and one male rat,decreased body and organ weights, especially of the thymus; foodconsumption was also decreased. Morphologically, a marked atrophy ofthe cortex of the thymus became apparent as well as severe lesions inthe liver, being more pronounced in the females. In the animals fedthe 20 ppb PeCDF diet lesions were less severe. No effects, except aweak but significant thymus atrophy, were observed in the femalesmaintained on the low-level diet. Alterations in blood chemistry andhaematology were seen predominantly in the medium and high dosegroups. The types of lesion observed with TCDD resembled thoseproduced by PeCDF but, at the same dosage levels, were more severe.From the present data it was concluded that for PeCDF a toxicityfactor of 0.4 (TCDD: 1) would be adequate for assessing its toxicityrelative to TCDD.46 BIOLAN 86051900 8800.AU PLETSITYI-K-D, DAVYDOVA-T-V, FOMINA-V-G, SUKHIKH-G-T, ASKEROV-M-A,CHA-HAK-GYU.TI CORRECTION OF STRESS-INDUCED IMMUNOLOGICAL DISORDERS BY VITAMIN A.SO BYULL-EKSP-BIOL-MED 104 (11). 1987. 609-611.IN LAB PATHOPHYSIOL SYST IMMUNITY, RES INST GEN PATHOL PATHOPHYSIOL,ACAD MED SCI USSR, MOSCOW, USSR.AB The experiments on CBA mice have shown that oral vitamin Aadministration prevents stress-induced immunological disorders:depression of antibody-forming cell production, decrease in naturalkiller cell activity and T-lymphocyte mitogenic response. Vitamin Aalso prevents the development of thymus atrophy, lymphopenia anddepression of phagocytic activity of peritoneal macrophages.47 BIOLAN 85081939 8800.AU PLETSITYI-A-D, PLETSITYI-K-D.TI IMMUNOLOGICAL DISORDERS IN VITAMIN A AND B-1 DEFICIENCIES.SO VOPR-PITAN 0 (3). 1987. 45-47.IN CENT RES INST EPIDEMIOL, MINIST HEALTH USSR, MOSCOW, USSR.AB Atrophy of the thymus, mitogen-induced inhibition of T-lymphocyteblast-transformation, and decrease of the humoral immune responsewere observed in rats with alimentary vitamin A deficiency. VitaminB1 deficiency induced by administration of oxythiamine led to thethymus atrophy, inhibition of T-lymphocyte blastogenic response inmice, and to suppression of delayed hypersensitivity in guinea pigs.48 BIOLAN 85032819 8800.AU KAMIMURA-H, YOSHIMURA-H.TI STIMULATION OF FECAL EXCRETION OF ETIOLOGICAL COMPOUNDS OF YUSHO INRATS.SO FUKUOKA-ACTA-MED 78 (5). 1987. 266-280.IN DEP HYGIENIC FORENSIC CHEM, FAC PHARM SCI, FUKUOKA 812, JPN.AB Studies on stimulation of fecal excretion of the causal agents ofYusho accumulated in the body, which should be valuable for thetreatment of this intoxication, have briefly been reviewed in thispaper. Since 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) has beenrecognized to be most important among various congeners of PCB andPCDF ingested, with respect to toxicity and persistency in the body,we selected this compound for this study and demonstrated, first ofall, that accumulated PenCDF in the rat was eliminated, though verygradually, through the intestinal wall into the lumen, and then tofeces. Then we investigated by using rats to learn effects ofsqualane, liquid paraffin, cholestyramine and activated charcoal onenhancement of the fecal excretion of PenCDF. In the case ofcharcoal, we used charcoal beads instead of the powder. They are thefine beads of agar in which activated charcoal powder is enwrapped.By 3-week treatments, all these compounds were found to givesignificant stimulating effects. Treatments with squalane andactivated charcoal beads afforded better results than did other two.The effect was due to inhibition of the re-absorption of PenCDF bydissolving or adsorbing, and then excreting efficiently into feces.Enhanced exsorption of PenCDF through the intestinal wall might alsocontribute to this effect. Rats given PenCDF were then maintained ona diet containing 5% squalane or 5% activated charcoal beads for 12weeks. Both treatments increased the fecal excretion of PenCDF about5-fold over the control and concomitantly lowered the blood and theliver level of PenCDF markedly. Appearance of fatty liver and thymusatrophy were also prevented significantly, and no appreciable sideeffect was observed during these treatments for 12 weeks.49 BIOLAN 85032812 8800.AU KOGA-N, KUROKI-J, HOKAMA-Y, YOSHIMURA-H.TI LONG-TERM EFFECT OF 3 4 5 3' 4' PENTACHLOROBIPHENYL ON THE TOXICITYAND LIVER ENZYME ACTIVITIES IN RATS.SO FUKUOKA-ACTA-MED 78 (5). 1987. 213-218.IN DEP HYGIENIC FORENSIC CHEM, FAC PHARM SCI, KYUSHU UNIV, FUKUOKA 812.AB Long-term effect of a single (0.1 mg/kg) or two (0.05 mg/kg .times.2) low dose of 3,4,5,3',4'-pentachlorobiphenyl (PenCB), a highlytoxic PCB congener, on the toxicity and liver enzyme activities inSprague-Dawley rats was investigated during 8 months after theinjection. In both PenCB-treated groups, the body weight wereincreased during the experiment, but the rate of growth wassignificantly suppressed from 52 days to 130 days. Such suppressioncontinued up to 8 months after the first PenCB-injection. Even at 8months, significant atrophy of thymus was still observed in bothgroups, but the tissue weights of liver and spleen were not affectedat all. On the other hand, benzo(a)pyrene (BP) 3-hydroxylase and DT-diaphorase, both of which are typical enzyme activities inducible byMC-type inducers, were increased markedly at 1 month after theinjection in both groups. DT-diaphorase level were lowered to thecontrol level at 4 months after the injection. Total P-450 contentwas induced 1.5-fold in both groups at 1 month after the injection,but was lowered near to the control level at 4 months. BP 3-hydroxylase in 2 injection group still retained 3 times higher levelthan that of the control at 8 months. These results showed asurprising persistency of biological effect of PenCB, and suggestedthat the multiple injections with divided small doses were moreeffective than a single injection of PenCB at once.50 BIOLAN 84124880 8700.AU YOSHIMURA-H, YONEMOTO-Y, YAMADA-H, KOGA-N, OGURI-K, SAEKI-S.TI METABOLISM IN-VIVO OF 3 4 3' 4' TETRACHLOROBIPHENYL AND TOXICOLOGICALASSESSMENT OF THE METABOLITES IN RATS.SO XENOBIOTICA 17 (8). 1987. 897-910.IN FAC PHARMACEUTICAL SCI, KYUSHU UNIV 62, 3-1-1 MAIDASHI, HIGASHI-KU,FUKUOKA 812, JAPAN.AB Metabolism in vivo of 3,4,3',4'-tetrachloribiphenyl (TCB) andtoxicological assessment of the metabolites were investigated in therat. Four metabolites were isolated from faeces of rats dosed with3,4,3',4'-TCB. Two were identified as 5-hydroxy-3,4,3',4'-TCB and achlorine-shift metabolite, 4-hydroxy-3,5,3',4'-TCB, by comparison ofmelting points, chromatographic mobilities and spectral features withthose of the synthetic samples. A dihydroxy-TCB andmonohydroxytrichlorobiphenyl were also indicated by mass spectrometryto be excreted in faeces as minor metabolites. 3. Faecal excretion ofunchanged 3,4,3',4'-TCB, 5-hydroxy-3,4,3',4'-TCB and 4-hydroxy-3,5,3',4'-TCB was 0.8%, 19.6% and 11.6% of dose,respectively, in 5 days after i.p. injection of 3,4,3',4'-TCB at adose of 50 mg/kg. From the inability to cause the liver hypertrophyand thymus atrophy, both monohydroxy-metabolites of 3,4,3',4'-TCB aremuch less toxic than the parent 3,4,3',4'-TCB. In addition, thesephenolic metabolites did not induce the activities of benzo(a)pyrenehydroxylase and DT-diaphorase, whereas 3,4,3',4'-TCB greatly inducedthese activities. These results indicated that unlike PCB congenereswith phenobarbital-type inducing ability, 3,4,3',4'-TCB, a prototypeof 3-methylcholanthrene-type inducers, is detoxified by metabolichydroxylation.51 BIOLAN 84030829 8700.AU HAKANSSON-H, WAERN-F, AHLBORG-U-G.TI EFFECTS OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD IN THE LACTATINGRAT ON MATERNAL AND NEONATAL VITAMIN A STATUS.SO J-NUTR 117 (3). 1987. 580-586.IN DEP TOXICOLOGY, KAROLINSK INST, S-104 01 STOCKHOLM, SWEDEN.AB Female Sprague-Dawley rats were given a single oral dose of 10 .mu.gTCDD/kg body wt after delivery. Pups were killed on postnatal day(PND) 0, 2, 4, 8, or 16. Dams and remaining weanlings were killed onPND 22 and 32, respectively. Thymus weight was lower in dams exposedto TCDD than in controls, whereas no differences in body weight orrelative liver weight were found. The total amount and theconcentration of vitamin A were lower in the liver but higher in thekidneys and in serum of TCDD-treated dams than in controls. TCDD-exposed weanlings showed lower weight gain, liver enlargement andthymus atrophy compared to controls. Growth reduction became morepronounced with time, liver enlargement was at its peak on PND 8 andthymus atrophy was most pronoucned on PND 16, although all threeeffects persisted throughout the study. The total amount of vitamin Aincreased at a similar rate in control and TCDD-exposed weanlingsthroughout lactation. When the young started to eat pelleted dietthere was a pronounced increase in hepatic vitamin A content. BetweenPND 16 and 32 controls increased their hepatic vitamin A content 21-fold, compared to 12-fold in TCDD-exposed offspring. The hepaticstores of TCDD-treated animals reached 45% of the stores of controlpups on PND 32. From PND 8 renal vitamin A was significantly higherin the TCDD-exposed young than in the controls. At PND 32 TCDD-exposed weanlings had six times more renal vitamin A than controls.52 BIOLAN 82019144 8600.AU HORI-S, OBANA-H, TANAKA-R, KASHIMOTO-T.TI COMPARATIVE TOXICITY IN RATS OF POLYCHLORINATED BIPHENYLSPOLYCHLORINATED QUATERPHENYLS AND POLYCHLORINATED DIBENZOFURANSPRESENT IN RICE OIL CAUSING YUSHO.SO EISEI-KAGAKU 32 (1). 1986. 13-21.IN OSAKA PREFECTURAL INST PUBLIC HEALTH, NAKAMICHI, HIGASHINARI-KU,OSAKA 537, JPN.AB To understand the nature of the chemical substances responsible forthe disease "Yusho, " a mixture of polychlorinated biphenyls (PCBs),polychlorinated quaterphenyls (PCQs) and polychlorinateddibenzofurans (PCDFs) having a composition similar to that found inthe rice oil causing "Yusho" was prepared in our laboratory. MaleSprague-Dawley rats were daily given orally for 22 d a regimenconsisting of PCBs, 1 mg/rat/d; PCQs, 1 mg/rat/d; PCDFs, 10 .mu.g/rat/d; or a mixture of PCBs, PCQs and PCDFs (Mixture, (1 mg + 1 mg + 10.mu.g)/rat/d). Rats treated with PCBs, PCDFs and Mixture showedhepatic enlargement, reduction of serum corticoid level, increase ofserum cholesterol level and increase in the hepatic microsomal drug-metabolizing enzyme activity, and the effect was larger in the orderof Mixture > PCDFs > PCBs. In addition, when PCDFs or Mixture wereadministered to rats, atrophy of the thymus and suppression of bodyweight gain were observed. When Mixture was administered to rats, asignificant decrease in serum glutamic pyruvic transaminase (GPT)level and a significant increase in serum triglyceride level wereobserved. In the PCQs-treated rats, increase in the hepaticmicrosomal drug-metabolizing enzyme activity and decrease in theadrenal corticoid levels were observed, but the degree of change wasfar less than that in the PCBs- or PCDFs-treated rats. PCDFs orMixture showed induction of hepatic microsomal drug-metabolizingenzyme activity of the 3-methylcholanthrene (MC) type in the rat. Onthe other hand, PCBs and PCQs showed intermediary-type induction ofthe phenobarbital (PB) and MC types. Therefore, the predominantetiology of "Yusho" may involve PCDFs contained inthe toxic riceoil.53 BIOLAN 82009301 8600.AU DECAPRIO-A-P, MCMARTIN-D-N, O-KEEFE-P-W, REJ-R, SILKWORTH-J-B,KAMINSKY-L-S.TI SUBCHRONIC ORAL TOXICITY OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN INTHE GUINEA-PIG COMPARISONS WITH A POLYCHLORINATED BIPHENYL-CONTAININGTRANSFORMER FLUID PYROLYSATE.SO FUNDAM-APPL-TOXICOL 6 (3). 1986. 454-463.IN WADSWORTH CENT LAB RES, NEW YORK STATE DEP HEALTH, ALBANY, NY 12201.AB In contrast to the well-characterized acute toxicity of theenvironmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin(2,3,7,8-TCDD) in the guinea pig, the effects of prolonged poexposure in this species are unknown. The present report describesthe results of administration to guinea pigs of 2,3,7,8-TCDD in thefeed at levels of 0,2, 10, 76, or 430 ppt for up to 90 days.Additional aims were to examine recovery following prolonged 2,3,7,8-TCDD exposure in the guinea pig and to generate data to facilitatecomparison of the previously reported toxixity of a transformer fluidpyrolysate with that of pure 2,3,7,8-TCDD. Animals receiving 430 ppt2,3,7.8-TCDD exhibited body weight loss, thymic atrophy, liverenlargement, and 60% mortality by Day 46 (males) and by Day 60(females), when surviving animals in this group were sacrificed.Total 2,3,7,8-TCDD consumption was approximately 1.3 and 1.9 .mu.g/kg, respectively. Animals receiving 76 ppt 2,3,7,8-TCDD for 90 days(total 0.44 .mu.g/kg) exhibited a decreased rate of body weight gainand increased relative (to body) liver weights. Male anmals alsodisplayed a reduction in relative thymus weights and elevated serumtriglycerides, while females exhibited hepatocellular cytoplasmicinclusion bodies and lowered serum alanine aminotransferaseactivities. Toxic effects were generally similar to those observedafter acute, 2,3,7,8-TCDD administration. No dose-related alterationswere seen in animals receiving either 10 ppt (total 0.06 .mu.g/kg) or2 ppt (total 0.01 .mu.g/kg) for 90 days, establishing a no-observed-effect level of approximately 0.65 ng 2,3,7,8-TCDD/kg/day. In therecovery study, groups of guinea pigs were administered 430 ppt2,3,7,8-TCDD for 11, 21, or 35 days and then allowed to recover foran additional 79, 69, or 55 days, respectively. Treatment-relatedmortality in each group was 0, 10, and 70%, respectively, by Day 90.An effective LD50 of 0.8 .mu.g 2,3,7,8-TCDD/kg for prolonged exposurewas calculated on the basis of these results, a value lower thanthose previously reported from this laboratory for acute exposure.The results also suggested a possible lowering of the body weight"set point" following 2,3,7,8-TCDD exposure. Comparison of thepresent findings with those previously reported for a transformerfluid pyrolysate containing a mixture of polychlorinated aromaticspecies indicated both a greater variety of toxic effects and flatterdose-response relationships for the pyrolysate in the guinea pig.54 BIOLAN 30025350 8600.AU VOS-J-G.TI DIOXIN-INDUCED THYMIC ATROPHY AND SUPPRESSION OF THYMUS-DEPENDENTIMMUNITY.SO BANRD/POLAND, A. AND R. D. KIMBROUGH (ED.). BANBURY REPORT, VOL. 18.BIOLOGICAL MECHANISMS OF DIOXIN ACTION; MEETING, COLD SPRING HARBOR,N.Y., USA, APR. 1984. XIV+500P. COLD SPRING HARBOR LABORATORY: COLDSPRING HARBOR, N.Y., USA. ILLUS. ISBN 0-87969-218-9. 0 (0). 1984(RECD. 1985). 401-410.IN LAB PATHOL, NATL INST PUBLIC HEALTH ENVIRON HYG, PO BOX 1, 3720 BABILTHOVEN, NETH.55 BIOLAN 30025320 8600.AU MCCONNELL-E-E.TI CLINICOPATHOLOGIC CONCEPTS OF DIBENZO-P-DIOXIN INTOXICATION.SO BANRD/POLAND, A. AND R. D. KIMBROUGH (ED.). BANBURY REPORT, VOL. 18.BIOLOGICAL MECHANISMS OF DIOXIN ACTION; MEETING, COLD SPRING HARBOR,N.Y., USA, APR. 1984. XIV+500P. COLD SPRING HARBOR LABORATORY: COLDSPRING HARBOR, N.Y., USA. ILLUS. ISBN 0-87969-218-9. 0 (0). 1984(RECD. 1985). 27-38.IN NATL TOXICOL PROGRAM, NATL INST ENVIRON HEALTH SCI, PO BOX 12233,RESEARCH TRIANGLE PARK, NC 27709.56 BIOLAN 80109643 8500.AU NAKANISHI-Y, KURITA-Y, KANEGAE-H, SHIGEMATHU-N.TI RESPIRATORY INVOLVEMENT AND IMMUNE STATUS IN POLYCHLORINATEDBIPHENYLS AND POLYCHLORINATED DIBENZOFURAN POISONING.SO FUKUOKA-ACTA-MED 76 (5). 1985. 196-203.IN RES INST DIS CHEST, FAC MED, KYUSHU UNIV FUKUOKA 812, JPN.AB Respiratory distress and abnormalities of clinical and laboratoryinvestigation of 401 patients with polychlorinated biphenyls (PCB)and polychlorinated dibenzofurans (PCDF) poisoning have been studiedsince 1969 to 1983. About 1/2 of the patients were complaining ofrespiratory distress and/or secondary airway infections at an earlystage. Thereafter the respiratory distress occurring in thesepatients improved gradually for the 10 yr following onset of thedisease. However, from 10 to 15 yr after onset little or noimprovement of respiratory symptoms was observed in most cases.Pathophysiological studies showed that respiratory involvement inYusho was mainly that of small airways disease and the disease statewas mildly improved in 1983. The effect of PCDF on 2 T-cell subsetsand the response to nonspecific mitogen-PHA (phytohemagglutinin) wasstudied in Japanese Yusho patients 14 yr after onset. High OKT 4/8ratio (helper/suppressor T-cell ratio) and lowered responsiveness toPHA were seen. A low OKT 4/8 ratio was reported and enhancedresponsiveness to PHA in Chinese PCB poisoning patients 3 yr afteronset. Lung tissue and immune status, animal experiments were done.Male rats of the SD strain were given 0.25 mg of PCDF 6 times within2 wk by gastric intubation. Severe necrotic changes of thebronchiolar Clara cells and mild pulmonary edema and vascularcongestion were seen. The thymus of rats which were given PCDFdecreased in size and thymic microscopic features showed severeatrophy. Female mice of the CH3 strain were given 5 .mu.g of PCDF byi.p. injection. Analysis of T-cell subsets of mice blood 4 wk afterinjection showed lowered anti Thy-1. 2 positive cells (pan T-cells)and low Thy 1/2 ratio (helper/suppressor ratio). Female mice of C57/Black strain were given 5 .mu.g of PCDF i.p. injection. Astatistically significant hyperfunction of white blood cells(predominantly neutrophils) in mice was observed by the measurementof chemiluminescence, when compared with those in control mice. PCDFleads to severe toxicity to bronchiolar Clara cells and thymus, ascompared with that of PCB. Helper T-cells are also selectivelydamaged in the acute phase of the PCDF poisoning as shown in Chinesepatients. In PCDF poisoning the T-cell function is suppressed, whilefunction of neutrophils is activated. It is not clear, whether thesechanges are direct effects or indirect ones of PCDF, but it may bethat these abnormalities correlate with chronic bronchitis-likesymptoms in Yusho patients.57 BIOLAN 80109524 8500.AU YOSHIMURA-H, KAMIMURA-H, OGURI-K, SAEKI-S.TI STIMULATING EFFECT OF SQUALANE ON FECAL EXCRETION OF A HIGH TOXIC 2 34 7 8 PENTACHLORODIBENZOFURAN IN RATS.SO FUKUOKA-ACTA-MED 76 (5). 1985. 184-189.IN DEP HYG FORENSIC CHEM, FAC PHARMACUETICAL SCI, KYUSHU UNIV, FUKUOKA812, JPN.AB 2,3,4,7,8-Pentachlorodibenzofuran (PenCDF) is regarded as the mostimportant etiologic agent for Yusho among various PCB(polychlorobiphenyls) and PCDF (polychlorodibenzofuran) congenersfound in the causal rice oil, because this Pen-CDF possesses a strongand long-lasting induction ability of 3-methylcholanthrene-type inthe rat liver and revealed a high toxicity. The present study hasbeen undertaken to learn whether or not squalane (2,6,10,15,19,23-hexamethyltetracosan) could stimulate fecal excretion and decreasetoxicity of PenCDF. Squalane did not show any significant effect onfood consumption and growth of rats during the treatment for 21 days.However, both enlargement of liver and atrophy of thymus caused byPenCDF were suppressed by squalane treatment. Moreover, fecalexcretion of PenCDF was stimulated about 3-fold, and the content ofPenCDF in the liver showed a tendency to decrease by squalane-treatment.58 BIOLAN 80072982 8500.AU HSIA-M-T-S, KREAMER-B-L.TI DELAYED WASTING SYNDROME AND ALTERATIONS OF LIVER GLUCONEOGENICENZYMES IN RATS EXPOSED TO THE 2 3 7 8 TETRACHLORODIBENZO-6 E-1 4-DIOXIN CONGENER 3 3' 4 4' TETRACHLOROAZOXYBENZENE.SO TOXICOL-LETT (AMST) 25 (3). 1985. 247-258.IN DEPARTMENT OF ENTOMOLOGY AND ENVIRONMENT TOXICOLOGY CENTER, 237RUSSELL LABORATORIES, UNIVERSITY OF WISCONSIN, MADISON, WIS 53706,USA.AB A delayed wasting syndrome similar to that induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was observed in male Sprague-Dawley rats exposed to 3,3',4,4'-tetrachloroazoxybenzene (TCAOB) and3,3',4,4'-tetrachloroazobenzene (TCAB). After a slow growth period,all treatment animals (25 mg/kg, i.p., 2 doses/wk) exhibited astarvation-like syndrome characterized by reduced food intake,dramatic loss of body weight and subsequent death. Although thegrowth of all major organs in the treatment animals was affected, thethymus appeared severely atrophied. The growth kinetics during theearlier phase were further analyzed using serially-killed ratsreceiving TCAOB. In addition, TCAOB was found to markedly depress thespecific activity (.mu.mol/min/g wet liver) of glucose-6-phosphatase,fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase andpyruvate kinase in the liver. Significant changes in the levels ofcytochrome P-450, glutamic-pyruvic transaminase and malic enzyme inthe liver were also observed.59 BIOLAN 80045541 8500.AU GREENLEE-W-F, DOLD-K-M, IRONS-R-D, OSBORNE-R.TI EVIDENCE FOR DIRECT ACTION OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN ONTHYMIC EPITHELIUM.SO TOXICOL-APPL-PHARMACOL 79 (1). 1985. 112-120.IN DEP OF CELL BIOLOGY, CHEMICAL INDUSTRY INSTITUT EOF TOXICOLOGY, POBOX 12137, RESEARCH TRIANGLE PARK, NC 27709.AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targetswithin the immune system to produce a characteristic profile ofpathologic responses typified by thymic atrophy, suppressed cellularimmunity and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivityto TCDD indicate that TCDD-induced thymic atrophy was mediated by areceptor protein (designated the Ah receptor). To study the cellularand molecular basis for TCDD-induced thymic atrophy, primary culturesof thymic epithelial (TE) cells were established from C57BL/6 mice, astrain sensitive to TCDD. Treatment of TE monolayers with TCDD(0.1-10 nM) resulted in the altered maturation of coculturedsyngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogensconcanavalin A and phytohemagglutinin. TE-conditioned medium enhancedthe mitogen responsiveness of thymocytes 3- to 4-fold; the enhancedmitogen response mediated by the TE-conditioned medium was notsuppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM)had been added directly. The suppression of TE-dependent maturationof thymocytes was concentration dependent (EC50 .apprx. 1 nM) andstereospecific, suggesting involvement of the Ah receptor. The Ahreceptor in cytosol fractions from cultured TE cells was measureddirectly and was found to be present at a concentration 3 and 3.5-fold greater than that measured in whole thymus and thymocytes,respectively. TCDD acted directly on epithelial target cells in thethymus. One consequence of this action appeared to be the alteredthymus-dependent maturation of T-lymphocyte precursors, mediatedthrough direct cell-cell contact between thymocytes and TE cells.Abstrakt from BIOSIS Jul 97. Christers home index |
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