Effects of Persistent Organic Pollutants on the Immune System: The Case of Dioxins

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.

Full text

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…
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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.
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