Thymus atropy and ( PCB or dioxin or vitamin )
AN 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. ISSN
IN Dep Biomedical Sci Pathobiol, VA-MD Regional Coll Vet Med, Virginia
Tech, Blacksburg, VA 24061, USA.
AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for its
immunotoxic effects particularly on the thymus. The exact mechanism
by which TCDD induces thymic atrophy is not clear. In the current
study, we investigated whether TCDD triggers apoptosis in thymocytes,
when administered in vivo, by using the TdT-mediated FITC -dUTP nick
end labeling method and analyzing the cell flow cytometrically.
Significant apoptosis was detected at 8-12 hr after the TCDD
injection but not at 24 hr or beyond, up to 120 hr of study.
Furthermore, the induction of apoptosis was confirmed using the JAM
test in which thymocytes from TCDD-treated mice, labeled with (3H)
thymidine, exhibited increased DNA fragmentation when compared to the
controls. Similar to TCDD treatment, administration of dexamethasone
(5 or 100 mg/kg) into C57BL/6 mice triggered apoptosis that was only
detected at 12 hr after administration of the drug and not
thereafter. When thymocytes from TCDD- or dexamethasone-treated mice
were cultured in vitro for 24 hr, they exhibited marked increase in
apoptosis when compared to the vehicle-treated controls. However,
TCDD, when added to in vitro cultures of thymocytes, failed to
trigger apoptosis. Together, our studies demonstrate that TCDD can
induce apoptosis in thymocytes in vivo. This can be detected only at
an early stage following TCDD administration, possibly because of
rapid clearance of apoptotic cells by the phagocytic cells in vivo.
AN 99436466 9714.
AU Nagarkatti-M, Kamath-A, Xu-H.
TI 2,3,7,8-Tetrachlorodibenzo-P-dioxin (TCDD) induced thymic atrophy is
mediated through apoptosis.
SO 4th International Union of Biochemistry and Molecular Biology
Conference, 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 Veterinary
Med, Va Tech, Blacksburg, VA 24061, USA.
AN 99240131 9645.
AU Fernandez-Salguero-P-M, Hilbert-D-M, Rudikoff-S, Ward-J-M, Gonzalez-
TI Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-
SO Toxicology-and-Applied-Pharmacology 140 (1). 1996. 173-179. ISSN
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 of
toxicologic and pathologic effects. The mechanism of some of these
effects has been studied extensively in vitro and correlative studies
have indicated the involvement of a transcription factor known as the
aryl hydrocarbon receptor (AHR). However, a definitive association of
the AHR with TCDD-mediated toxicity has been difficult to establish
due to the diversity of effects and the ubiquitous expression of this
receptor. In an effort to distinguish AHR-mediated TCDD toxicities
from those resulting from alternative pathways, we have made use of
the recently described AHR-deficient mouse that was generated by
locus-specific homologous recombination in embryonic stem cells.
Present studies demonstrate that AHR-deficient mice are relatively
unaffected by doses of TCDD (2000 mu-g/kg) 10-fold higher than that
found to induce severe toxic and pathologic effects in littermates
expressing a functional AHR. Analyses of liver, thymus, heart,
kidney, pancreas, spleen, lymph nodes, and uterus from AHR-deficient
mice identified no significant TCDD-induced lesions. The resistance
of AHR-deficient mice to TCDD-induced thymic atrophy appears
restricted to processes involving AHR since the corticosteroid
dexamethasone rapidly and efficiently induced cortical depletion in
both AHR-deficient and normal littermate control mice. Taken together
these results suggest that the pathological changes induced by TCDD
in the liver and thymus are mediated entirely by the AHR. However, it
is important to note that at high doses of TCDD, AHR-deficient mice
displayed limited vasculitis and scattered single cell necrosis in
their lungs and livers, respectively. The mechanism(s) responsible
for these apparently receptor-independent processes remain unclear
but may involve novel, alternative pathways for TCDD-induced
AN 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 its
immunotoxic effects particularly on the thymus as well as on T and B
lymphocyte functions. Previous studies have suggested that TCDD may
induce apoptosis in thymocytes although its demonstration in vivo has
met with limited success. TCDD has also been shown to alter the major
histocompatiblity complex- (MHC) encoded molecules, however, its role
in immunotoxicity is not clear. In the current study, we investigated
the role of Fas (CD95), an important molecule involved in the
induction of apoptosis, on TCDD-mediated immunotoxicity using mice
bearing homozygous lpr mutation which leads to failure of expression
of 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 the
thymocytes from C57BL/6 lpr/lpr mice (Ah-responsive, Fas-) when
compared to C57BL/6 +/+ mice (Ah-responsive, Fas+). Similar results
were obtained when peripheral T cell responsiveness to antigenic
challenge with conalbumin was studied in these mice. When mice that
differed only at the MHC were compared for immunotoxic effects of
TCDD, it was noted that B10 cntdot D2 (Ah-responsive, H-2-d) were
more sensitive to TCDD-mediated thymic atrophy and peripheral T cell
dysfunction when compared to B10 mice (Ah-responsive, H-2-b). In all
TCDD-sensitive strains tested, the thymic atrophy was accompanied by
a uniform depletion of all four subset of T cells (CD4+, CD4+ CD8+,
CD4- CD8-, and CD8+) and the percentage of these subsets was not
altered. Furthermore, in these strains, TCDD suppressed the antigen-
specific peripheral T cell responsiveness but not the responsiveness
of naive resting T cells to polyclonal mitogens. Lastly, using cell-
mixing experiments, it was demonstrated that TCDD directly affected
the T cells responding to conalbumin but not the antigen presenting
cells (APCs). Together, our studies demonstrate that although Ah
locus plays the primary role, determining the toxicity of TCDD on the
T cells, there are secondary factors such as expression of Fas or the
MHC-phenotype which may play an important role in TCDD-mediated
immunotoxicity. The role of Fas further suggests that TCDD may induce
toxicity in T cells by triggering apotosis.
AN 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 of
SO Biochimica-et-Biophysica-Acta 1289 (2). 1996. 275-283. ISSN
IN Dep Biochem, Univ Wisconsin-Madison, 420 Henry Mall, Madison, WI
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 loss
of their thymocytes and decreased proliferation in response to
concanavalin A mitogen. The present study investigated the effect of
short-term treatment with 1,25-(OH)-2D-3 on the thymic architecture
and thymocyte subsets. Daily treatment with 1,25-dihydroxyvitamin D-3
at 20 ng per mouse for 4 days induced significant involution of
thymic tissue. The atrophy was predominantly observed in the cortical
component. Flow cytometric analysis of thymocyte subsets showed that
the CD4+ CD8+ population was the primary target. Since the treated
mice experienced profound hypercalcemia, we studied the effect of
1,25-(OH)-2D-3 on animals fed a vitamin D-deficient, low calcium diet
or the same diet containing vitamin D for 25 days prior to treatment.
The low calcium fed mice showed severe hypocalcemia and slight
thinning of thymic cortex. Treatment with 1,25-(OH)-2D-3 moderately
improved the hypocalcemia but had no further effect on the thymus of
these animals. On the other hand, hypercalcemia and thymic atrophy
were found in the animals fed the diet containing vitamin D. Overall,
the atrophy effect on the thymus caused by 1,25-(OH)-2D-3 treatment
was prevented by eliminating the hypercalcemia observed in +D+Ca
treated animals. Thus, thymic atrophy probably resulted from
hypercalcemia and not from 1,25-(OH)-2D-3 itself.
AN 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-
SO Toxicology 103 (3). 1995. 195-203. ISSN 0300-483X.
IN Lab Pathol, Natl Inst Public Health Environmental Protection, PO Box
1, 3720 BA, Bilthoven, Netherlands.
AB Tolerance to minor lymphocyte stimulatory-1-a (Mls-1-a) antigens is
associated with clonal deletion of cells carrying the T cell receptor
variable region V-beta-6. Thymic epithelial cells may contribute to
the 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 may
interfere with intrathymic selection processes. In the present study,
this was addressed by exposing Mls-1-a DBA/2 mice to a single
thymotoxic dose of TCDD. The emergence of V-beta-6+ cells in thymus,
spleen, and mesenteric lymph nodes was investigated during the
subsequent recovery of TCDD-induced thymic atrophy. In addition. the
extrathymic differentiation of T lymphocytes in the liver was
studied. TCDD exposure resulted in a severe thymic atrophy, and an
increase in hepatic mononuclear cells. However, we were not able to
demonstrate any emergence of potentially autoreactive mature V-
beta-6+ T cells, that differentiated either intrathymically or
extrathymically, in TCDD-exposed DBA/2 mice.
AN 99465042 9700.
AU Weber-L-W-D, Greim-H.
TI The toxicity of brominated and mixed-halogenated dibenzo-p-dioxins
and dibenzofurans: An overview.
SO Journal-of-Toxicology-and-Environmental-Health 50 (3). 1997. 195-215.
IN Dep Pathol Lab Med, Univ Kansas Med Cent, Kansas City, KS 66160-7410,
AB Brominated dibenzo-p-dioxins and dibenzofurans can be formed under
laboratory conditions by pyrolysis of flame retardants based on
polybrominated biphenyls and biphenyl ethers. Their occurrence in the
environment, however, is due to combustion processes such as
municipal waste incineration and internal combustion engines. As
these processes generally take place in the presence of an excess of
chlorine, predominantly mixed brominated and chlorinated compounds
have been identified so far in environmental samples. Brominated
dibenzo-p-dioxins or dibenzofurans bind to the cytosolic Ah receptor
about as avidly as their chlorinated congeners and induce hepatic
microsomal enzymes with comparable potency. The same holds true for
mixed brominated-chlorinated compounds. Gross pathologic symptoms-
hypothyroidism, thymic atrophy, wasting of body mass, lethality-also
occur at doses that, on a molar concentration basis, are virtually
identical to those seen with the chlorinated compounds. Their potency
to induce malformations in mice following prenatal exposure is
equivalent to that of chlorinated dibenzo-p-dioxins and
dibenzofurans. Possible activities as (co)carcinogens and endocrine
disrupters have not been evaluated, but are likely to exist.
Considering the overall similarity in action of chlorinated and
brominated dibenzo-p-dioxins and dibenzofurans, environmental and
health assessments should be based on molar body burdens without
discrimination for the nature of the halogen.
AN 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 oral
intubation 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, PO
Box 1, 3720 BA Bilthoven, Netherlands.
AB Atrophy of the thymus and thymic lymphodepletion occurs after
exposure to sublethal doses of TCDD. Previous studies using high
doses of TCDD (150 mu-g/kg) have indicated a preferential
lymphodepletion of the thymus cortex on day 4 after a single oral
intubation. Here we describe the effects of a single oral intubation
of lower dose levels of TCDD (1, 5, and 25 mu-g/kg) on thymic weights
and thymocyte subpopulations in Wistar rats on day 4 after exposure.
A single administration of 1 mu-g/kg TCDD induced a significant
reduction in the number of immature CD4+CD8+ double-positive (DP)
thymocytes. At this time point the numbers of mature medullary
thymocytes were not affected at any dose level tested. We conclude
that also lower dose CD3-high levels of TCDD induce thymic atrophy
via a preferential lymphodepletion of the thymus cortex.
AN 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-
SO Experimental-and-Clinical-Immunogenetics 11 (2-3). 1994. 86-93. ISSN
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 species
investigated. Lymphodepletion is first seen in the cortex of the
thymus, but also occurs in the medulla at later time points. This
article surveys in vivo and in vitro studies on TCDD-induced thymus
toxicity. It is concluded that the first intrathymic target cell for
the action of TCDD is the cortical epithelial cell.
AN 97552961 9448.
AU Esser-C, Lai-Z, Gleichmann-E.
TI Proliferation inhibition and CD4-CD8 thymocyte subset skewing by in
vivo exposure of C57BL-6 mice to Ah receptor-binding 3,3',4,4'-
SO Experimental-and-Clinical-Immunogenetics 11 (2-3). 1994. 75-85. ISSN
IN Med Inst Environ Hygiene, Auf'm Hennekamp 50, D-40225 Duesseldorf,
AB 3,3',4,4'-Tetrachlorobiphenyl (TCB) and other Ah receptor-binding
xenobiotics lead to thymus atrophy and immunosuppression, the former
possibly causing the latter. In order to better understand the TCB-
induced events in the murine thymus, we analyzed the effects of TCB
on the proliferation capacity and maturation kinetics of different
thymocyte subsets in 2-week-old C57BL/6 mice (i.e. of the Ah-b-1
'dioxin-sensitive' genotype). Mice were injected with a single dose
of TCB, and the development of thymocytes was followed up for 10 days
using flow cytometric surface marker analysis combined with
measurement of DNA content by 7-amino-actinomycin D staining. Already
2 days after exposure to TCB, fewer of the more immature thymocytes
(CD4-CD8-, CD4CD8+alpha-beta-TCR-) were proliferating than in thymi
from control animals. Eventually this led to a severe decrease in
thymus cellularity. Moreover, a shift towards the CD4-CD8+ mature
subpopulation was observed. The effects were reversible, and
proliferation and CD4/CD8 subset distribution returned to normal
levels within the observation period. The results are in good
agreement with the data obtained previously in vitro with fetal
thymus organ cultures.
AN 97520688 9446.
TI An inhibitory factor in rat thymus which interferes with binding of
cytosol Ah receptor to xenobiotic responsive element.
SO Biochemistry and Molecular Biology International 34 (1). 1994. 55-66.
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 aryl
hydrocarbon hydroxylase in several tissues in the rat. This effect of
TCDD is mediated by the Ah receptor. However, TCDD does not
significantly enhance aryl hydrocarbon hydroxylase activity in the
rat thymus. Analysis of 3H-TCDD bound Ah receptor on sucrose
gradients revealed the presence of radioactivity sedimenting at 8-9S
and 5-6S in the cytosol and nuclei of thymus respectively. Incubation
of rat thymic cytosol with TCDD increased protein kinase C dependent
phosphorylation, which reached saturation levels at high
concentrations of TCDD, but the TCDD bound receptor did not
appreciably retard 32P-labeled XRE-3 as determined by electrophoretic
mobility shift assay. Incubation of rat hepatic cytosol with TCDD
also increased protein kinase C dependent phosphorylation in a
concentration dependent manner as well as retarded the mobility of
32P-labeled XRE far more than that observed with thymic cytosol. The
ability of the Ah receptor to bind to XRE was temperature dependent.
Incubation of thymic cytosol either with okadaic acid or with sodium
fluoride did not increase the binding of the Ah receptor to XRE. On
mixing hepatic cytosol with thymic cytosol prior to the
electrophoretic mobility shift assay, the binding of the hepatic Ah
receptor to XRE was reduced in a concentration-dependent manner. A
similar effect was observed when renal cytosol was used instead of
hepatic cytosol. Thymic cytosol also reduced the binding of the
hepatic glucocorticoid receptor to its cognate responsive element.
Thymic cytosol did not alter the topology/integrity of XRE. These
data suggest that the thymus contains a factor(s) which interferes
with the binding of AhR to its cognate responsive element.
AN 97505492 9444.
AU De-Heer-C, Verlaan-A-P-J, Penninks-A-H, Vos-J-G, Schuurman-H-J, Van-
TI Time course of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced
thymic atrophy in the Wistar rat.
SO Toxicology-and-Applied-Pharmacology 128 (1). 1994. 97-104. ISSN
IN Lab for Pathol, National Inst of Public Health and Environmental
Protection, 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 thymic
cellularity. In a first experiment, rats were once orally intubated
with 0, 1, 5, 25, 50, and 150 mu-g TCDD/kg body wt and sacrificed at
Day 10. The dose that produced one-half of the maximal thymic
involution was estimated at about 10-20 mu-g/kg. The time course
(Days 0-21) of thymic atrophy induced by a single oral intubation of
25 mu-g TCDD/kg body wt revealed four phases. In phase 1 (initiation
phase, Days 0-2) a decrease in proliferative activity was seen in
cortical thymocytes, whereas no changes occurred in thymic
cellularity. Phase 2 (lymphodepletion phase, Days 2-8) was
characterized by an initial strong depletion of immature CD4+CD8+
double-positive (DP) cells (Day 4), followed by a more gradual
decrease in the number of mature thymocytes (Day 6). On Day 8 the
lymphodepletion was maximal. In phase 3 (stationary phase, Days 8-13)
no changes occurred in thymic cellularity. Although the first signs
of recovery were already seen on Day 6, indicated by a recovery in
proliferative activity in the thymus cortex, an increase in thymic
cellularity was observed first after Day 13 (phase 4, recovery phase,
Day 13 onward). Reversibility of thymic atrophy is therefore observed
within the estimated half-life of TCDD in the rat thymus ( gt 16
days). We conclude that TCDD exerts a rapidly reversible effect on an
intrathymic cortical target cell population.
AN 97505399 9444.
AU Kremer-J, Gleichmann-E, Esser-C.
TI Thymic stroma exposed to aryl hydrocarbon receptor-binding
xenobiotics fails to support proliferation of early thymocytes but
SO Journal-of-Immunology 153 (6). 1994. 2778-2786. ISSN 0022-1767.
IN Div Immunol, Med Inst Environ Hygeine, Heinrich Heine Univ
Duesseldorf, 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 thymus
atrophy. These processes are mediated by binding of TCDD or TCB to
the cytosolic arylhydrocarbon receptor (AhR) abundant in the thymus,
which acts as a ligand-activated transcription factor. At several
stages of their maturation thymocytes need the interaction with
thymus stroma. We tested whether thymocytes themselves or the thymus
stroma are targets of AhR-binding compounds for interference with
thymocyte maturation. We depleted fetal thymus lobes from
proliferating cells, i.e., thymocytes, by treatment with
deoxyguanosine and recultivated them with immature thymocytes (CD4-
CD8-), exposing either the stroma or the thymocytes to TCDD or TCB
before recultivation. Although CD4-CD8- immature thymocytes could
differentiate in TCB-treated stroma, expansion of the cells was
severely impaired. Selective exposure of thymocytes to AhR-binding
compounds likewise did not impair the capacity of differentiation of
CD4-CD8- thymocytes. These cells, however, could expand when
transferred into new lobes that had not been exposed to TCDD or TCB.
TCB treatment of fetal thymi leads to an accumulation of
phenotypically mature CD4-CD8+ cells. We show here that these cells
do not belong to the transient CD4-CD8+ thymocytes, as previously
suggested, because in recultivation experiments they do not give rise
to any thymocyte subset further down the maturation pathway.
AN 97505252 9444.
TI Processes of cell necrosis: Apoptosis-and their modifications by
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 synonim
of a complex multistage process of cell reduction described during
the 1970s. It occurs during metamorphosis on insects and amphibians
as well as during embryogenesis, intrauterine and extrafetal life of
mammals. 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 of
proliferation and it guarantees homeostasis of the number, structure
and biochemical activity of tissues and organs. It is developed by
apoptosis 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 arrested
by so called "survival factors" -erythropoietin, CSF, NGF, IL-1
2, certain hormones, phenobarbital, ciproteron. The process of a
programmed necrosis is associated with spectacular "events" of
morphological, biochemical and macromolecular nature. Steering is
provided by a group of genes, partly recognized, particularly in the
Nematode of Caenorhabolitis elegans. They are among others killer
genes which remove the remnants of decaying cells and genes which
hinder the expression of death genes. Transduction of calcic signal
from the receptor to the nuclear chromatin releasing a programmed
necrosis of cells is also discussed.
AN 97426340 9438.
TI Dioxins and the Immune System: Mechanisms of Interference: A Meeting
Report. (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 an
environmental pollutant, infamous for its extremely high toxicity.
Dioxin mimicks the unknown natural ligand of the cytosolic
arylhydrocarbon receptor which is conspicuously abundant in the
thymus, and acts as a transcription factor upon ligand engagement.
Thymus atrophy and immunosuppression have long been known to be maj
or effects of dioxin exposure, evident at even very low doses. In a
meeting held in Dusseldorf, FRG, the immunotoxicology of dioxin was
discussed with respect to the pathomechanisms of dioxins on
lymphocyte stem cells, thymus and T cells, cytokine modulation, and
other components of the immune system. Such immunological insults may
have consequences for the risk assessment of chemical compounds like
AN 97379838 9433.
AU Silverstone-A-E, Frazier-D-E-Jr, Fiore-N-C, Soults-J-A, Gasiewicz-T-
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. ISSN
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 and
thymocyte phenotype alterations were examined. The results imply
differences in the mechanisms by which these compounds act. Of the
three compounds, DEX induced maximal atrophy by 3 days with complete
recovery by Day 12. At the point of maximal atrophy, the RAG-1+Td
T+CD4+8+3-int thymocyte population was proportionately the most
depleted. In contrast, TCDD and E2 caused maximal thymic atrophy by
Day 12. E2 treatment, like DEX, resulted in a preferential decrease
in the RAG-1+TdT+CD4+8+3-int population, but unlike DEX, this
decrease persisted. TCDD-induced thymic atrophy resulted from a
proportional loss of all classes of thymocytes. There was no
significant relative reduction of TdT+RAG-+ cells by TCDD in the
thymus. A slow and persistent reduction of TdT and RAG-1 in bone
marrow by both TCDD and E2 contrasted with the rapid reduction and
quick recovery of these markers in marrow from DEX-treated animals.
Additional studies showed that only DEX-induced atrophy was
accompanied by the induction of thymocyte apoptosis, as detected by
multiple nucleosomal length DNA fragments within the first 24 hr. The
different kinetics and proportions of subsets in the atrophied
thymuses, as well as the distinct patterns of alterations of RAG and
TdT expression, and the presence or the absence of apoptosis provide
evidence for different mechanisms of thymic atrophy by these agents.
The slow induction and longer persistence of thymic atrophy induced
by E2 and TCDD, as well as their effects on bone marrow stem cell
markers, suggest that bone marrow thymocyte precursors are major
targets for these agents.
AN 97379737 9433.
AU Frazier-D-E-Jr, Silverstone-A-E, Gasiewicz-T-A.
TI 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced thymic atrophy and
lymphocyte stem cell alterations by mechanisms independent of the
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 and
antagonist effects on estrogen-mediated activities and estrogen
receptor (ER) levels in epithelial tissues following exposure. We
previously demonstrated that TCDD alters bone marrow lymphocyte stem
cells, including prothymocytes, as measured by functional assays and
alterations in the lymphocyte stem cell-specific markers terminal
deoxynucleotidyl 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 has
been suggested that the effect of TCDD on these lymphocyte stem cells
may be mediated directly or indirectly through estrogenic action and
/or the ER. Studies were designed to evaluate whether endogenous
estrogens or the ER mediate TCDD-elicited bone marrow alterations and
thymic atrophy. Ovariectomy did not alter the sensitivity of mice to
TCDD-induced thymic atrophy or to a reduction in TdT biosynthesis in
bone marrow cells compared with either intact or sham-operated mice.
The pure estrogen antagonist ICI 164,384 blocked E-2V-induced uterine
hypertrophy, thymic atrophy and reductions in lymphocyte stem cell
markers. 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 of
TCDD on the thymus and/or bone marrow are mediated by mechanisms
independent of estrogens or the ER.
AN 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. ISSN
IN Dep Environmental Med, Environmental Health Sci Center, Univ
Rochester Sch Med, Rochester, NY 14642, USA.
AB Our previous studies have shown that bone marrow lymphocyte stem
cells are affected following perinatal or adult exposure to 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD). These alterations may, in part,
be responsible for thymic atrophy that is also observed following
TCDD exposure. However, other investigators have suggested that the
thymus or thymic-derived lymphocytes can affect bone marrow stem cell
development. The purpose of these studies was to determine whether
the TCDD-elicited effects that we have observed on lymphocyte stem
cells in bone marrow were secondary to the actions of this chemical
on the thymus. A single intraperitoneal dose of TCDD (30 mu-g/ kg) to
sham-operated or neonatally thymectomized female BALB/c mice reduced
the levels of mRNA in the bone marrow for the lymphocyte stem cell-
specific enzymes terminal deoxynucleotidyl transferase (TdT) and
recombinase activating gene (RAG-1). TdT biosynthesis was also
reduced by TCDD treatment. Thus, neonatal thymectomy had no effect on
the TCDDelicited reduction of TdT or RAG-1 mRNAs or TdT biosynthesis.
Genetically athymic (nu/nu) mice were used to further determine if
the actions of TCDD on the thymus or long-lived T-cells altered
lymphocyte stem cell development. As observed in BALB/c mice, TCDD
treatment decreased the expression of TdT and RAG-1 mRNAs in bone
marrow from athymic nu/nu and intact nu/+ littermates. We conclude
that TCDD-elicited alterations in bone marrow lymphocyte stem cells
are not secondary to any actions, direct or indirect, that TCDD has
on the thymus or thymic-derived T-cells.
AN 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, 42096
AB 2,3,7,8-Tetrabromodibenzo-p-dioxin (2,3,7,8-TBDD) was administered
daily to male and female rats for 91 days by gavage. Ten male and 10
female 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. At
1 mu-g/kg per day and above, body weight gain was dose-dependently
reduced by treatment. Animals in the 3 and 10 mu-g/kg dose groups
showed symptoms of wasting syndrome. Fifty percent of the animals in
the 3 mu-g/kg dose-group died and all animals of the highest dose (10
jug/kg) died or had to be killed in extremis. Hematological
investigations indicated changes - mainly in the 1 and 3 mu-g/kg
dose-groups - in hemoglobin content, packed cell volume and number of
thrombocytes. The prothrombin-time was markedly prolonged after 3 mu-
g/kg in week 13. Clinical chemistry performed at the end of treatment
revealed an increase in plasma alkaline phosphatase (APh), aspartate
aminotransferase, ASAT and alanine aminotransferase, ALAT (females
only) in the highest surviving dose-group (3 mu-g/kg). Marginal
changes 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 thyroxin
was 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 lymphatic
tissue in thymus and spleen. Investigations of the liver indicated
peliosis hepatis after treatment with 3 or 10 mu-g/kg. Activities of
microsomal enzymes (ethoxyresorufin O-deethylase, ethoxycoumarin O-
deethylase, aryl hydrocarbon hydroxylase, UDP-glucuronyltransferase)
investigated in liver, lung and kidney were dose-dependently elevated
after 13 weeks of treatment. At a dose of 3.0 mu-g/kg, activities
were below those of the dose 1.0 mu-g/kg, probably due to liver
toxicity. The induction ratio of kidney was generally higher than in
liver and lung. No signs of treatment-related toxicity were observed
in the 0.01 and 0.1 mu-g/kg groups after the subchronic
administration of 2,3,7,8-TBDD by gavage.
AN 97040348 9402.
AU De-Waal-E-J, Rademakers-L-H-P-M, Schuurman-H-J, Van-Loveren-H, Vos-J-
TI Ultrastructure of the cortical epithelium of the rat thymus after in
vivo 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 inducing
cortical atrophy in the rat thymus. The present study was conducted
to provide ultrastructural evidence for the cortical epithelium to be
a target for TCDD in vivo. Juvenile male Wistar rats were orally
intubated once with either 50 or 150 mu-g/kg TCDD and killed 4 or 10
days thereafter. Major changes were found in the cortical thymic
epithelium. First, a relative shift occurred from "pale" to darker
cortical epithelial cell types, as judged by their nuclear and
cytoplasmic electron density. This effect was most prominent at 10
days after exposure to 150 mu-g/kg TCDD. The increased electron
density of the cortical epithelium indicates an altered state of
cellular differentiation. Secondly, at the 150 mu-g/kg dose level
focal epithelial cell aggregates were seen both at day 4 and day 10
after administration. This aggregation may either be compound induced
or represent a secondary event to the collapse of the thymic stroma.
Thirdly, increased vacuolation of cortical epithelial cells was
apparent. This effect is interpreted as a consequence rather than a
cause of thymocyte depletion from the cortex. This study indicates
that TCDD exposure affects the cortical epithelium of the rat thymus
at a high dose level. Electron microscopy reveals that the
differentiation of epithelial cells is altered. In addition,
epithelial cell aggregates are formed.
AN 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 AND
TREATMENT 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) requirement
diet, i.e. 0.2 mg.cntdot.100 gbw.cntdot.-1.cntdot.d-1 for one week
and then thirty-five rats were induced a 3rd degree burn of 20% BSA,
another 7 uninjured rats served as normal controls. The burned rats
were 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. The
results showed that the serum and liver VE contents were lower and
the serum LPO higher significantly in the burned rats as compared
with the normal control, it was also found that thymus was atrophic,
the thymic cortex become thinner thymocytes constricted, and the
splenic corpuscles decreased, the sperm and spermatocytes were
markedly decreased with testis atrophy. When burned rats were fed VE,
as the dosage increased to 2 mg.cntdot. 100gbw-1.cntdot.d-1, the
serum and liver VE levels significantly raised and the serum LPO
returned to control level. The histological changes of thymus, spleen
and testes were nearly similar to the normal control rats.
AN 96040400 9330.
AU HALOUZKA-R, JURAJDA-V.
TI EFFECTS OF POLYCHLORINATED BIPHENYLS ON THE INFECTION OF CHICKENS
WITH 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 and
K) and Marek's disease virus (MDV) and observed during a 5-week
period. Two groups of chicks were each infected with MDV isolates M
and K, respectively, in doses of 103 PFU per bird and fed a non-
contaminated feed mixture. Two other groups were infected in the same
way and fed the same feed mixture contaminated with PCB at 50 mg per
kg feed. Non-infected chickens fed the non-contaminated feed mixture
were used as controls. At weekly intervals the birds were subjected
to serological examination and weighted and their lymphoid organs,
skin, nerves and gonads were examined histopathologically. PCB
produced apathy, a reduction in body mass, moulting disorders and
white discolouration of the feathers. They reduced the production of
active MD-precipitating antibody and the incidence of microscopic MD-
lymphoproliferative lesions, as compared with the data obtained in
the birds only infected. They potentiated cytolytic changes in the
lymphoid organs and, at the end of the experiment, caused atrophy of
the bursa of Fabricius and of the thymus. Morphological signs of
local cell-mediated immunity in the lymphoid organs were observed
very rarely. The results are helpful to the differentiation of
morphological immunosuppressive changes of different etiology and
contribute to a better understanding of the causes of reduced
immunological competence in poultry.
AN 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-VIVO
EXPOSURE TO 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD AN
SO TOXICOL-APPL-PHARMACOL 115 (1). 1992. 80-88.
IN NATL INST PUBLIC HEALTH EVIRON PROTECTION, LAB MED MED DEVICES, PO
BOX 1, 3720 BA BILTHOVEN, NETH.
AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces thymic atrophy in
rats. The present study was initiated to provide (immuno)histological
data on the mechanism of action. Juvenile male Wistar rats were
orally intubated once with 50 or 150 .mu.g/kg TCDD. They were
euthanized 4 or 10 days thereafter, or were allowed to stay alive
until Day 20 or 26. Growth retardation occurred rapidly in all TCDD-
treated animals. Lethality was demonstrated within 20-21 days after
administration. At Days 4 and 10 after intubation, thymic atrophy was
shown by reduction of thymic weight and cortex/medulla ratio.
Staining patterns for T-cell markers in the atrophic thymuses
coincided with the reduction of cortical areas. There was no evidence
indicating that the effects were indirectly caused by stress. TCDD-
induced thymic atrophy persisted until Day 26 after administration.
Immunohistochemical analysis revealed prominent changes in the
cortical thymic epithelium at the 150-.mu.g/kg dose level. First, in
the cortex epithelial cell aggregates were observed both at Day 4 and
at Day 10 after administration. Apparently, the architecture of the
epithelium had changed in these animals. Second, at 10 days after
administration epithelial cells were found with the simultaneous
expression of markers that in the normal uninvoluted thymus only
occur either in the subcapsular/medullary area or in the cortex. This
phenotype points to an unusual stage of differentiation. We conclude
that TCDD exposure affects the cortical epithelium of the rat thymus
at a high dose level. Apparently, it disturbs the epithelial network
and interferes with the differentiation of epithelial cells.
AN 43005204 9224.
AU SILVERSTONE-A-E, FIORE-N-C, SOULTS-J-A, CUNNINGHAM-L-M, GASIEWICZ-T-
TI SHRINKING A THYMUS DIFFERENCES BETWEEN DIOXIN CORTICOSTEROIDS AND
SO MEETING OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL
BIOLOGY (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.
AN 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 FOLLOWING
SUBCHRONIC 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 acute
susceptibility to responses mediated by the Ah receptor have a
pattern of suppression of the antibody response which is consistent
with a role by the putative dioxin receptor. The objective of the
present investigation was to compare the TCDD-induced suppression of
the antibody response following acute and subchronic exposures in
B6C3F1 mice, an Ah-high-responder strain, and DBA/2 mice, an Ah-low-
responder strain. Results of our initial studies demonstrate that
suppression of humoral immunity can be enhanced in DBA/2 mice
approximately 10-fold following subchronic versus acute exposures to
the same cumulative doses of TCDD. This change in suppression of the
antibody response in DBA/2 mice was not accompanied by significant
changes in liver weight (hepatomegaly), as was observed in the B6C3F1
strain when exposed under comparable conditions. In contrast, effects
on thymus weight (involution) were enhanced in the DBA/2 mice
following subchronic exposure and demonstrated a higher degree of
atrophy than was seen in the B6C3F1 strain (68 versus 56% decrease in
thymic weight at the 42 .mu.g/kg cumulative dose). These findings
suggest that multiple mechanisms may be operating to suppress humoral
immunity in vivo and that the conditions of exposure can alter the
toxic effects of TCDD in the DBA/2, Ah-low responsive, mouse strain.
AN 42023691 9200.
AU DE-WAAL-E-J, RADEMAKERS-L-H-P-M, SCHUURMAN-H-J, VAN-LOVEREN-H, VOS-J-
TI ATROPHY OF THE RAT THYMUS EFFECTS OF 2 3 7 8 TETRACHLORODIBENZO-P-
DIOXIN ON THE EPITHELIAL MICROENVIRONMENT ASSESSED AT THE
ULTRASTRUCTURAL LEVEL A COMPARISON WITH BISTRI-N-BUTYLTINOXIDE.
SO IMHOF, B. A., S. BERRIH-AKNIN AND S. EZINE (ED.). LYMPHATIC TISSUES
AND IN-VIVO IMMUNE RESPONSES; TENTH INTERNATIONAL CONFERENCE ON
LYMPHATIC TISSUES AND GERMINAL CENTRES IN IMMUNE REACTIONS,
COMPIEGNE, FRANCE, JULY 1-5, 1990. XX+1007P. MARCEL DEKKER, INC.: NEW
YORK, 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.
AN 92094523 9139.
AU HANIOKA-N, SAEKI-H-K, ISHIDA-C, KOGA-N, YOSHIMURA-H.
TI TOXICOLOGICAL ASSESSMENT OF 2 5 2'5' TETRACHLOROBIPHENYL AND ITS
MAJOR 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, KYUSHU
UNIVERSITY 62, FUKUOKA 812.
AB We observed previously that piolychlorinated biphenyl (PCB) could be
classified to two groups, 3-methylcholanthrene (MC)-type and
phenobarbital (PB)-type, in term of inducibility of the hepatic
enzymes. 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 parallel
with their induction ability of microsomal benzo(a)pyrene 3-
hydroxylase and cytosolic DT-diaphorase. On the contrary, PB-type
PCBs such as 2,5,2',5'-TCB and 2,4,5,2',4',5'-HexCB which induce
microsomal benzphetamine N-demethylase and NADPH-cytochrome P-450
reductase activities showed virtually no or very low toxicity. In the
present study, we examine effects of 2,5,2',5'-TCB and its major
metabolite 3-hydroxy-2,5,2',5'-TCB on body weight gain, organ weights
and activities of hepatic enzymes in rats and assessed acute toxicity
of 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 during
the experiment, but the rate of growth was significantly supressed
after 3 days. Significant hypertrophy of the liver and decrease of
total liver lipid content were observed in 2,5,2',5'-TCB group, but
the atrophy of spleen and thymus was not affected in both groups. On
the other hand, in 2,5,2',5'-TCB group, benzo(a)pyrne 3-hydroxylase
and benzphetamine N-demethylase activities were increased to 2.4-fold
and 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% of
the 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 also
excreted after injection of 3-hydroxy 2,5,2',5'-TCB for 2 days. These
results suggest that 2,5,2',5'-TCB possesses only low toxicity and
its major metabolite, 3-hydroxy-2,5,2',5'-TCB is also an inactive
AN 92063350 9134.
TI DEXAMETHASONE AND 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN CAN INDUCE
THYMIC 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-751
AB The effects of in vivo exposure to dexamethasone (DEX) and 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) on thymocyte proliferation and
thymocyte number were compared. In the thymus of DEX-treated mice (1
mg/kg) both proliferation and cell number had decreased by 70% one
day after exposure. This decrease was, however, transient, and values
returned to normal within 2 weeks. By contrast, in TCDD exposed mice
(50 .mu.g/kg), a reduction in proliferation was not observed until
day 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 throughout
the observation period (8 days). DEX had a direct and immediate
effect on cells in all thymocyte subpopulations whereas TCDD
initially only affected the immature double negative (DN) and double
positive (DP) populations.
AN 92041331 9131.
AU VAN-LOVEREN-H, SCHUURMAN-H-J, KAMPINGA-J, VOS-J-G.
TI REVERSIBILITY OF THYMIC ATROPHY INDUCED BY 2 3 7 8
TETRACHLORODIBENZO-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,
AB We studied the reversibility of thymic atrophy induced by intubation
of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 10 days after a single
dose of 50 .mu.g/kg, or bis(tri-n-butyltin)oxide (TBTO), 4 days after
a single dose of 75 mg/kg. This was done by an experimental design in
which the atrophic thymus was placed in an in vivo situation in which
the toxic chemical was no longer present, e.g. by transplantation of
atrophic thymic lobes in untreated normal rats with connection to the
vasculature of the recipient. At 20 days after the transplantation,
the atrophic thymus showed the morphology and architecture of a
normal uninvoluted thymus: lymphocyte counts and phenotypic
expression of markers on lymphocytes, epithelium, and macrophages in
the transplanted lobe did not differ from those in untreated donor
rats or those in the normal uninvoluted thymus. Considering the
mechanism of action of the toxic chemicals, TBTO has been claimed to
affect preferentially (passenger) lymphocytes in the thymus: the
recovery after transplantation therefore is explained on the mere
influx of newly-recruited precursor cells from the bone marrow. For
TCDD a toxic action on the stationary epithelial component of the
thymus has been claimed. We conclude that this epithelial damage is
reversible within the 3-week period of the present experiment, with
respect to both the morphology and immunologic phenotype of
epithelium and other cell populations, as well as the recruitment of
AN 91079747 9112.
AU ANDERSSON-L, NIKOLAIDIS-E, BRUNSTROM-B, BERGMAN-A, DENCKER-L.
TI EFFECTS OF POLYCHLORINATED BIPHENYLS WITH AH RECEPTOR AFFINITY ON
LYMPHOID DEVELOPMENTS IN THE THYMUS AND THE BURSA OF FABRICIUS OF
CHICK 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 to
the Ah receptor and are known to cause thymic atrophy in most
experimental animal species and also to inhibit lymphoid development
in the embryonic thymus (T-cells) and in the bursa of Fabricius of
chick 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 receptor
ligands) were administered to chick embryos by air chamber injection
on Day 13 of incubation. The numbers of lymphoid cells (on Day 19) in
the thymus and the bursa of Fabricius were lower, in a dose-dependent
manner, in embryos treated with the coplanar PCBs compared with
controls. Approximate ED50 values for inhibition of bursal cell
development were 4 .mu.g for PeCB, 50 .mu.g for TCB, and 300 .mu.g/kg
egg for HCB. The most immunotoxic of the mono-ortho-chlorinated
analogues of TCB and PeCB were about 1000 times less potent than Pe
CB. The in vitro effects of the PCBs were studied in organ cultures
of thymi from 15-day-old mouse fetuses. The three coplanar
chlorobiphenyls inhibited lymphoid development in this culture system
in 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 Pe
CB. No inhibition of lymphoid development by the mono-ortho-
chlorinated PCBs was observed using concentrations as high as 10-6 M.
AN 91079745 9112.
AU PUHVEL-S-M, CONNOR-M-J, SAKAMOTO-M.
TI VITAMIN A DEFICIENCY AND THE INDUCTION OF CUTANEOUS TOXICITY IN
MURINE 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 toxic
polyhalogenated aromatic hydrocarbons, are largely unknown. To test
the hypothesis that TCDD-induced toxicity involves the reduction of
vitamin A levels, we investigated the role of vitamin A deficiency in
modulating the cutaneous response of congenic haired (+/+) and
hairless (hr/hr) mice to TCDD. Hairless mice are recognized as
sensitive 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 sex-matched
controls raised on standard chow, were treated topically with TCDD
and their cutaneous response monitored histologically. Body weights
and thymus gland weights were monitored as additional parameters of
toxicity. Liver and skin vitamin A levels were determined by HPLC.
Vitamin A depletion by itself had no effect on the normal cutaneous
histology of the haired phenotype, nor were any changes in cutaneous
morphology attributable to TCDD toxicity observed in haired, TCDD-
treated animals even when they were severely vitamin A depleted. On
the other hand, in hairless mice, vitamin A deficiency caused a
distinct increase in keratinization of dermal epithelial cysts, and
an increase in the sensitivity of these cysts to TCDD-induced
hyperkeratinization. TCDD-induced body weight loss and atrophy of the
thymus gland were not affected by the vitamin A status of either the
haired or hairless animals. Analysis of vitamin A levels in skin and
liver, following topical treatment of mice with TCDD, indicated that
TCDD exposure did not affect cutaneous levels, but did significantly
lower liver levels of vitamin A. These experiments suggest that
although systemic vitamin A deficiency may potentiate the expression
of TCDD-induced toxicity in skin of hairless mice, expression of
TCDD-induced toxicity probably involves more complex mechanisms than
a reduction in vitamin A levels.
AN 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 8
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 immune
suppression in experimental animals is poorly understood. A previous
study from our laboratory found that terminal deoxynucleotidyl
transferase-synthesizing lymphocyte stem cell populations in fetal
liver and neonatal bone marrow, but not thymus, were profoundly
altered after perinatal TCDD exposure, implying that a defect in the
prothymocyte population in liver and marrow may play a role in the
etiology of thymic atrophy in TCDD-exposed animals. In this report,
we present results of experiments designed to directly assess the
prothymocyte compartment in mice exposed to TCDD perinatally by
examining the ability of these stem cells to reconstitute an
irradiated thymus. Maternal TCDD exposure (15 .mu.g/kg) caused a
significant impairment of both fetal liver and neonatal bone marrow
prothymocyte activity. These alterations occurred at tissue
concentrations less than 200 fg of TCDD per mg. TCDD treatment also
resulted in a mild reduction in colony-forming unit-spleen in these
organs and a decrease in colony-forming unit-granulocyte-macrophage
in fetal and neonatal liver, but not bone marrow. Overall, these data
provide evidence that alterations to early stages of T-lymphopoiesis,
at the level of the prothymocyte, may be involved in the development
of TCDD-induced thymic atrophy and cell-mediated immunosuppression.
AN 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 IN
C57BL-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, TRIANGLE
PARK, NC 27711, USA.
AB The acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was
examined in male C57BL/6J mice differing only at the Ah locus. Wild
type mice (Ahb/b; "b/"b) were treated once with 0, 50, 100, 200,
and 400 .mu.g TCDD/kg po while congenic mice (Ahd/d, "d/d") received
a single dose of 0, 400, 800, 1600, 2400, and 3200 .mu.g TCDD/kg.
Mice were checked daily, weighed twice a week, and those that
survived, killed 35 days post-treatment. The LD50 values were 159 and
3351 .mu.g/kg for b/b and d/d mice, respectively. Mean time to death
was 22 days and was independent of dose and genotype. Decrease in
body weight gain was noted in both strains 5 days after treatment and
occurred at doses .gtoreq. 100 .mu.g/kg in b/b mice and 1600 .mu.g/kg
in d/d mice. Dose-related increases in liver weight (both absolute
and relative to body weight) and decreases in thymus, spleen, testes,
and epididymal fat pad weights were observed at 8-24-fold higher
doses in d/d than in b/b mice. A dose-related increase in segmented
neutrophils was observed in both strains. Serum chemistry values
indicated that 8-24 .times. greater doses of TCDD were needed to
elevate sorbitol dehydrogenase, alanine aminotransferase, and 5'-
nucleotidase and to decrease total and esterified cholesterol in d/d
than in b/b mice. Few effects were seen on total bile acids, serum
triglycerides, glucose, or on esterified cholesterol. In the liver,
hepatocellular cytomegaly, fatty change, and bile duct hyperplasia
occurred in both strains in a dose-related manner, as did thymic and
splenic atrophy. Necrosis of germinal epithelium in the testes and
edema in the stomach submucosa occurred at acutely toxic doses. These
lesions also occurred at doses 8-24.times. greater in d/d than in b/b
mice. Thus, the spectum of toxicity is independent of the allele at
the Ah locus, but the relative dose needed to bring about various
acute responses is approximately 8-24.times. greater in congenic mice
homozygous for the "d" allele than for the wild type animals carrying
two copies of the "b" gene.
AN 89110723 9017.
TI THE SYSTEMIC TOXICITY OF PRUDHOE BAY CRUDE AND OTHER PETROLEUM OILS
TO 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 of
Prudhoe Bay (PBCO), South Louisiana and Arabian Light crude oils,
Bunker C oil (BCO), mineral oil (MO) and corn oil. Minor decreases in
packed cell volume and increases in mean corpuscular hemoglobin
concentration occurred after ingestion of crude oils and BCO. Dietary
depletion of vitamin E and selenium failed to enhance hematological
changes. Pronounced liver enlargement and atrophy of thymus and
spleen accompanied ingestion of all petroleum oils except MO and were
shown to be dependent on dose of PBCO. Concentration of RNA and total
RNA were increased while total DNA, but not concentration of DNA, was
increased in enlarged livers. Liver enlargement was attributed
primarily to hyperplasia with an additional contribution due to
hypertrophy. The severe hemolytic anemia reported in marine birds
that ingested PBCO was not reproduce in mice. Liver enlargement and
lymphoid tissue atrophy were similar to those reported in other
species exposed to petroleum oils.
AN 89093818 9016.
AU FINE-J-S, SILVERSTONE-A-E, GASIEWICZ-T-A.
TI IMPAIRMENT OF PROTHYMOCYTE ACTIVITY BY 2 3 7 8 TETRACHLORODIBENZO-P-
SO J-IMMUNOL 144 (4). 1990. 1169-1176.
IN ENVIRON HEALTH SCI CENT, BOX EHSC, UNIV ROCHESTER SCH MED, ROCHESTER,
AB Exposure of experimental animals to 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) results in severe thymic atrophy and suppression of
cell-mediated and humoral immune functions. However, despite much
effort the mechanism by which TCDD produces these responses,
particularly thymic atrophy, remains unclear. In this report, we have
examined the effect of acute TCDD exposure on lymphocyte stem cells
in young adult BALB/c mice to determine whether alterations to events
early in T lymphopoiesis contribute to TCDD-induced thymic atrophy.
TCDD produced a dose-dependent reduction in thymic weight and
cellularity following a single dose of 5 to 120 .mu.g TCDD/kg. This
thymic atrophy correlated with a dose-dependent suppression of the
biosynthesis and mRNA levels of the lymphocyte stem cell-specific DNA
polymerase terminal deoxynucleotidyl transferase in bone marrow and
thymus. However, the reduction in thymic terminal deoxynucleotidyl
transferase synthesis, on a per cell basis, was less than that
observed in bone marrow. Intrathymic CD4/CD8 and IL-2R expression
demonstrated only mild alterations after exposure to 30 .mu.g TCDD
/kg. These data suggest that thymocytes are more refractory to TCDD
than are pre-T cells. To assess the possibility directly, bone marrow
prothymocytes from TCDD-treated donor mice were examined for their
capacity to reconstitute the thymuses of adoptive, irradiated
recipients. Our results indicate that prothymocyte activity was
severely impaired by TCDD exposure and that this effect occurred at
low tissues levels of TCDD. In contrast, we observed no reduction in
the number of colony-forming unit-granulocyte macrophage and a
moderate decrease in colony-forming unit-spleen. These data suggest
that TCDD-induced thymic atrophy is the result, at least in part, of
impaired thymic seeding by prothymocytes.
AN 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 BY
BINDING 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 syndrome
accompanied by a variety of specific organ changes including atrophy
of the thymus and spleen. TCDD toxicity in most tissues is thought to
be mediated by the Ah receptor. Although the spleen is a prime target
for TCDD toxicity, the possible presence of Ah receptor in the spleen
has not previously been investigated. Specific binding of (3H)TCDD to
Ah receptor in spleen cytosols was assessed by velocity sedimentation
on sucrose gradients. Ah receptor was detected in spleen cytosols
from adult Rhesus monkeys (mean .+-. SEM, 36 .+-. 8 fmol/mg cytosol
protein), 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 not
detectable in spleen cytosol from genetically "nonresponsive"
mice or from Golden Syrian hamsters, a species resistant to toxicity
of TCDD. Molecular properties of Ah receptor from spleen were similar
to those of the receptor from liver of the same species. The high Ah
receptor content in spleen cytosols from those species that are most
susceptibel to TCDD toxicity is consistent with the view that the Ah
receptor mediates TCDD toxicity in spleen as well as in other
AN 88090925 8909.
AU KOGA-N, NAKASHIMA-H, KAMIMURA-H, HOKAMA-Y, YOSHIMURA-H.
TI TISSUE DISTRIBUTION INDUCTIVE EFFECT ON LIVER ENZYMES AND ACUTE
TOXICITY OF 2 3 4 7 8 PENTACHLORODIBENZOFURAN IN GOLDEN SYRIAN
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 mammalian
species to the acute toxicity of highly toxic polyhalogenated
hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. In the
present study, the tissue distribution, inductive effect of liver
enzymes and acute toxicity of 2,3,4,7,8-pentachlorodibenzofuran (Pen
CDF) in male Golden Syrian hamsters were examined. The highest
content (about 48% of dose) of PenCDF was found in the liver 5 days
after a single i.p. dose of 1.0 mg/kg. The amount ranging about 5 to
10% of dose was also distributed to mesentery, skin and muscle. In
liver, the distribution of PenCDF was just parallel to that of
cytochrome P-450 (P-450), marker enzymes of liver endoplasmic
reticulum, suggesting that PenCDF binds to P-450. The mode of
inductive effects of PenCDF in hamsters was 3-methylcholanthrene-type
as reported previously in rats. However, the typical enzymes such as
benzo(a)pyrene 3-hydroxylase and DT-diaphorase were induced to a
relatively less extent than did in rats. In hamsters pretreated with
PenCDF at a dose of 0.5 mg/kg, the potent atrophy of thymus and the
3-fold increase of liver lipid peroxide were observed, whereas the
body weight gain was not suppressed at all. These results suggest
that the induction of liver enzymes and the atrophy of thymus might
not be the direct cause of PenCDF-induced lethality in hamsters.
AN 88076969 8909.
AU KONO-K, HAYAKAWA-M, ASAI-K, KUZUYA-F, HARADA-T.
TI THE RELATIONSHIP BETWEEN ILLNESS IN THE AGED AND IN INHERENTLY
SCORBUTIC 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 the
pathophysiological findings of this rat mutant (ODS rats) in acute
and chronic vitamin C deficient states. In experiment 1, 0DS rats
aged 63 days showed severe body loss and atrophy of thymus, spleen
and bone. In experiment 2, ODS rats aged 285 days showed osteoporotic
and 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 to
those found in elderly people, that is, corneitis and findings
suggesting the presence of immune deficiency due to atrophic change
of T and B-lymphocytes in thymus and spleen. From these findings,
vitamin C deficiency might have an etiological relationship with the
above mentioned geriatric diseases.
AN 87110224 8905.
AU SILKWORTH-J-B, CUTLER-D-S, SACK-G.
TI IMMUNOTOXICITY OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN IN A COMPLEX
ENVIRONMENTAL 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, NY
AB The organic phase of the leachate (OPL) from the Love Canal chemical
dump site contains more than 100 organic compounds including 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD). The immunotoxic potential of OPL
was determined in two mouse strains which differ in their sensitivity
to aromatic hydrocarbon (Ah) receptor-mediated toxicity. OPL was
administered 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 immunized
with sheep erythrocytes (SRBC). The antibody response (PFC) and organ
weights were evaluated 4 days later. OPL produced thymic atrophy and
hepatomegaly in both strains at all dose levels. The PFC/spleen in
BALB/cByJ mice was significantly reduced at the three doses to 34,
13, and 15%, respectively, of the control response. Serum anti-SRBC
antibody levels and relative spleen weights were also reduced. The
only 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 the
relative thymus and spleen weights only in BALB/cByJ mice. However,
TCDD produced hepatomegaly, a decrease in serum antibody, and a
decrease in PFC/spleen in both BALB/cByJ and DBA/2J mice to 3 and
15%, respectively, at 16 .mu.g/kg. Thus, the TCDD dose required to
cause a 50% suppression (ED50) of PFC/spleen for the BALB/cByJ and
DBA/2J strains was 1.84 and 3.89 .mu.g/kg, respectively. The ED50 for
OPL was 0.24 g/kg in BALB/cByJ mice. The TCDD concentration in the
OPL was estimated to be 7.6 ppm, which agrees closely with the
chemical analysis (3 ppm). The results suggest that the
immunosuppression caused by OPL in BALB/cByJ mice was primarily due
to TCDD, that the non-TCDD components of OPL diminished the TCDD
immunotoxicity in the DBA/2J strain, and that the thymic atrophy and
hepatomegaly were caused primarily by the non-TCDD components of the
AN 87088227 8900.
AU FINE-J-S, GASIEWICZ-T-A, SILVERSTONE-A-E.
TI LYMPHOCYTE STEM CELL ALTERATIONS FOLLOWING PERINATAL EXPOSURE TO 2 3
7 8 TETRACHLORODIBENZO-P-DIOXIN.
SO MOL-PHARMACOL 35 (1). 1989. 18-25.
IN ENVIRONMENTAL HEALTH SCIENCES CENTER, DEP BIOPHYSICS, UNIV ROCHESTER
SCH MED, ROCHESTER, NY 14642.
AB Perinatal exposure of experimental animals to the environmental
contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to
thymic atrophy and a suppression of cell-mediated immunity that is
more severe and persistent than that caused by adult exposure,
suggesting that events involved in the maturation of the immune
system are particularly sensitive to TCDD. We report here that
perinatal TCDD exposure produces an alteration in the lymphocyte stem
cell population in the fetus and neonate, as evidenced by a
significant reduction in the lymphocyte stem cell-specific enzyme
terminal deoxynucleotidyl transferase (TdT). After maternal treatment
with a single dose of TCDD (10 .mu.g/kg of body weight) on
gestational day (gd) 14, TdT biosynthesis and TdT-specific mRNA were
reduced more than 50% in fetal liver lymphoid cells on gd 18. An even
more extensive reduction was seen in neonatal bone marrow through
postnatal day 18. In contrast, thymic TdT synthesis appeared to be
relatively unaffected on a per cell basis of perinatal TCDD exposure,
although the actual number of TdT-synthesizing thymocytes was
diminished due to extensive thymic atrophy. These effects occurred at
concentrations of 1-31 fg of TCDD/mg of thymus. Flow cytometric
analysis of thymocyte surface marker expression revealed a slight
decrease in the percentage of Lyt-2+L3T4+ thymocytes on gd 18 and
postnatal day 4. This alteration was no longer apparent by postnatal
day 11, when marrow TdT biosynthesis was most suppressed. These
results suggest that TCDD-induced thymic atrophy during the perinatal
period may be due, in part, to an effect on the prothymocyte.
AN 87065928 8900.
AU GORSKI-J-R, MUZI-G, WEBER-L-W, PEREIRA-D-W, IATROPOULOS-M-J, ROZMAN-
TI ELEVATED PLASMA CORTICOSTERONE LEVELS AND HISTOPATHOLOGY OF THE
ADRENALS AND THYMUSES IN 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN-TREATED
SO TOXICOLOGY 53 (1). 1988. 19-32.
IN INST FUER TOXIKOLOGIE DER GESELLSCHAFT FUER STRAHLEN- UND
UMWELTFORSCHUNG MUENCHEN MBM, 8042 NEUHERBERG, WEST GERMANY.
AB The relationship between thymic atrophy and plasma corticosterone
levels was examined in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-
treated, pair-fed and ad libitum-fed male Sprague-Dawley rats given a
usually lethal (125 .mu.g/kg) or non-lethal (25 .mu.g/kg) dose of
TCDD. At both dosages, corticosterone levels in TCDD-treated animals
begun to rise as early as day 4 after treatment. At later time points
corticosterone levels were 5-7 times higher in rats given the non-
lethal dose, and 6-10 times higher in rats administered the lethal
dose than the levels observed in ad libitum-fed controls.
Corticosterone levels in control rats pair-fed to the lethal dose
group (as a result of the severe reduction in feed intake) were
similarly elevated as in TCDD-treated rats but this was not the case
in pair-fed rats of the non-lethal TCDD dosage (due to an essentially
unchanged feed intake). At both dosages, relative thymus weights of
TCDD-treated rats started decreasing by day 4 and continued to
decline for the most part of the study. Relative thymus weights of
rats pair-fed to the non-lethal TCDD dosage were not different from
ad libitum-fed rats. However, the decrease in relative thymus weights
of rats pair-fed to the lethal TCDD dosage paralleled that of TCDD-
treated rats with an apparent 8-day lag period. Morphologically, the
thymus as well as the adrenal revealed differential changes in TCDD-
treated rats from those observable in pair-fed rats. These results
suggest that either TCDD exerts a direct effect on the thymus and the
adrenals or it causes an additional stresss (e.g., a metabolic
stress) over and above the starvation stress, which may be
responsible for the differential morphological changes in these
AN 87065884 8900.
AU NIKOLAIDIS-E, BRUNSTROM-B, DENCKER-L.
TI EFFECTS OF TCDD AND ITS CONGENERS 3 3' 4 4' TETRACHLOROAZOXYBENZENE
AND 3 3' 4 4' TETRACHLOROBIPHENYL ON LYMPHOID DEVELOPMENT IN THE
THYMUS 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 duck
embryos were cultured in media containing 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) for 5 days. The maximal TCDD-induced decrease in
lymphoid cell number of chick embryo thymus (to about 60% of the
control number) occurred at concentrations of 10-10 M and above. To
produce the same effect on lymphoid cell number in the cultures of
thymus anlagen from turkey and duck embryos, about a 100-fold higher
concentration of TCDD was needed. The toxicity of the TCDD congeners
3,3'4,4'-tetrachloroazoxybenzene (TCAOB) and 3,3',4,4'-
tetrachlorobiphenyl (TCB) to embryonic chicken thymus was tested in
vitro and in ovo. In chick embryo thymus cultures, TCAOB and TCB were
about two orders of magnitude less toxic than TCDD. Injection of
TCAOB and TCB into chicken eggs preincubated for 11 days resulted in
a dose-dependent decrease in thymic lymphoid cell number 5 days
later, declining to about 14% of the controls at 10 .mu.g TCAOB/kg
egg. The ED50 value was estimated to be 3.6 and 60 .mu.g/kg egg for
TCAOB and TCB, respectively.
AN 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 THE
MALE FISCHER RAT.
SO FUNDAM-APPL-TOXICOL 11 (2). 1988. 236-249.
IN SYSTEMIC TOXICOL BRANCH, NATL INST ENVIRON HEALTH SCI, RESEARCH
TRIANGLE PARK, NC 27709.
AB Polychlorinated dibenzofurans are ubiquitous environmental pollutants
which have great potential for human exposure. To characterize the
toxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), male F344
rats were administered a single oral dose of 0, 100, 250, 500, 1000,
or 2000 .mu.g 4PeCDF/kg. A progressive and dose-dependent loss of
body weight was evident by 3 days after treatment. Signs of toxicity
included piloerection, hair loss, hypoactivity, morbidity, and death.
Death occurred as soon as 14 days after treatment and continued
throughout the 35-day observation period. The LD50/35 was estimated
to 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 sorbitol
dehydrogenase and aspartate aminotransferase activities. The
hematocrit, hemoglobin, mean corpuscular volume, and mean corpuscular
hemoglobin concentrations were depressed in a dose-dependent fashion.
Hepatic ethoxyresorufin-O-deethylase (EROD) activity was increased in
all treatment groups approximately 25 times above that of control
animals. Lymphoid depletion in the thymus and spleen was observed in
the three highest doses and thymic atrophy was present at all dose
levels. Absolute liver weight and the liver:body weight ratio were
significantly increased above controls. Hepatotoxicity was dose-
dependent and was characterized by lipid accumulation resulting in
hepatocytomegaly. Epithelial hyperplasia and focal ulcerations of the
forestomach 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 biochemical
mechanisms(s) of toxicity for these chemicals may be similar.
AN 86097960 8800.
AU PLUSS-N, POIGER-H, HOHBACH-C, SUTER-M, SCHLATTER-C.
TI SUBCHRONIC TOXICITY OF 2 3 4 7 8 PENTACHLORODIBENZOFURAN PECDF IN
SO CHEMOSPHERE 17 (6). 1988. 1099-1110.
IN INST TOXICOL, FEDERAL INST TECHNOL, UNIV ZURICH, CH-8603
AB Groups of rats were maintained for 13 weeks on diets containing 2, 20
and 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). The
high PeCDF diet caused death of all female and one male rat,
decreased body and organ weights, especially of the thymus; food
consumption was also decreased. Morphologically, a marked atrophy of
the cortex of the thymus became apparent as well as severe lesions in
the liver, being more pronounced in the females. In the animals fed
the 20 ppb PeCDF diet lesions were less severe. No effects, except a
weak but significant thymus atrophy, were observed in the females
maintained on the low-level diet. Alterations in blood chemistry and
haematology were seen predominantly in the medium and high dose
groups. The types of lesion observed with TCDD resembled those
produced by PeCDF but, at the same dosage levels, were more severe.
From the present data it was concluded that for PeCDF a toxicity
factor of 0.4 (TCDD: 1) would be adequate for assessing its toxicity
relative to TCDD.
AN 86051900 8800.
AU PLETSITYI-K-D, DAVYDOVA-T-V, FOMINA-V-G, SUKHIKH-G-T, ASKEROV-M-A,
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 A
administration prevents stress-induced immunological disorders:
depression of antibody-forming cell production, decrease in natural
killer cell activity and T-lymphocyte mitogenic response. Vitamin A
also prevents the development of thymus atrophy, lymphopenia and
depression of phagocytic activity of peritoneal macrophages.
AN 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-lymphocyte
blast-transformation, and decrease of the humoral immune response
were observed in rats with alimentary vitamin A deficiency. Vitamin
B1 deficiency induced by administration of oxythiamine led to the
thymus atrophy, inhibition of T-lymphocyte blastogenic response in
mice, and to suppression of delayed hypersensitivity in guinea pigs.
AN 85032819 8800.
AU KAMIMURA-H, YOSHIMURA-H.
TI STIMULATION OF FECAL EXCRETION OF ETIOLOGICAL COMPOUNDS OF YUSHO IN
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 of
Yusho accumulated in the body, which should be valuable for the
treatment of this intoxication, have briefly been reviewed in this
paper. Since 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) has been
recognized to be most important among various congeners of PCB and
PCDF ingested, with respect to toxicity and persistency in the body,
we selected this compound for this study and demonstrated, first of
all, that accumulated PenCDF in the rat was eliminated, though very
gradually, through the intestinal wall into the lumen, and then to
feces. Then we investigated by using rats to learn effects of
squalane, liquid paraffin, cholestyramine and activated charcoal on
enhancement of the fecal excretion of PenCDF. In the case of
charcoal, we used charcoal beads instead of the powder. They are the
fine beads of agar in which activated charcoal powder is enwrapped.
By 3-week treatments, all these compounds were found to give
significant stimulating effects. Treatments with squalane and
activated charcoal beads afforded better results than did other two.
The effect was due to inhibition of the re-absorption of PenCDF by
dissolving or adsorbing, and then excreting efficiently into feces.
Enhanced exsorption of PenCDF through the intestinal wall might also
contribute to this effect. Rats given PenCDF were then maintained on
a diet containing 5% squalane or 5% activated charcoal beads for 12
weeks. Both treatments increased the fecal excretion of PenCDF about
5-fold over the control and concomitantly lowered the blood and the
liver level of PenCDF markedly. Appearance of fatty liver and thymus
atrophy were also prevented significantly, and no appreciable side
effect was observed during these treatments for 12 weeks.
AN 85032812 8800.
AU KOGA-N, KUROKI-J, HOKAMA-Y, YOSHIMURA-H.
TI LONG-TERM EFFECT OF 3 4 5 3' 4' PENTACHLOROBIPHENYL ON THE TOXICITY
AND 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 highly
toxic PCB congener, on the toxicity and liver enzyme activities in
Sprague-Dawley rats was investigated during 8 months after the
injection. In both PenCB-treated groups, the body weight were
increased during the experiment, but the rate of growth was
significantly suppressed from 52 days to 130 days. Such suppression
continued up to 8 months after the first PenCB-injection. Even at 8
months, significant atrophy of thymus was still observed in both
groups, but the tissue weights of liver and spleen were not affected
at all. On the other hand, benzo(a)pyrene (BP) 3-hydroxylase and DT-
diaphorase, both of which are typical enzyme activities inducible by
MC-type inducers, were increased markedly at 1 month after the
injection in both groups. DT-diaphorase level were lowered to the
control level at 4 months after the injection. Total P-450 content
was 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 level
than that of the control at 8 months. These results showed a
surprising persistency of biological effect of PenCB, and suggested
that the multiple injections with divided small doses were more
effective than a single injection of PenCB at once.
AN 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 TOXICOLOGICAL
ASSESSMENT 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) and
toxicological assessment of the metabolites were investigated in the
rat. Four metabolites were isolated from faeces of rats dosed with
3,4,3',4'-TCB. Two were identified as 5-hydroxy-3,4,3',4'-TCB and a
chlorine-shift metabolite, 4-hydroxy-3,5,3',4'-TCB, by comparison of
melting points, chromatographic mobilities and spectral features with
those of the synthetic samples. A dihydroxy-TCB and
monohydroxytrichlorobiphenyl were also indicated by mass spectrometry
to be excreted in faeces as minor metabolites. 3. Faecal excretion of
unchanged 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 a
dose of 50 mg/kg. From the inability to cause the liver hypertrophy
and thymus atrophy, both monohydroxy-metabolites of 3,4,3',4'-TCB are
much less toxic than the parent 3,4,3',4'-TCB. In addition, these
phenolic metabolites did not induce the activities of benzo(a)pyrene
hydroxylase and DT-diaphorase, whereas 3,4,3',4'-TCB greatly induced
these activities. These results indicated that unlike PCB congeneres
with phenobarbital-type inducing ability, 3,4,3',4'-TCB, a prototype
of 3-methylcholanthrene-type inducers, is detoxified by metabolic
AN 84030829 8700.
AU HAKANSSON-H, WAERN-F, AHLBORG-U-G.
TI EFFECTS OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN TCDD IN THE LACTATING
RAT 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.g
TCDD/kg body wt after delivery. Pups were killed on postnatal day
(PND) 0, 2, 4, 8, or 16. Dams and remaining weanlings were killed on
PND 22 and 32, respectively. Thymus weight was lower in dams exposed
to TCDD than in controls, whereas no differences in body weight or
relative liver weight were found. The total amount and the
concentration of vitamin A were lower in the liver but higher in the
kidneys and in serum of TCDD-treated dams than in controls. TCDD-
exposed weanlings showed lower weight gain, liver enlargement and
thymus atrophy compared to controls. Growth reduction became more
pronounced with time, liver enlargement was at its peak on PND 8 and
thymus atrophy was most pronoucned on PND 16, although all three
effects persisted throughout the study. The total amount of vitamin A
increased at a similar rate in control and TCDD-exposed weanlings
throughout lactation. When the young started to eat pelleted diet
there was a pronounced increase in hepatic vitamin A content. Between
PND 16 and 32 controls increased their hepatic vitamin A content 21-
fold, compared to 12-fold in TCDD-exposed offspring. The hepatic
stores of TCDD-treated animals reached 45% of the stores of control
pups on PND 32. From PND 8 renal vitamin A was significantly higher
in the TCDD-exposed young than in the controls. At PND 32 TCDD-
exposed weanlings had six times more renal vitamin A than controls.
AN 82019144 8600.
AU HORI-S, OBANA-H, TANAKA-R, KASHIMOTO-T.
TI COMPARATIVE TOXICITY IN RATS OF POLYCHLORINATED BIPHENYLS
POLYCHLORINATED QUATERPHENYLS AND POLYCHLORINATED DIBENZOFURANS
PRESENT 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 for
the disease "Yusho, " a mixture of polychlorinated biphenyls (PCBs),
polychlorinated quaterphenyls (PCQs) and polychlorinated
dibenzofurans (PCDFs) having a composition similar to that found in
the rice oil causing "Yusho" was prepared in our laboratory. Male
Sprague-Dawley rats were daily given orally for 22 d a regimen
consisting 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 showed
hepatic enlargement, reduction of serum corticoid level, increase of
serum cholesterol level and increase in the hepatic microsomal drug-
metabolizing enzyme activity, and the effect was larger in the order
of Mixture > PCDFs > PCBs. In addition, when PCDFs or Mixture were
administered to rats, atrophy of the thymus and suppression of body
weight gain were observed. When Mixture was administered to rats, a
significant decrease in serum glutamic pyruvic transaminase (GPT)
level and a significant increase in serum triglyceride level were
observed. In the PCQs-treated rats, increase in the hepatic
microsomal drug-metabolizing enzyme activity and decrease in the
adrenal corticoid levels were observed, but the degree of change was
far less than that in the PCBs- or PCDFs-treated rats. PCDFs or
Mixture showed induction of hepatic microsomal drug-metabolizing
enzyme activity of the 3-methylcholanthrene (MC) type in the rat. On
the other hand, PCBs and PCQs showed intermediary-type induction of
the phenobarbital (PB) and MC types. Therefore, the predominant
etiology of "Yusho" may involve PCDFs contained inthe toxic rice
AN 82009301 8600.
AU DECAPRIO-A-P, MCMARTIN-D-N, O-KEEFE-P-W, REJ-R, SILKWORTH-J-B,
TI SUBCHRONIC ORAL TOXICITY OF 2 3 7 8 TETRACHLORODIBENZO-P-DIOXIN IN
THE GUINEA-PIG COMPARISONS WITH A POLYCHLORINATED BIPHENYL-CONTAINING
TRANSFORMER 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 the
environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin
(2,3,7,8-TCDD) in the guinea pig, the effects of prolonged po
exposure in this species are unknown. The present report describes
the results of administration to guinea pigs of 2,3,7,8-TCDD in the
feed 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 facilitate
comparison of the previously reported toxixity of a transformer fluid
pyrolysate with that of pure 2,3,7,8-TCDD. Animals receiving 430 ppt
2,3,7.8-TCDD exhibited body weight loss, thymic atrophy, liver
enlargement, 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 gain
and increased relative (to body) liver weights. Male anmals also
displayed a reduction in relative thymus weights and elevated serum
triglycerides, while females exhibited hepatocellular cytoplasmic
inclusion bodies and lowered serum alanine aminotransferase
activities. Toxic effects were generally similar to those observed
after acute, 2,3,7,8-TCDD administration. No dose-related alterations
were seen in animals receiving either 10 ppt (total 0.06 .mu.g/kg) or
2 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 the
recovery study, groups of guinea pigs were administered 430 ppt
2,3,7,8-TCDD for 11, 21, or 35 days and then allowed to recover for
an additional 79, 69, or 55 days, respectively. Treatment-related
mortality 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 exposure
was calculated on the basis of these results, a value lower than
those 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 the
present findings with those previously reported for a transformer
fluid pyrolysate containing a mixture of polychlorinated aromatic
species indicated both a greater variety of toxic effects and flatter
dose-response relationships for the pyrolysate in the guinea pig.
AN 30025350 8600.
TI DIOXIN-INDUCED THYMIC ATROPHY AND SUPPRESSION OF THYMUS-DEPENDENT
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: COLD
SPRING 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 BA
AN 30025320 8600.
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: COLD
SPRING 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.
AN 80109643 8500.
AU NAKANISHI-Y, KURITA-Y, KANEGAE-H, SHIGEMATHU-N.
TI RESPIRATORY INVOLVEMENT AND IMMUNE STATUS IN POLYCHLORINATED
BIPHENYLS 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 laboratory
investigation of 401 patients with polychlorinated biphenyls (PCB)
and polychlorinated dibenzofurans (PCDF) poisoning have been studied
since 1969 to 1983. About 1/2 of the patients were complaining of
respiratory distress and/or secondary airway infections at an early
stage. Thereafter the respiratory distress occurring in these
patients improved gradually for the 10 yr following onset of the
disease. However, from 10 to 15 yr after onset little or no
improvement of respiratory symptoms was observed in most cases.
Pathophysiological studies showed that respiratory involvement in
Yusho was mainly that of small airways disease and the disease state
was mildly improved in 1983. The effect of PCDF on 2 T-cell subsets
and the response to nonspecific mitogen-PHA (phytohemagglutinin) was
studied in Japanese Yusho patients 14 yr after onset. High OKT 4/8
ratio (helper/suppressor T-cell ratio) and lowered responsiveness to
PHA were seen. A low OKT 4/8 ratio was reported and enhanced
responsiveness to PHA in Chinese PCB poisoning patients 3 yr after
onset. Lung tissue and immune status, animal experiments were done.
Male rats of the SD strain were given 0.25 mg of PCDF 6 times within
2 wk by gastric intubation. Severe necrotic changes of the
bronchiolar Clara cells and mild pulmonary edema and vascular
congestion were seen. The thymus of rats which were given PCDF
decreased in size and thymic microscopic features showed severe
atrophy. Female mice of the CH3 strain were given 5 .mu.g of PCDF by
i.p. injection. Analysis of T-cell subsets of mice blood 4 wk after
injection 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. A
statistically significant hyperfunction of white blood cells
(predominantly neutrophils) in mice was observed by the measurement
of chemiluminescence, when compared with those in control mice. PCDF
leads to severe toxicity to bronchiolar Clara cells and thymus, as
compared with that of PCB. Helper T-cells are also selectively
damaged in the acute phase of the PCDF poisoning as shown in Chinese
patients. In PCDF poisoning the T-cell function is suppressed, while
function of neutrophils is activated. It is not clear, whether these
changes are direct effects or indirect ones of PCDF, but it may be
that these abnormalities correlate with chronic bronchitis-like
symptoms in Yusho patients.
AN 80109524 8500.
AU YOSHIMURA-H, KAMIMURA-H, OGURI-K, SAEKI-S.
TI STIMULATING EFFECT OF SQUALANE ON FECAL EXCRETION OF A HIGH TOXIC 2 3
4 7 8 PENTACHLORODIBENZOFURAN IN RATS.
SO FUKUOKA-ACTA-MED 76 (5). 1985. 184-189.
IN DEP HYG FORENSIC CHEM, FAC PHARMACUETICAL SCI, KYUSHU UNIV, FUKUOKA
AB 2,3,4,7,8-Pentachlorodibenzofuran (PenCDF) is regarded as the most
important etiologic agent for Yusho among various PCB
(polychlorobiphenyls) and PCDF (polychlorodibenzofuran) congeners
found in the causal rice oil, because this Pen-CDF possesses a strong
and long-lasting induction ability of 3-methylcholanthrene-type in
the rat liver and revealed a high toxicity. The present study has
been undertaken to learn whether or not squalane (2,6,10,15,19,23-
hexamethyltetracosan) could stimulate fecal excretion and decrease
toxicity of PenCDF. Squalane did not show any significant effect on
food consumption and growth of rats during the treatment for 21 days.
However, both enlargement of liver and atrophy of thymus caused by
PenCDF were suppressed by squalane treatment. Moreover, fecal
excretion of PenCDF was stimulated about 3-fold, and the content of
PenCDF in the liver showed a tendency to decrease by squalane-
AN 80072982 8500.
AU HSIA-M-T-S, KREAMER-B-L.
TI DELAYED WASTING SYNDROME AND ALTERATIONS OF LIVER GLUCONEOGENIC
ENZYMES 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, 237
RUSSELL LABORATORIES, UNIVERSITY OF WISCONSIN, MADISON, WIS 53706,
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) and
3,3',4,4'-tetrachloroazobenzene (TCAB). After a slow growth period,
all treatment animals (25 mg/kg, i.p., 2 doses/wk) exhibited a
starvation-like syndrome characterized by reduced food intake,
dramatic loss of body weight and subsequent death. Although the
growth of all major organs in the treatment animals was affected, the
thymus appeared severely atrophied. The growth kinetics during the
earlier phase were further analyzed using serially-killed rats
receiving TCAOB. In addition, TCAOB was found to markedly depress the
specific activity (.mu.mol/min/g wet liver) of glucose-6-phosphatase,
fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase and
pyruvate kinase in the liver. Significant changes in the levels of
cytochrome P-450, glutamic-pyruvic transaminase and malic enzyme in
the liver were also observed.
AN 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 ON
SO TOXICOL-APPL-PHARMACOL 79 (1). 1985. 112-120.
IN DEP OF CELL BIOLOGY, CHEMICAL INDUSTRY INSTITUT EOF TOXICOLOGY, PO
BOX 12137, RESEARCH TRIANGLE PARK, NC 27709.
AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets
within the immune system to produce a characteristic profile of
pathologic responses typified by thymic atrophy, suppressed cellular
immunity and inhibition of antibody production to T-lymphocyte-
dependent antigens. Studies in inbred mice differing in sensitivity
to TCDD indicate that TCDD-induced thymic atrophy was mediated by a
receptor protein (designated the Ah receptor). To study the cellular
and molecular basis for TCDD-induced thymic atrophy, primary cultures
of thymic epithelial (TE) cells were established from C57BL/6 mice, a
strain sensitive to TCDD. Treatment of TE monolayers with TCDD
(0.1-10 nM) resulted in the altered maturation of cocultured
syngeneic thymocytes as judged by suppression (40% of control at 10 n
M TCDD) of TE-dependent responsiveness of thymocytes to the mitogens
concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced
the mitogen responsiveness of thymocytes 3- to 4-fold; the enhanced
mitogen response mediated by the TE-conditioned medium was not
suppressed 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 maturation
of thymocytes was concentration dependent (EC50 .apprx. 1 nM) and
stereospecific, suggesting involvement of the Ah receptor. The Ah
receptor in cytosol fractions from cultured TE cells was measured
directly 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 the
thymus. One consequence of this action appeared to be the altered
thymus-dependent maturation of T-lymphocyte precursors, mediated
through direct cell-cell contact between thymocytes and TE cells.
Abstrakt from BIOSIS Jul 97.
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