ArticlePDF Available

Abstract

Persistent organic pollutants can be traced in air, water, soil and biota in industrialized and non industrialized regions. Although the production of these chemicals has been banned since 1980's when their toxicity was proven, their use, trade and disposal as well as persistence due to previous use, continues to contaminate the environment and threaten human health. Recent studies on the immunological consequences of dioxin contamination and exposure indicate that these compounds and specifically 2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin activates the aryl hydrocarbon receptor on lymphocytes. This activation results in an array of effects on T, B and APC cells, biological mediators of the immune response and thereby results in suppression or remodelling of the immune response. This review attempts to shed light on the recent research developments in this field and to provide insight into the vast and long term health consequences of persistent organic pollutants.
Iranian J Env Health Sci Eng, 2004, Vol.1, No.2, pp.1-7
1
Review Paper
Effects of Persistent Organic Pollutants on the Immune System:
The Case of Dioxins
*MEbtekar
Dept. of Immunology, School of Medical Sciences, Tarbiat Modarres University, Iran
ABSTRACT
Persistent organic pollutants can be traced in air, water, soil and biota in industrialized and non industrialized
regions. Although the production of these chemicals has been banned since 1980's when their toxicity was
proven, their use, trade and disposal as well as persistence due to previous use, continues to contaminate the
environment and threaten human health. Recent studies on the immunological consequences of dioxin
contamination and exposure indicate that these compounds and specifically 2, 3, 7, 8-
Tetrachlorodibenzo-p-dioxin activates the aryl hydrocarbon receptor on lymphocytes. This activation results in
an array of effects on T, B and APC cells, biological mediators of the immune response and thereby results in
suppression or remodelling of the immune response. This review attempts to shed light on the recent research
developments in this field and to provide insight into the vast and long term health consequences of persistent
organic pollutants.
Keywords: Persistent organic pollutants,Dioxins,Immune response, Aryl hydrocarbon receptor, Pollution
INTRODUCTION
The production of thousands of chemicals has
contributed to industrial and economic develop-
ment in many parts of the world. This trend how-
ever has been associated with the release of new
chemicals and possibly toxic substances into the
environment and food chain and adversely ef-
fecting human health in many instances. Nota-
bly, the increased incidence of asthma in urban
and industrial areas has been attributed to air-
borne chemicals and pollutants (Ebtekar and
Moien, 2001). Polycyclic aromatic hydrocar-
bons have been shown to affect immune com-
petence in several studies (Laupeze et al., 2002).
*Correspondence: E-mail: head1-2000-2000@yahoo.com,
Tel: +98 21 88903724, Fax: +98 21 88908196
Among these chemicals some were later recog-
nized to remain intact and active for very long
periods of time in the environment and thus
easily transported to other regions. Termed Per-
sistent Organic Pollutants (POPs), were known
to adversely affect human health and biodiver-
sity. According to current statistics from 1929 to
1989, 1.5 million tons of POPs were produced
globally. Industrial activity, ferrous and nonfer-
rous metal facilities and foundries emit Poly-
chlorinated Biphenyls (PCBs) which are one of
the most important types of POPs. Chlorinated
pesticides are also less biodegradable and pose
serious health and environmental risks. Poly-
chlorinated biphenyls are compounds with 2-6
carbon rings in which 1-6 hydrogens are re-
placed by chlorine. To date 150 types of PCBs
have been recognized. Dioxins are an important
Iranian J Env Health Sci Eng, 2004, Vol.1, No.2, pp.1-7
MEbtekar: Effects of Persistent…
2
category known to have direct immune system
effects.
POPs may enter the host through the food cycle
or inhaled air; they pass mucosal barriers and
interact with the immune system. The toxicity of
PCBs was recognized in 1980, and it became
clear that PCBs accumulate in the food chain
particularly in aquatic food. Trace amounts of
dioxins can be measured in the peripheral blood
of most residents in industrialized and urban
areas, while 50 years ago it was not traceable.
Realizing the serious health risks and particu-
larly the persistence of these compounds, the
global community took action to develop a legal
international treaty to prevent the production,
use and trade and proper management of these
substances. This international campaign led to
the creation of the Stockholm Convention on
Persistent Organic Pollutants in 2000. The Is-
lamic Republic of Iran has signed the treaty and
the final stages of ratification are followed in the
Parliament.
The Iranian Department of Environment has
recently initiated an international project with
the Convention for enabling the country to fulfil
its commitments to the Convention. The Con-
vention has entered into force recently and
therefore there is much hope to create better
environmental conditions with regard to POPs
(Ebtekar, 2000).
Among the environmental factors linked to the
development of autoimmunity are heavy metals
such as mercury, chlorinated pesticides contain-
ing chlordecone methoxychlore, crystalline sil-
ica dust and solvents such as trichloroethylene.
Mice exposed to occupationally relevant doses
of the contaminant trichloroethylene in their
drinking water developed lupus like syndromes
and autoimmune hepatitis in association with the
activation of IFN-gamma producing CD4+T
cells. Studies on one of its major metabolites
trichloroacetaledhyde (TCAA) also shows that
TCAA promotes T cell activation via stimula-
tion of the mitogen activated protein kinase
pathway in association with Schiff base forma-
tion on T cell surface proteins. By demonstrating
that TCAA can stimulate T cell function directly
these results may explain how the environment
toxicant promotes T cell activation and related
autoimmunity in vivo (Gilbert et al., 2004).
Molecular mechanisms of dioxins Dioxins as
aclass of POPs that can be found in both
contaminated air and water are relatively diffi-
cult to detect (Shimomura et al., 2001) and in-
teract specifically with the immune system.
Studies indicate that dioxin acts specifically on
cells by ligand activated induction of transcrip-
tion through the cyotosolic Aryl Hydrocarbon
Receptor (AHR). The Ah receptor exists on cells
including lymphocytes, in the thymus, lung and
liver. Further studies have elucidated the
molecular mechanisms after binding of dioxins
with AHR. This complex faces conformational
changes and translocates to the nucleus to bind
to specific regulatory sequences and induce
transcription through NF-kb (Baccarelli et al.,
2002; Smialowicz, 2002).
2, 3, 7, 8 tetrachlorodibenzo-p dioxin (TCDD)
has been recognized to be a potent antagonist of
the aryl hydrocarbon receptor (AHR).
Activation of the aryl hydrocarbon receptor
(AHR), a basic helix-loop-helix transcription
factor in lymphocytes by TCDD has been shown
to cause thymic atrophy in every species studied.
Studies indicated that AHR was only activated
in thymocytes to cause thymic atrophy.
Therefore, intrathymic progenitor cells are
direct targets of TCDD in the thymus and TCDD
cause thymic atrophy by reducing entrance to
the cell cycle in these populations (Laiosa et al.,
2003).
Moreover, dioxins have been demonstrated to
induce a 40% increase in double positive cells in
murine fetal thymus cells and over expression of
CD44 and MHC class I on thymocytes. A higher
rate of positive selection has also been reported
due to the effect of dioxins. This event could
increase the incidence of autoimmunity in the
host (Kerkvliet et al., 2002). The influence of
TCDD on haematopoietic stem cells which pos-
sess the ability to reconstitute long term multi-
lineage haematopoiesis was studied in another
Iranian J Env Health Sci Eng, 2004, Vol.1, No.2, pp.1-7
3
work. This work indicated that TCDD treated
stem cells almost lost long term reconstitution
activity (Sakai et al., 2003). Rats exposed to
TCDD developed signs of immunosuppression,
with reduced thymus weight, suppressed T cell
responses and reduced NK as well as Ab specific
responses (Smialowicz, 2002).
Effects on T cells and cytokine production
Tcells upon activation undergo apoptosis, a
process termed activation induced cell death
(AICD). Research indicates that the immu-
notoxic effects of TCDD in activated peripheral
Tcells may stem from increased AICD medi-
ated through Fas-Fas ligand interactions
(Camacho et al., 2001). One study has shown
that TCDD induces Fas-dependent activation
induced cell death in superantigen- primed T
cells (Camacho et al., 2002). In other studies it
was shown that TCDD induced suppression of
CD4+ T cells involves, in part increased cell
death that may be mediated by Fas/FasL
interaction (Dearstyne and Kerkevliet, 2002) .
Exposure to TCDD clearly impairs T cell de-
pendent immune responses. (Shepard et al.,
2000). In a recent study on T cell receptor trans-
genic mice it was shown that TCDD suppressed
the antibody response while in wild type mice
only the expansion and differentiation of CD8+
cells was suppressed (Mitchell and Lawrence,
2003A). Also TCDD can induce the Il-2 gene
through the AhR (Vorderstrasse and Kerkvliet,
2001). Other studies showed that the murine Il-2
promoter contains distal regulatory elements
responsive to the AhR receptor, these motifs
after binding to the AhR are sufficient to trans-
activate luciferase expression (Jeon and Esser,
2000).
In one study the effect of TCDD on T cell de-
rived cytokine production in mice was observed.
TCDD caused an initial increase in IL-2 but this
increase was suppressed by day 4, also the pro-
duction of Th2 cell derived cytokines IL-4, IL-5
and IL-6 were significantly suppressed as com-
pared with control mice (Ito et al, 2002, Fuji-
maki et al., 2002). Therefore impaired suppres-
sion of antigen specific antibody production
following exposure may be related to the im-
paired cytokine response. (Ito et al, 2002;
Nohara et al., 2002)
Effects on B cells and humoral immunity
Research also has demonstated that TCDD alters
Bcell differentiation as evidenced by a marked
decrease in IgM secretion and the number of
antibody forming cells. Findings also suggest
that cyclin dependent kinase inhibitors may be
an important intracellular target in TCDD medi-
ated inhibition of B-cell differentiation. Other
studies demonstrate that TCDD exposure inhib-
its the generation of high affinity antibody
forming cells and high affinity antibody produc-
tion during the primary humoral immune re-
sponse and suggest that these alterations were
caused by the suppression of antigen responding
B-cell proliferation induced by TCDD during
GC formation (Inouye et al., 2003).
TCDD also directly effects spontaneous IgE
production in B cells from atopic patients.
TCDD failed to induce other immunoglobulin
types and in non atopic patients TCDD could not
induce increased IgE production. These results
suggest that TCDD may aggravate allergic dis-
eases by enhancing IgE mediated allergic re-
sponses (Kimata, 2003). Nuclear factor kappa-
beta and AP-1 both play an important role in
B-cell activation, differentiation and immu-
noglobulin gene expression. Studies show that
LPS induced DNA binding and transcriptional
activity of AP-1 was markedly inhibited by
TCDD, however the chemical had no effect on
the activity of NK-kb. This study indicates that
The TCDD induced inhibition of IgM expres-
sion by B cells may be mediated at least in part
through a down regulation of AP-1 activity in an
Ah-R dependent manner (Sulentic et al., 2000;
Suh et al., 2002). According to one study TCDD
exposure suppressed rather than enhanced the
development of allergic immune responses as
well as the expression of immune mediated lung
disease (Luebke et al., 2001).
Effects on APCs TCDD has been demonstrated
to induce activation changes in splenic dendritic
cells in the absence of antigen challenge. It
MEbtekar: Effects of Persistent…
4
however did not affect the ability of splenic
dendritic cells to internalize latex beads
administered in vivo. This study concludes that
TCDD does not suppress the ability of DC to
process and present antigen but may enhance
their ability to provide activation signals to T
cells.This might alter the survival of the T cells,
the DC or both and may contribute to the dys-
regulation of the immune response (Vorder-
strasse et al., 2003). TCDD has also been shown
to affect the number and function of murine
splenic dendritic cells and their expression of
accessory molecules. These effects were dose
dependant and persisted for two weeks after
exposure. DC from TCDD treated mice
Expressed higher levels of several accessory
molecules including ICAM-1, CD24, B7-2 and
CD40 while the expression of LFA-1 was sig-
nificantly reduced (Vorderstrasse and Kerkvliet,
2001).
Response to infection In mice treated with
TCDD and infected by influenza A virus, re-
searchers observed a significant increase in
mortality as compared with infected mice not
contaminated with TCDD. The study indicated
that decreased antibody production and hyper
inflammation may contribute to the increased
mortality of mice (Vorderstrasse et al., 2003).
Exposure to TCDD suppressed the clonal expan-
sion of influenza virus specific CD8+ T cells
resulting in a three to five fold reduction in the
number of cytotoxic T lymphocytes (CTL) in
the lymph node as compared to control mice.
Studies to identify possible mechanisms for the
diminished CTL response failed to show evi-
dence for increased apoptosis in virus specific
CD8+ T cells from TCDD exposed mice. In this
study however treatment with TCDD reduced
the number of proliferating virus specific CD8+
Tcells by as much as 70% on day 7 post infec-
tion. Restimulation could not completely restore
proliferation or IFN gamma production by
CD8+ cells suggesting that exposure to TCDD
drives antigen specific CD8+ cells into a state of
unresponsiveness similar to anergy (Mitchell
and Lawrence, 2003B).
Other studies indicate that TCDD increased IFN
gamma and TNF alpha gene expression thereby
enhancing the production of proinflammatory
cytokines. (Ho-Jun et al., 2002).
In one research mice exposed to TCDD and
infected with influenza virus did not have an
increased pulmonary virus burden suggesting
either that TCDD treatment alters the host re-
sponse to infection, creating a cellular environ-
ment that is less supportive for viral growth, or
that exposure to TCDD directly affects influenza
virus leading to impaired virus replication
within lung epithelial cells (Lawrence et al.,
2000).
In another study on lactational exposure to
TCDD in Listeria infection in newborn mice, the
exposure had little effect on the weight of im-
mune organs but it enhanced the production of
tumor necrosis factor alpha (TNF-alpha) and
interferon gamma in the serum after Listeria
infection.The clearance of Listeria monocyto-
genes from the spleen was impaired in the new-
born (Sugita-Konishi et al., 2003).
The effect of TCDD on myocarditic cox-
sackievirus B3 infection in mice was studied
focusing on inflammatory lesion and mortality.
TCDD seemed to have limiting effect on viral
replication and the development of the inflame-
matory lesion in the myocardium; however
mortality was increased by TCDD in this infec-
tion model (Funseth et al., 2002).
Response to allogenic tumours Studies per-
formed on mice challenged with P815 tumour
cells and exposed to TCDD indicated an in-
creased percentage of CD11b+ Mac-1 + (Gr1 +)
cells in the spleens of these mice. These
CD11b+ Gr-1 + myeloid suppressor cells MSC
have been described as that which prevents
cytotoxic T lymphocyte (CTL) development in a
variety of disease states. This study also shows
that TCDD exposure alters the host response to
allogeneic tumour graft resulting in enhanced
myelopoiesis perhaps as a compensatory re-
sponse to the suppressed T cell mediated im-
mune response in the face of an increasing P815
tumour burden.
Iranian J Env Health Sci Eng, 2004, Vol.1, No.2, pp.1-7
5
Furthermore, within the context of the P815
response, TCCD appears to alter the functional
capabilities of mature neutrophils, by enhancing
their oxidative burst capacity but reducing the
tumouricidal response (Choi et al., 2003)
Studies on CTL precursors show that TCDD
induces an early defect in CTLp activation that
is not due to insufficient numbers or deletion of
CD8+ cells and may implicate a novel mecha-
nism by which ligands of the Ah R disrupt CTL
precursor activation (Prell et al., 2000).
Genetic studies Genetic studies have indicated
that dioxins may induce certain genes including
oncogenes, cytochrome p450, plasmino- gen
activator inhibitor 2, Il-1beta and certain
cytokines. PCBs have been known to induce
genes which affect cell decisions on prolifera-
tion and differentiation therefore possibly
disrupting cell funtions and homeostasis in a
broader sense. Expression of NF-kb, c-jun and
p27 (kip1) genes was increased by TCDD treat-
ment according to one study (Crawford et al.,
2003). In addition, some genes like insulin like
growth factor binding protein-6 and IL-5R alpha
subunit genes were upregulated while the other
genes like CD14 were down regulated (Park et
al., 2001).
Human studies The residents of Seveso Italy
were exposed in 1976, due to an accident to high
levels of TCDD. Recent studies on the immu-
noglobulin and complement plasma levels in a
random sample of the most highly exposed and
in the surrounding contaminated area showed
that plasma IgG levels decreased with increasing
TCDD plasma concentration. Also the increased
incidence of lymphatic tumours in the area of the
accident requires more investigation (Baccarelli
et al., 2002).
Recent advances and future prospects Many
studies have been conducted to elucidate the
underlying biochemical mechanisms by which
dioxins disrupt immunological functions and
much research has been done focussing on the
effects of TCDDi . Some studies point to a new
paradigm for the mechanism of suppression of
immune functions by TCDD emphasising on
inappropriate activation of cells, leading to an-
ergy or death and the consequent premature
termination of the immune response. This para-
digm has also been characterized by enhanced
activation of B cells, DC and CD4+ T cells by
TCDD and earlier disappearance of the two lat-
ter populations from the peripheral lymphoid
organs (Kerkvliet, 2002). The exact mechanism
involved and the signalling pathways need to be
studied and identified. Considering the contin-
ued use of many chemicals including persistent
organic pollutants in most parts of the world and
also the increased risks of contamination, stud-
ies to understand and identify the possible risks
and effects on human health should continue.
The long term consequences and serious adverse
effects of these chemicals point to the impor-
tance of environmental regulation and monitor-
ing to control their use and release into the
environment at local as well as international
levels.
REFERENCES
Baccarelli A, Mocarelli P, Patterson D G,
Bonzini M, Pesatori A C, Caporaso N, Landi
MT (2002). Immunologic effects of dioxin:
new results from Seveso and comparison
with other studies. Environ Health Perspect,
110: 1169-73.
Camacho I A, Hassuneh M R, Nagarkatti M, Na-
garkatti P S (2001). Enhanced activationin-
duced cell death as a mechanism of 2, 3, 7,
8-tetrachlorodibenzo-p-dioxin) (TCDD) - in-
duced immunotoxicity in peripheral T cells.
Toxicology,165: 51-63.
Camacho I A, Nagarkatti M, Nagarkatti Ps
(2002). 2, 3, 7, 8- Tetrachlorodibenze-p- di-
oxin (TCDD) induces Fas-dependent ac-
tivation-induced cell death in super antigen-
primed T cells. Arch Toxicol,76: 570-80.
Choi J Y, Oughton J A, Kerkvliet N I (2003).
Functional alterations in CD11b (+) Gr-1(+)
cells in mice injected with allogeneic tumor
cells and treated with 2, 3, 7, 8- Tetra-
MEbtekar: Effects of Persistent…
6
chlorodibenzo-p-dioxin. Int Immunopharma-
col,3: 553-70.
Crawford R B, Sulentic C E, Yoo B S, Kaminski
N E (2003). 2, 3, 7, 8-Tetrachlorodibenzo-
p-dioxin (TCDD) alters the regulation and
posttranslational modification of p27kip1 in
lipopolysaccharide-activated B cells. Toxicol
Sci,75: 333-42.
Dearstyne E A, Kerkvliet N I (2002). Mechanism
of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin
(TCDD)-induced decrease in a CD3- acti-
vated CD3-activated CD4 (+) T cells: the
roles of apoptosis, Fas, and TNF. Toxicology,
170: 139-51.
Ebtekar M, (2000). Environmental Hazards and
the Immune System:”The Case of POPs “,
Proceedings of the 5th Iranian Congress of
Immunology and Allergy, 125.
Ebtekar M, Moien M (2001). Role of Air
Pollutants in Asthma, In: Asthma, Basic and
Clinical Studies,Tehran University Publica-
tions, Tehran, p.106.
Fujimaki H, Nohara K, Kobayashi T, Suzuki K,
Eguchi-Kasai K, Tsukumo S, Kijima M, To-
hyama C (2002). Effect of a single oral dose
of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin on
immune function in male NC/Nga mice.
Toxicol Sci,66: 117-24.
Funseth E, Wesslén L, Lindh U, Friman G, Il-
bäck N G (2002). Effect of 2, 3, 7, 8- Tetra-
chlorodibenzo-p-dioxin on trace elements,
inflammation a viral clearance in the myocar-
dium during coxsackievirus B3 infection in
mice. Sci Total Environ,284: 135-47.
Gilbert K M, Whitlow A B, Bumford N R
(2004). Environmental contaminant and
disinfection by-producut
trichbroacetaldehyle stimulates T cells in
vitro. Int Immunopharm,4: 25-36.
Ho-Jun K, Kang B N, Cho S W, Son H Y, Jeong
KS, Park S J, Kim S H, Kim S R, Kim T H,
My, Ryu S Y (2002). Effects of benzo [a]
pyrene, 2-bromopropane, phenol and 2, 3, 7,
8- Tetrachlorodibenzo-p-dioxin on proinflam-
matory cytokines gene exression by mice
spleen cells. JVet Sci,3: 247-54.
Inouye K, Ito T, Fujimaki H, Takashashi Y,
Takemori T, Pan X, Tohyama C, Nohara K
(2003). Suppressive effects of 2, 3, 7, 8-
Tetrachlorodibenzo-p-dioxin (TCDD) on the
high-affinity antibody response in C57BL/6
mice. Toxicol Sci,74: 315-24.
Ito T, Inouye K, Fujimaki H, Tohyama C, No-
hara K (2002). Mechanism of TCDD-induced
suppression of antibody production: effect on
Tcell derived cytokine production in the pri-
mary immune reaction of mice. Toxicol Sci,
70: 46-54.
Jeon M S, Esser C (2000).The murine Il-2 pro-
moter contains distal regulatory elements re-
sponsive to the Anr receptor, a member of the
evolutionarily conserved bHLH-PAS
transcription factor family. JImmunol,165:
6975-83.
Kerkvliet N I (2002). Recent advances in
understanding the mechanisms of TCDD
immunotoxicity. Intl Immunopharmacol,2:
277-91.
Kerkvliet N I, Shepherd D M, Baecher-Steppan
L(2002). T Lymphocytes are direct, aryl
hydrocarbon receptor (AhR)-dependent tar-
gets of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin
(TCDD): AhR-expression in both CD4+and
CD8+Tcells is necessary for full suppression
of a cytotoxic T Iymphocyte response by
TCDD. Toxicol Appl Pharmacol,185:
146-52.
Kimata H (2003). 2, 3, 7, 8-Tetrachlorodibenzo-
p-dioxin selectively enhances spontaneous
IgE production in B cells from atopic patients.
Int J Hyg Environ Health,206: 601-4.
Laiosa M D, Wyman A, Murante F G, Fiore N C,
Staples J E, Gasiewicz TA, Silverstone A E
(2003). Cell proliferation arrest within intra-
thymic Lymphocyte progenitor cells causes
thymic atrophy mediated by the aryl hydro-
carbon receptor. JImmunol,171: 4582- 91.
Laupeze B, Amiot L, Sparfel L, Le Ferrec E,
Fauchet R, Fardel O (2002). Polycyclic aro-
matic hydrocarbons affect functional differ-
entiation and maturation of human mono-
cyte-derived dendritic cells. J Immunol,168:
2652-58.
Iranian J Env Health Sci Eng, 2004, Vol.1, No.2, pp.1-7
7
Lawrence B P, Warren T K, Luong H (2000).
Fewer T Lymphocytes and decreased pulmo-
nary influenza virus burden in mice exposed
to 2, 3, 7, 8- Tetrachlorodibenzo- p-dioxin
(TCDD). JToxicol Environ Health A,61:
39-53.
Luebke R W, Copeland C B, Daniels M,
Lambert A L, Gilmour M I (2001).
Suppression of allergic immune responses to
house dust mite (HDM) in rats exposed to 2,
3, 7, 8-TCDD. Toxicol Sci,62: 71-9.
Mitchell K A, Lawrence B P (2003 A). T cell
receptor transgenic mice provide novel in-
sights into understanding cellular targets of
TCDD: suppression of antibody production,
but not the response of CD8+Tcells, during
infection with influenza virus. Toxicol Appl
Pharmacol, 192: 275-86.
Mitchell K A, Lawrence BP (2003 B). Exposure
to 2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin
(TCDD) renders influenza virus-specific
CD8+T cells hyporesponsive to antigen.
Toxicol Sci,74: 74-84.
Nohara K, Fujimaki H, Tsukumo S, Inouye K,
Sone H, Tohyama C (2002). Effects of 2, 3, 7,
8-tetrachlorodibenzo-p-dixoin (TCDD) on T
cell-derived cytokine production in Ovalbu-
min (OVA)-immunized C57BI/6 mice. Toxi-
cology,172: 49-58.
Park J H, Lee Sw, Kim I T, Shin B S, Cheong S
W, Cho U H, Huh M J, Oh GS (2001).
TCDD- up-regulation of IGFBP-6 and IL-5R
alpha subunit genes in vivo and in vitro. Mol
Cells,12: 372-9.
Prell R A, Dearstyne E, Steppan L G, Vella A T,
Kerkvliet N I (2000).CTL hyporesponsive-
ness induced by 2,3,7,8-Tetrachlorodibenzo-
p-dioxin: role of cytokines and apoptosis.
Toxicol Appl Pharmacol,166: 214-21.
Sakai R, Kajiume T, Inoue H, Kanno R, Miya-
zaki M, Ninomiya Y,Kanno M (2003).
TCDD treatment eliminates the long-term
reconstitution activity of hematopoietic stem
cells. Toxicol Sci,72: 84-91.
Shepherd D M, Dearstyne E A, Kerkvliet N I
(2000). The effects of TCDD on the activa-
tion of ovalbumin (OVA)-specific DO11.10
transgenic CD4 (+) T cells in adoptively
transferred mice. Toxicol Sci,56: 340-50.
Shimomura M, Nomura Y, Lee K H, Ikebukuro
K, Karube I (2001). Dixoin detection based
on immunoassay using a polyclonal antibody
against octa chlorinated dibenzo-p-dioxin
(OCDD). Analyst,126: 1207-9.
Smialowicz R J (2002). The rat as a model in
developmental immunotoxicology. Hum Exp
Toxicol,21: 513-9.
Suh J, Jeon Y J, Kim H M, Kang J S, Kaminski
NE, Yang K H (2002). Aryl hydrocarbon
receptor-dependent inhibition of AP-1
activity by 2, 3, 7,
8-tetrachlorodibenzo-p-dioxin in activated B
cells. Toxicol Appl Pharmacol,181: 116-23.
Sugita-Konishi Y, Kobayashi K, Naito H, Miura
K, Suzuki Y (2003). Effect of lactational
exposure to 2, 3, 7, 8-Tetrachlorodibenzo-
p-dioxin on the susceptibility to Listeria
infection. Biosci Biotechnol Biochem,67:
89-93.
Sulentic C E, Holsapple M P, Kaminski N E
(2000). Putative link between transcriptional
regulation of IgM - expression by 2, 3, 7,
8-tetrachlorodibenzo-p-dioxin and the aryl
hydrocarbon receptor/dioxin-responsive en-
hancer signaling pathway. JPharmacol Exp
Ther,295: 705-16.
Vorderstrasse B A, Kerkvliet N I (2001). 2, 3, 7,
8-Tetrachlorodibenzo-p-dioxin affects the
number and function of murine splenic den-
dritic cells and their expression of accessory
molecules. Toxicol Appl Pharmacol,171:
117-25.
Vordenstrasse B A, Dearstyne E A, Kerkvliet N
I(2003). Influence of 2, 3, 7, 8-Tetra-
chlorodibenzo-p-dioxin on the antigen-
presenting activity of dendritic cells. Toxicol
Sci,72: 103-12.
Vorderstrasse B A, Bohn A A, Lawrence B P
(2003). Examining the relationship between
impaired host resistance and altered immune
function in mice treated with TCDD.
Toxicology,188: 15-28.
... Although major air pollution abatement plans are successfully underway, its air pollution problem will persist for several years before up to standard ambient air quality is achieved. 2 Cardiovascular and respiratory diseases, asthma and allergy, immunological disorders, and cancer are among the complications listed in current scientific literature related to air pollution. Respiratory illness alone account for hundreds of million person days of restricted activity and lost work each year. ...
... Airborne pollutants may enter the respiratory tract as 1) volatile gases: such as, carbon monoxide, ozone, and benzene 2) liquid droplets: sulfuric acid, oxides of nitrogen 3) particulate matter: components of diesel exhaust and poly aromatic hydrocarbons. 2,3 ...
Article
Full-text available
In recent decades, clinicians and scientists have witnessed a significant increase in the prevalence of allergic rhinitis and asthma. The factors underlying this phenomenon are clearly complex; however, this rapid increase in the burden of atopic disease has occurred in parallel with rapid industrialization and urbanization in many parts of the world. Consequently, more people are exposed to air pollutants than at any point in human history. Worldwide increases in allergic respiratory disease have mainly been observed in urban communities. Epidemiologic and clinical investigations have suggested a strong link between particulate air pollution and detrimental health effects, including cardiopulmonary morbidity and mortality. The purpose of this review is to provide an evidence-based summary of the effects of air pollutants on asthma, focusing on particulate matter PMs, diesel exhaust particles (DEPs), and ozone as major air pollutants. An overview of observational and experimental studies linking these pollutants with asthma will be provided, followed by consideration of the mechanisms underlying pollutant induced immune response and inflammation. The cytokine response will be viewed in depth and a brief discussion of future research and clinical directions is provided.
... [8]. POPs are considered to be one of the factors associated with the development of autoimmune reactions by modulating the immune response, activating T-helper cells (CD4 + ) and suppressing cytotoxic cells (CD8 + ) [9,10]. ...
Article
Full-text available
The human body in adverse living conditions, such as in the Arctic, goes through the risk of impairing functional systems including the immune system. These disturbances lead to appear states of weakness or hyperactivity of the organism protective function. This study investigates the state of the adaptive immune response of 40-60-year-old women living in the Russian Arctic and South Ossetia. The indirect immunoperoxidase assay with monoclonal antibodies was used to analyze the immune parameters of lymphoid subpopulations in 40-60-year-old women living in Nadym city in the Yamalo-Nenets Autonomous Okrug and in Tskhinval city in South Ossetia. After analyzing the received data, the deficiency of mature T-lymphocytes (CD3 ⁺ ) was found in 96-100% of the examined individuals. We also revealed a decrease in the concentration of T-helper (CD4 ⁺ ) and B-activated (HLA-DR ⁺ ) cells in 30% of Arctic zone cases and in 50% of the southern zone cases on the background of increasing concentrations of cytotoxic T-lymphocytes. A deficiency of cells with apoptosis receptors (CD95 ⁺ ) was registered mainly in Tskhinval women (80%). Thus, it can be assumed that the deficiency of mature lymphoid cells with a receptor (CD3 ⁺ ) leads to disruption of the T-cell pool of the immune response and delay of the adaptive immune response overall. The increase in the cytotoxic T-lymphocyte count indicates the stress state of the adaptive immune component to compensate for the lack of T-helper and B-activated cells concentration. Additional comprehensive studies are needed to identify environmental factors having a significant impact on the mechanism of the adaptive immune response development.
... It is known that SCC increases significantly with the use of toxic feed [65,90,91,[95][96][97]. Most likely, this is due to the negative effect of toxic components of feed on the immune system of animals, whose function can be suppressed both by representatives of mycotoxins [66,[82][83][84][100][101][102] and PAHs and POPs [103][104][105][106]. It is also known that many mycotoxins in vitro exhibit cytotoxic and cytostatic properties. ...
Article
Full-text available
The steady growth of inflammatory diseases of the udder in dairy cattle forces us to look for the causes of this phenomenon in the context of growing chemical pollution of the environment and feeds. Within the framework of this concept, an analysis was made of the polarity level of the three toxic impurity groups, which are commonly present in dairy cattle feeds. These impurities are presented by mycotoxins, polyaromatic hydrocarbons (PAH) and persistent organic pollutants (POP). It has been determined that 46% of studied mycotoxins (n = 1500) and 100% of studied polyaromatic hydrocarbons (n = 45) and persistent organic pollutants (n = 55) are lipophilic compounds, prone to bioaccumulation. A comparative evaluation of the sorption capacity of four adsorbents of a different nature and polarity with respect to the simplest PAH, naphthalene and lipophilic estrogenic mycotoxin, zearalenone in vitro has been carried out. The highest efficiency in these experiments was demonstrated by the reversed-phase polyoctylated polysilicate hydrogel (POPSH). The use of POPSH in a herd of lactating cows significantly reduced the transfer of aldrin, dieldrin and heptachlor, typical POPs from the “dirty dozen”, to the milk. The relevance of protecting the main functional systems of animals from the damaging effects of lipophilic toxins from feeds using non-polar adsorbents, and the concept of evaluating the effectiveness of various feed adsorbents for dairy cattle by their influence on the somatic cell count in the collected milk are discussed.
... In addition to these industrial pollutions infiltration of pollutions from air, sewage and surface water in metropolises led to accumulation of hazardous contaminating materials in soil ( Herva et al ., 2014) which enter the food cycle and cause serious risks for health (Ebtekar, 2004) (Table 3). ...
Article
Full-text available
Environmental protection is a key element in urban management. In metropolises due to complex relationships between human and environment the importance of environment is ever-increasing. In this paper The current situation of environment in Tehran metropolis including air, water, biodiversity and human habitat along with the most crucial threats, their effect as well as the associated agencies and organizations have been investigated, using the indicators of OECD (Organization for Economic Co-operation and Development), UNEP (United Nation Environmental Program) and GFF (Global Environmental Fund). The current management of Tehran environment is studied based on a conceptual model and using SWOT analysis. Then, an ideal urban environmental management model is proposed for Tehran, with regard to the higher order legal documents of national and international levels and the global models such as: UN Habitat Program, Sustainable Cities Program, Policy and Regulatory Framework for Sustainable Cities Program, Healthy Cities Program, Agenda 21, Strategies of the Environmental European commission and a Good Governance Model, as well as the results of the SWOT analysis. In this model, the authorities in charge of urban management and their responsibilities are determined and classified at three levels of policy-making, decision making and implementation. The target and the relationship between them are clarified.
... This trend however has been associated with the release of new chemicals and possibly toxic substances into the environment and food chain and adversely affecting human health in many instances. The pollutants associated with the anthropogenic activities could be inorganic as well organic compounds [1]. The air pollution is very complex dynamic phenomena. ...
Article
Full-text available
In recent years several techniques have been developed to measure and monitor the pollution of the air. Among these techniques, remote sensing using optical methods stands out due to several advantages for air quality control applications. A Passive Differential Optical Absorption Spectroscopy system that uses the ultraviolet region from 200 to 355 nm of the solar radiation is presented. The developed system is portable; therefore it is practical for real time and in situ measurements. The enhanced wavelength range of the system is intended to detect the ultraviolet light penetration in the Mexican Valley considering the solar zenith angle and the altitude. The system was applied to retrieve atmospheric SO2 columns emitted either by anthropogenic (power plant) or natural sources (volcano), reaching a detection limit of about 1 ppm. The measurement of the penetrating solar radiation on the earth surface at the UVC range is presented and the possibility to measure pollution traces of some contaminants as O3, NO2 and aromatic compounds in real time and in situ in the ultraviolet region is discussed.
... While generally their ambient concentrations in air and water are not considered to exert severe direct hazards via inhalation and ingestion, respectively, their hydrophobicity, combined with their resistance to degradation via mechanisms like photolysis, hydroxyl radical attack and biological action has resulted in global dispersion of PBDEs and subsequently biomagnification in terrestrial, freshwater, aquatic, and pelagic food chains. Whereas the legacy persistent organic pollutants (POPs) (e.g Dioxins) pose much sever toxic effects on human health (Ebtekar, 2004) than the PBDEs, their widely reported presence and rapidly rising levels in wildlife and human tissue (i.e. doubling concentration time of ~3-7 years) has raised concerns over PBDEs potential health effects (Meironyte et al., 1999, Hites, 2004). ...
Article
Full-text available
In order to characterize polybrominated diphenyl ether (PBDE) contamination in vehicle interiors, airborne concentrations of polybrominated diphenyl ethers were investigated using PUF disk passive air samplers in 25 private cars. Passive air samplers were fixed inside the selected cars for a period of 4 to 6 weeks. EPBDE concentrations (sum of the 10 congeners) ranged between 0.01 and 8.2 ng/m 3 with respective arithmetic and geometric mean concentrations of 0.71 and 0.091 ng/m 3 . High concentrations of polybrominated diphenyl ethers found in cars might provide an important source of human exposure to PBDEs either via inhalation or dust ingestion. A driver spending 8 hours a day inside a contaminated car (the worst scenario) would receive a daily inhalation intake of 54 ng. Age of the vehicles was found to be the most influential factor affecting polybrominated diphenyl ether emission in car interiors (R=0.47, r<0.01). Furthermore, significant variations were observed in polybrominated diphenyl ether concentrations between cars from same manufacturer with similar ages. The median ratio of BDE 47:99 for air samples was 1.7 comparing with the respective values of ~1 and ~0.7 reported for BK 70-5DE and DE-71, suggesting these commercial formulations to be likely sources of polybrominated diphenyl ethers in the car indoor environments.
Article
Objectives : The purpose of this study is to investigate the effect of concurrent administration of KKSDU and AJ on atopic dermatitis in an in-vivo experiment using an NC/Nga atopic dermatitis mouse, which has histological and clinical similarities to the condition in humans. Methods : We evaluated clinical skin score, hematology, serum total IgE and IgG1 of NC/Nga atopic dermatitis mouse and analyzed the cytoline level, total cell number, immunohistochemical staining, histological features of axillary lymph node(ALN), draining lymph node(DLN), peripheral blood mononuclear cells(PBMCs) and dorsal skin tissue in NC/Nga mouse. Results : Orally administration of KKSDU and concurrent administration of KKSDU and AJ decreased the clinical skin score, total cell number of WBC, platelet, neutrophils, eosinophils in blood, serum total IgE & IgG1, IL-5, IL-13. Also, total cell number of ALN and dorsal skin tissue, absolute cell number of CD3e+&CD19+, CD4+&CD8+, CD3+/CCR3+, CCR3+, CD3+/CD69+, CD3+/CXCR5+ in ALN, PBMCs, absolute cell number of CCR3+, CD3+/CD69+, CD11b+/Gr-1+ in dorsal skin tissue, Eotaxin2 mRNA, CCR3 mRNA in dorsal skin tissue and gene expression of IL-5 mRNA, IL-13 mRNA in ALN are significantly decreased. Furthermore, thickness of epidermis, infiltrated inflammatory immune cell & mast cell in dermis, histologic infiltration of mast cell, the size of inflammatory lymphocytes cells & plasma cells in ALN and histologic infiltration of CD4+ & CCR3+ in ALN and dorsal skin tissue are significantly decreased. However, total cell number of DLN, absolute cell number of CD3+&CD19+, CD4+&CD8+, B220+/CD23+, CD3+/CD69+ in DLN and CD4+CD25+foxp3+Treg cell, foxp3 mRNA in dersal skin tissue are increased significantly. Conclusions : Concurrent administration of KKSDU and AJ on atopic dermatitis in an in-vivo experiment using an NC/Nga atopic dermatitis mouse was very effective to the atopic detmatitis treatment.
Article
Full-text available
Activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix transcription factor, in lymphocytes by the immunosuppressive environmental contaminant 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause thymic atrophy in every species studied. We set out to identify the specific hemopoietic cellular populations in which the AHR was activated to lead to thymic atrophy and to determine the effect of AHR activation in those cellular populations. Initially, we examined whether AHR activation in intrathymic dendritic cells could mediate TCDD-induced thymic atrophy. It was found that thymic atrophy occurred only when the AHR could be activated in the thymocytes but not hemopoietic-derived dendritic cells or other APCs. We next analyzed the effect of TCDD on the proliferation of thymocytes in vivo. There was a significant increase in the percentage of thymocytes in the G(1) phase of the cell cycle and a significant decrease in the percentage of S plus G(2)/M thymocytes, especially in the CD4(-)CD8(-)CD3(-) triple-negative intrathymic progenitor cell population 24 h after exposure to 30 micro g/kg TCDD. Furthermore, by 12 h after exposure to TCDD, we observed approximately 60% reduction of 5-bromo-2'-deoxyuridine incorporation in specific intrathymic progenitor cell populations. This reduction persisted for at least 6 days. These data indicate that intrathymic progenitor cells are direct targets of TCDD in the thymus and suggest that TCDD causes thymic atrophy by reducing entrance into cell cycle in these populations.
Article
Full-text available
Exposure to the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the generation of T cell-dependent immunity, both humoral and cell-mediated. However, the mechanism of TCDD-induced immune suppression remains to be defined. We hypothesized that exposure to TCDD suppresses the activation of naive CD4(+) T cells and prevents their expansion and differentiation into effector T-helper cells capable of driving T cell-dependent immune responses. To test this hypothesis, we adoptively-transferred DO11.10 OVA-specific T-cell receptor (TCR) transgenic T cells into syngeneic recipients and used a TCR-specific monoclonal antibody to track the in vivo activation of naive CD4(+) T lymphocytes following exposure to OVA. The production of OVA-specific antibodies was suppressed in a dose-dependent manner in adoptively transferred mice that had been exposed to TCDD. Although TCDD exposure had little effect on the expansion or activation of the adoptively transferred, OVA-specific CD4(+) T cells, these cells disappeared from the spleen more rapidly in TCDD-treated mice and produced significantly decreased levels of the T cell-derived cytokines IL-2 and IL-10. There was also a trend towards reduced IFN-gamma and IL-4 production following in vitro re-stimulation. These data suggest that TCDD may interfere with the survival and/or differentiation of OVA-specific T-helper cells. These results demonstrate for the first time the potential of the DO11.10 adoptive transfer system to directly assess immunotoxic effects of xenobiotics on antigen-specific CD4(+) T cells in vivo.
Article
Full-text available
Signaling through the TCR and costimulatory signals primarily control transcription of the IL-2 gene in naive T cells. The minimal promoter necessary for this expression lies proximal, between -300 and the transcription start site. We had previously shown that activation of the arylhydrocarbon receptor (AHR), a member of the bHLH-PAS family of transcription factors, leads to increased mRNA expression of IL-2 in murine fetal thymocytes. The AHR is abundant in the thymus and may play a role for the development of the immune system. Moreover, its overactivation by chemicals such as dioxins leads to immunosuppression and thymic involution. Binding motifs for the liganded AHR can be identified in the distal region -1300 to -800 of the mouse IL-2 promoter. We show here that these DNA motifs, the so-called dioxin response elements, after binding to the liganded AHR are sufficient to transactivate luciferase expression in a reporter gene system. The IL-2 gene can be induced by the AHR also in thymocytes in vivo after injection of 2,3,7, 8-tetrachlorodibenzo-p-dioxin, a potent ligand of the AHR. The AHR mediates the IL-2 induction as shown with AHR-deficient mice. However, in spleen cells in vitro costimulation via the TCR is necessary for optimal IL-2 gene induction. Thus, the IL-2 promoter region contains novel distal regulatory elements that can be addressed by the AHR to induce IL-2 and can cooperate with the proximal promoter in this.
Article
Although exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) clearly impairs T cell-dependent immune responses, the mechanisms underlying TCDD-induced T cell dysfunction are unclear. With the goal of determining precisely how exposure to TCDD impairs the activation of CD8(+) T cells in vivo, we used a well-defined T cell receptor (TCR) transgenic system. Greater than 95% of the CD8(+) T cells in F5 transgenic mice possess TCR specific for a peptide from influenza A virus expressed in the context of H-2D(b). Unexpectedly, we discovered that exposure to TCDD did not alter CD8(+) T cell function in the transgenic mice. Specifically, treatment of F5 mice with TCDD did not affect the recruitment of virus-specific CD8(+) T cells to the lung, nor did it impair the ability of CD8(+) T cells in the lymph node to produce cytokines, or to clonally expand or differentiate. This is in direct contrast to the suppressive effects of TCDD on the response of CD8(+) T cells in wild-type mice. Exposure of F5 mice to TCDD induced CYP1A1 and suppressed the production of virus-specific antibodies. Likewise, upon adoptive transfer into wild-type mice, TCDD suppressed the expansion and differentiation of F5-derived CD8(+) T cells. This indicates that the F5 mice and lymphocytes derived from them are not inherently resistant to the immunosuppressive effects of TCDD. Rather, our data suggest that in the context of a supraphysiological number of antigen-specific CD8(+) T cells, the function of these cells was not affected by exposure to TCDD. Given that antibody production in the F5 mice was sensitive to suppression by TCDD, while the CD8 response was resistant, our data provide a new perspective on the ways in which exposure to TCDD adversely affects B and T lymphocyte function.
Article
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disrupting chemical (EDC), can cause carcinogenesis, immunosuppression, and teratogenesis, through a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Despite remarkable recent advances in stem cell biology, the influence of TCDD on hematopoietic stem cells (HSCs), which possess the ability to reconstitute long-term multilineage hematopoiesis, has not been well investigated. In this study we examined the influence of TCDD on HSCs enriched for CD34(-), c-kit(+), Sca-1(+), lineage negative (CD34-KSL) cells. The number of the CD34-KSL cells was found to be increased about four-fold upon a single oral administration of TCDD (40 mug/kg body weight). Surprisingly, we found that these TCDD-treated cells almost lost long-term reconstitution activity. This defect was not present in AhR(-/-) mice. These findings suggest that modulation of AhR/ARNT system activity may have an effect on HSC function or survival.
Article
T cells upon activation undergo apoptosis, a process termed activation-induced cell death (AICD). In the current study, we investigated whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases AICD and whether this constitutes one of the mechanisms by which TCDD induces immunotoxicity. To this end, C57BL/6+/+, C57BL/6 gld/gld (Fas ligand-defective) and C57BL/6 lpr/lpr (Fas-deficient) mice were injected with TCDD (50 μg/kg body weight, ip) or the vehicle (corn oil) and with anti-CD3 mAbs into the footpads. 3 days later, inguinal and popliteal lymph node cells were harvested, pooled and enumerated. Cells were cultured in vitro with anti-CD3 mAbs and cell proliferation was measured. Also, such cells were studied for their ability to undergo apoptosis upon in vitro culture with either tissue culture medium alone or with anti-CD3 mAbs. The data demonstrated that lymph nodes from TCDD-treated wild-type (+/+) mice showed a decrease in cellularity and the T cells exhibited decreased responsiveness to anti-CD3 mAbs when compared to the vehicle-treated control group. Furthermore, such cells from TCDD-treated mice exhibited increased levels of apoptosis upon in vitro culture when compared to the cells from vehicle-treated mice. In contrast, activated lymph nodes from TCDD-treated C57BL/6 gld/gld and C57BL/6 lpr/lpr mice showed normal cellularity and T cell responsiveness to anti-CD3 stimulation when compared to the vehicle controls. In addition, the activated lymph node T cells from the TCDD-treated C57BL/6 gld/gld and C57BL/6 lpr/lpr mice failed to exhibit increased apoptosis when compared to the controls. The current study demonstrates that the immunotoxic effects of TCDD in activated peripheral T cells may result from increased AICD mediated through Fas-Fas ligand interactions.
Article
Primary T cell-mediated immune responses are highly susceptible to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, yet direct effects of TCDD on T cells have been difficult to demonstrate. Since the activation of naive T cells has been shown to be initiated primarily by dendritic cells (DC), these cells represent a potential target for TCDD immunotoxicity. In this report, we have examined the influence of TCDD exposure on splenic DC phenotype and function in the absence of antigenic stimulation. Results showed that DC from TCDD-treated mice expressed higher levels of several accessory molecules including ICAM-1, CD24, B7–2, and CD40, whereas the expression of LFA-1 was significantly reduced. These effects were dose-dependent and persisted for at least 14 days after exposure. The effects were also dependent upon the aryl hydrocarbon receptor (AhR), as similar effects were observed in AhR+/+ C57Bl/6 and Balb/c mice but not in AhR−/− mice. When DC from TCDD-treated mice were cultured with allogeneic T cells, the proliferative response and production of IL-2 and IFN-γ by the T cells were increased. Production of IL-12 by the DC was likewise enhanced in comparison to cells from vehicle-treated mice. Interestingly, however, the number of DC recovered from TCDD-treated mice was significantly decreased. Taken together, these results suggest that, in the absence of antigen, TCDD provides an activation stimulus to DC that may lead to their premature deletion. Since the survival of DC has been shown to influence the strength and duration of the immune response, these results suggest a possible novel mechanism for TCDD-induced immune suppression.
Article
Studies have shown that blocking B7-mediated costimulation induces T cell tolerance via anergy or apoptosis. Provision of exogenous IL-2 can reverse or prevent the induction of tolerance. We have previously shown that TCDD-induced suppression of the CTL response to allogeneic P815 tumor cells is accompanied by decreased expression of CD86 (B7-2) as well as suppressed IL-2 and IFNgamma production. In the present studies, the role of IL-2 and IFNgamma and the analysis of inappropriate deletion of CD8(+) cells was examined. Administration of IL-2 on days 7-9 relative to the injection of P815 tumor cells dose-dependently increased the CTL activity and the generation of CD8(+) CTL effector cells in TCDD-treated mice. This increased CTL response was not due to recruitment of naive CTL precursors (CTLp), suggesting that a small pool of activated CTLp in TCDD-treated mice could respond to the IL-2. A much larger pool of activated CTLp in control mice was also expanded by IL-2 treatment. In contrast, treatment with IFNgamma during the same time period did not alter CTL activity in control or TCDD-treated mice. To address the possibility that insufficient IL-2 early in the response was responsible for the reduced pool of activated CTLp in TCDD-treated mice, IL-2 was administered on days 1-3 after P815 injection. However, not only did early treatment with IL-2 fail to restore the response in TCDD-treated mice, it suppressed the CTL response of non-TCDD-treated mice. To test whether exposure to TCDD induced apoptosis of activated CD8(+) T cells, phosphatidylserine (PS) expression was measured on various days after P815 tumor challenge. Surprisingly, the percentage of apoptotic CD8(+) T cells was significantly lower in TCDD-treated mice compared to controls throughout the allograft response. Similarly, exposure to TCDD failed to enhance peripheral deletion of Vbeta3(+)CD8(+) T cells after injection of the superantigen Staphylococcal enterotoxin A (SEA). Taken together, the data indicate that TCDD induces an early defect in CTLp activation that is not due to insufficient IL-2 or deletion of CD8(+) cells and may implicate a novel mechanism by which ligands of the Ah receptor disrupt CTL precursor activation.
Article
The B-cell, a major cellular component of humoral immunity, has been identified as a sensitive target of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). The actual molecular mechanism responsible for the immunotoxic effects produced by TCDD is unclear; however, many of the biological effects produced by TCDD are thought to be mediated by the aryl hydrocarbon receptor (AhR). Using the CH12.LX B-cell line, the present studies show that inhibition of mu gene expression and IgM protein secretion by polychlorinated dibenzo-p-dioxin congeners follow a structure-activity relationship for AhR binding. Furthermore, these effects may be mediated by the two dioxin-responsive enhancer (DRE)-like sites that were identified within the Ig heavy chain 3'alpha-enhancer. Electrophoretic mobility shift assay-Western analysis demonstrated TCDD-induced binding of the AhR nuclear complex to both DRE-like sites as well as TCDD-induced binding of several nuclear factor-kappa B/Rel proteins to a kappa B site, which overlaps one of the DRE-like sites. Interestingly, kappa B binding in the AhR-deficient BCL-1 B-cells was also induced by TCDD, demonstrating an AhR-independent effect of TCDD on kappa B binding. Taken together, these results support an AhR/DRE-mediated mechanism for TCDD-induced inhibition of IgM expression.
Article
Exposure to various xenobiotics, including oxidant gases, diesel exhaust, and certain pesticides, has been reported to exacerbate pulmonary allergic hypersensitivity responses. Increased lymphocyte proliferative responses to parasite antigens or increased antibody responses to sheep erythrocyte have also been reported in rats exposed to TCDD before infection or immunization. As a result, these studies were conducted to test the hypothesis that TCDD exposure exacerbates the allergic response to house dust mite antigen. Brown Norway rats were injected, ip, with 0, 1, 10, or 30 microg TCDD/kg 7 days before intratracheal (it) sensitization to semipurified house dust mite allergen (HDM). Fourteen days later, rats were challenged with HDM and immediate bronchospasm was measured. At this time point, plus 2 and 7 days later, inflammatory cells in bronchoalveolar lavage fluid (BALF), HDM-specific IgE levels in serum, and HDM-driven cell proliferation in bronchial lymph nodes and spleen were evaluated. TCDD exposure decreased both immediate bronchoconstriction and specific IgE synthesis after the HDM challenge; 7 days later, HDM-specific IgE responses remained suppressed. Total serum IgE levels were similar in all groups. HDM challenge alone significantly increased cellular and biochemical indicators of lung injury, both of which were suppressed by TCDD exposure. The proliferative response of lymph node cells, but not of spleen cells, to HDM was also suppressed at the highest TCDD dose, although the splenic response to Concanavalin A was elevated. It appears that early events in the response to HDM are affected by TCDD exposure, since message for IL5 was dramatically reduced 2 days after sensitization, but not after challenge. We therefore conclude that TCDD exposure suppressed, rather than enhanced the development of allergic immune responses and the expression of immune-mediated lung disease.