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Transcript
1040
Arsenic ecotoxicology and innate immunity
Christopher R. Lage, Akshata Nayak, and Carol H. Kim*
Department of Biochemistry, Microbiology and Molecular Biology, University of Maine, Orono, ME 04469, USA
Synopsis Understanding the ecotoxicological effects of arsenic in the environment is paramount to mitigating its
deleterious effects on ecological and human health, particularly on the immune response. Toxicological and long-term
health effects of arsenic exposure have been well studied. Its specific effects on immune function, however, are less well
understood. Eukaryotic immune function often includes both general (innate) as well as specific (adaptive) responses to
pathogens. Innate immunity is thought to be the primary defense during early embryonic development, subsequently
potentiating adaptive immunity in jawed vertebrates, whereas all other eukaryotes must rely solely on the innate immune
response throughout their life cycle. Here, we review the known ecotoxicological effects of arsenic on general health,
including immune function, and propose the adoption of zebrafish as a vertebrate model for studying such effects on innate
immunity.
Natural sources
Arsenic is a naturally occurring metalloid element
that is found in soil, air and water (Huang and
others 2004; Duker and others 2005). Environmental
arsenic exists in both organic and inorganic states.
Organic arsenicals are generally considered nontoxic
(Gochfield 1995), whereas inorganic forms are toxic.
The most acutely toxic form is arsine gas (Leonard
1991). Inorganic arsenic exists predominantly in
trivalent (As3þ) and pentavalent (As5þ) forms, where
trivalent compounds are more toxic than pentavalent
ones (Cervantes and others 1994; Smedley and
others 1996; Duker and others 2005). Both trivalent and
pentavalent arsenicals are soluble over a wide pH range
(Bell 1998) and are routinely found in surface and
groundwater (Feng and others 2001). Under aerobic
conditions, pentavalent arsenic is more stable and
predominates, whereas trivalent species predominate
under anaerobic conditions (Duker and others 2005).
Arsenic ranks 20th in abundance in relation to
other elements in the earth’s crust and high
concentrations are found in granite and in many
minerals including copper, lead, zinc, silver and
gold (NAS 1977). The geochemistry of arsenic in
the environment was recently reviewed by Duker
and others (2005). Arsenic naturally accumulates as
both organic and inorganic forms in soil, surface
and groundwater (Attrep and Anirudhan 1977;
Lloyd-Smith and Wickens 2000), and seawater
(Penrose and others 1977). The primary source of
arsenic in soil is the parent rock (Smedley and
Kinniburgh 2002). Additionally, volcanoes are a major
natural source of arsenic released into the environment (Nriagu and Pacyna 1988; Nriagu 1989) that can
generate high arsenic concentrations in natural waters
(Smedley and Kinniburgh 2002). The chemistry of
arsenic in aqueous environments has been reviewed by
Ferguson and Gavis (1972). Arsenic concentrations in
lakes are often less than in rivers, due to adsorption by
iron oxides, although changes in water levels (Nimick
and others 1998; Smedley and Kinniburgh 2002) and
geothermal activity can enhance concentrations in
some cases (Aggett and Kriegman 1988; Duker and
others 2005). Groundwater from alluvial and deltaic
watersheds generally has high arsenic concentration
due to predominantly reducing conditions (Smedley
and Kiniburgh 2002).
Anthropogenic influences
Human activities have intensified arsenic accumulation
in the environment (Bell 1998) such as fossil fuel
combustion and metal smelting, as well as the
semiconductor and glass industries. Arsenic is also an
ingredient in many commonly used materials including
wood preservatives, pigments, insecticides, herbicides,
rodenticides and fungicides (Hathaway and others
1991). Although most arsenic in soil is derived from the
parent rock, the application of arsenic compounds in
agriculture and forestry practices may lead to extreme
soil contamination and subsequent groundwater
From the symposium “Ecological Immunology: Recent Advances and Applications for Conservation and Public Health” presented at the
annual meeting of the Society for Integrative and Comparative Biology, January 4–8, 2006, at Orlando, Florida.
1 E-mail: [email protected]
Integrative and Comparative Biology, volume 46, number 6, pp. 1040–1054
doi:10.1093/icb/icl048
Advance Access publication October 11, 2006
Ó The Author 2006. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved.
For permissions please email: [email protected]
1041
Effects of arsenic on innate immunity
contamination, while the burning of coal and smelting
of metals may be major sources of airborne arsenic.
Mining activities may result in high levels of arsenic
contamination in soil, surface water, groundwater and
vegetation (Amasa 1975; Smedley and others 1996;
Smedley and Kinniburgh 2002). Additionally, human
modifications to the natural hydrograph, including the
construction of dams (Armah and others 1998),
wastewater recycling and irrigation practices (Siegel
2002), can potentiate arsenic accumulation in soil and
in water supplies.
The role of microbes
Many microorganisms have adapted to arsenic-rich
environments, including soils and waters (Nakahara
and others 1977; De Vicente and others 1990;
Cervantes and Chavez 1992; Ahmann and others
1994; Cervantes and others 1994; Laverman and
others 1995; Saltikov and Olson 2002) and may be
important factors in arsenic biotransformation
(Shariatpanahi and others 1981) and mobilization
(Cummings and others 1999) in the environment.
Bacterial resistance to the toxic effects of arsenic may
be a function of a specific arsenic-resistance operon,
ars (Carlin and others 1995; Cai and others 1998), and
may be facilitated by reduction in arsenic uptake and
increased phosphate transport (Willsky and Malamy
1980). Homology across microbial taxa suggests that
the ars operon is conserved in Gram-negative bacteria
and that it has a functional role in arsenic
detoxification (Diorio and others 1995). Bacterial
populations have been shown to be associated with
both oxidation and reduction of arsenic in soils
(Macur and others 2004). Degradation of arsenic
species has even been shown in bacterial symbionts of
marine mussels (Jenkins and others 2003). Under
anaerobic conditions, some microbes can reduce the
less toxic arsenate to the more toxic arsenite (Andreae
1978; Nies and Silver 1995; Rensing and others 1999)
through an energy-generating process (Ilyaletdinov
and Abdrashitova 1981). Additionally, other microbes
are able to methylate arsenic compounds (Gadd
1993), which may serve as a detoxification process.
Seasonal variations in temperature and water levels
can have strong effects on arsenic concentration and
speciation in soil and water due to changes in
microbial uptake (Andreae 1978, 1979). During warm,
dry periods arsenic compounds are often oxidized
(Maest and others 1992), potentially increasing
toxicity (Savage and others 2000), while during wet
periods oxidized arsenic is solubilized and distributed
throughout the environment (McLaren and Kim 1995;
Rodriguez and others 2004).
Bioaccumulation and metabolism
Arsenic accumulates across highly diverse environments within the soil, water and air where it is
subsequently taken up and processed by microbes,
plants and animals. Soluble arsenic taken up by plants
rapidly accumulates in the food chain (Green and
others 2001). Freshwater plants and peat moss have
been shown to contain considerable amounts of
arsenic (Reay 1972; Minkkinen and Yliruokanen
1978). Due to the high metal-binding affinity of
their soils, wetlands may have elevated concentrations
of arsenic (Beining and Ote 1996) when compared
with uplands. High arsenic concentrations have
been found in the tissues of wild birds (Fairbrother
and others 1994) and in many marine organisms,
including algae (Lunde 1972, 1973), crustaceans
(Edmonds and others 1977), cetaceans, pinnipeds,
sea turtles and sea birds (Kubota and others 2003).
Ecotoxicants released into the environment, including
arsenic, often accumulate most rapidly in aquatic
habitats where they enter the biota and are subsequently transferred to higher trophic levels and, in
many cases, eventually to humans. Extremely high
levels of arsenic have been observed in many fish taxa
(Bosnir and others 2003; Juresa and Blanusa 2003)
and have been shown to be toxic (Suhendrayatna and
others 2002; Tisler and Zagorc-Koncan 2002). Some
species possess specific arsenic-binding proteins
(Oladimeji 1985) that may increase bioaccumulation.
Monitoring arsenic levels and their associated health
effects in aquatic organisms, particularly in taxa at
high trophic levels such as fish, may provide insight
into overall ecosystem health (Zelikoff and others
2000) as well as into potential impacts on human
health (Zelikoff 1998; Adams and Greeley 1999).
Exposure from air and soil is usually minimal in
humans. The major sources of exposure for humans
are food and water (Bernstam and Nriagu 2000). Once
ingested, arsenic that is not eliminated from the body
may accumulate in the muscles, skin, hair and
nails (Ishinishi and others 1986; Kitchin 2001). Food
contains both organic and inorganic arsenic, whereas
water primarily contains inorganic forms. Seafood
may provide higher concentrations of arsenic when
compared with terrestrial food products (Sakurai
and others 2004), presumably due to increased
bioaccumulation through generally longer trophic
chains. As elemental arsenic is poorly absorbed, it is
predominantly eliminated from the body unchanged
(Duker and others 2005). Inorganic arsenic is absorbed through the gastrointestinal tract and is eliminated via renal function (Hindmarsh and McCurdy
1986); however, a small amount is biotransformed
1042
into "detoxified" forms via methylation and reduction
in the liver (Winski and Carter 1995; Bernstam and
Nriagu, 2000). Once thought to be a purely detoxification process, it has been shown that methylation of
arsenic may, in some cases, actually increase arsenic
toxicity in humans and rodents (Petrick and others
2000, 2001; Styblo and others 2000; Del Razo and
others 2001). Variation in arsenic metabolism has
been shown to occur in humans (Abernathy and
others 1999). Interestingly, some mammals, including nonhuman primates, are deficient in arsenite
methyltransferases necessary for effective methylation
(Aposhian 1997). They may also show different tissuespecific expression (Abernathy and others 1999). The
relationships between arsenical exposure, methylation
and toxicity are paramount to understanding the risks
posed to humans.
Toxicology of arsenic
Acute and chronic arsenic toxicities have been shown
in a variety of organisms, and the data suggest that
most inorganic arsenicals are more toxic than organic
forms (Abernathy and others 1999; Duker and others
2005). Toxic effects of inorganic arsenic include
denaturing of cellular enzymes through interaction
with sulfhydryl groups (Graeme and Pollack 1998;
Gebel 2000), causing cellular damage through
increased reactive oxygen species (ROS) (Wang and
others 1996; Ahmad and others 2000), and altering
gene regulation (Rossman 1998; Abernathy and others
1999). Arsenic is known to inhibit more than 200
enzymes (Abernathy and others 1999) and has been
implicated in multisystemic health effects via interference with enzymatic function and transcriptional
regulation (NRC 1995). A variety of inhibitory effects
on cellular metabolism have been shown, affecting
mitochondrial respiration (Klaassen 1996; Abernathy
and others 1999) and synthesis of adenosine triphosphate (ATP) (Winship 1984). Other effects of arsenic
include activation of the estrogen receptor, inhibition
of angiogenesis and tubulin polymerization, induction
of heat-shock proteins, and oxidation of glutathione
(Bernstam and Nriagu 2000). Due to its structural
similarity to phosphate, arsenate may replace phosphorus in bone (Ellenhorn and Barceloux 1988).
Among fish taxa, arsenic has been shown to induce
apoptosis of fin cells (Wang and others 2004), to cause
liver inflammation, hyperplasia and necrosis (Pedlar
and others 2002), gall bladder inflammation, fibrosis
and edema (Cockell and others 1991; Pedlar and others
2002;), kidney fibrosis (Kotsanis and IliopoulouGeorgudaki 1999), and the induction of various heatshock proteins (Kothary and Candido 1982). Arsenic
C. R. Lage et al.
has been shown to cause morphological changes,
as well as to increase numbers of necrotic bodies,
abnormal lysosomes and autophagic vacuoles in fish
hepatocytes (Sorensen and others 1985). Additionally,
effects on reproduction in fishes include disrupting
ovarian cell cycles (Wang and others 2004), inhibiting
ovarian follicle development (Shukla and Pandey
1984a), impairing spermatogenesis and changing
testicular architecture (Shukla and Pandey 1984b).
There is clear evidence that arsenic can disrupt gene
expression, particularly through its effects on signal
transduction (Abernathy and others 1999). Arsenic
can interact directly with the glucocorticoid receptor
(GR), selectively inhibiting GR-mediated transcription
(Kaltreider and others 2001). It has been found to
inhibit the Janus family of tyrosine kinase-signal
transducers and activators of transcription (JAKSTATs) by interacting directly with JAK (Cheng and
others 2004), to inhibit IkB-kinase (Roussel and
Barchowsky 2000), as well as to inactivate protein
tyrosine phosphatases, promote the activation of AP-1
and upregulate levels of MAPK (Cavigelli and others
1996). At low concentrations, arsenic has been shown
to affect the DNA-binding capabilities of transcription
factors NFkB and AP-1, leading to increased gene
expression and stimulation of cell proliferation (Chen
and others 2000; Wijeweera and others 2001).
However, at high concentrations, arsenic may lower
NFkB activation, inhibit cell proliferation and induce
apoptosis (Shumilla and others 1998; Wei and others
2005).
It has been suggested that arsenic can disrupt
cell division by deranging the spindle apparatus
(Abernathy and others 1999). Arsenic induces large
deletion mutations (Hei and others 1998), chromosome damage and aneuploidy (Abernathy and others
1999) and causes micronucleus formation, DNA–
protein cross-linking, and sister chromatid exchange
(Huang and others 2004). It is known to inhibit
DNA repair (Lynn and others 1997; Rossman 1998;
Brochmoller and others 2000) and even to exacerbate
the effects of other mutagenic agents (Abernathy and
others 1999), thereby increasing susceptibility to
multiple diseases (Duker and others 2005).
Arsenic and the immune response
Chronic exposure to arsenic, in addition to its general
toxicity and its stimulation of many diseases, may
affect lymphocyte, monocyte and macrophage activity
in many mammals, resulting in immunosuppression
(Blakley and others 1980; Gonsebatt and others 1994;
Lantz and others 1994; Yang and Frenkel 2002; Wu
and others 2003; Duker and others 2005; Sakurai and
1043
Effects of arsenic on innate immunity
others 2006). Likewise, phagocytic activity of macrophages and other immune responses were found to be
significantly reduced by arsenic exposure in birds
(Fairbrother and others 1994; Vodela and others
1997). Generally, arsenic can disrupt glucocorticoid
regulation of immune function (Kaltreider and others
2001) and arsenic-mediated apoptosis may lead to a
diminished immune response in mice (Harrison and
McCoy 2001), rats (Bustamante and others 1997) and
humans (de la Fuente and others 2002; GonzalesRangel and others 2005). Additionally, arsenic
exposure in mice has been shown to suppress the
primary antibody response (Sikorski and others 1991),
reduce macrophage and neutrophil abundance
(Patterson and others 2004), increase susceptibility
to infection (Aranyi and others 1985), increase
mortality due to bacterial infection (Hatch and others
1985), decrease adhesion of macrophages, decrease
nitric oxide (NO) production, and reduce chemotactic
and phagocytotic indices (Sengupta and Bishayi 2002;
Bishayi and Sengupta 2003). A field study of the
effects of environmental arsenic exposure along a
pollution gradient has also been shown to suppress
immune function in wood mice (Tersago and others
2004). Arsenic has been shown to affect not only the
immune response, but also behavior in rats (Schultz
and others 2002). Dose-dependence of the immunotoxicological effects of arsenic is unclear. Dosedependent immunosuppressive relationships have
been observed in mice (Burns and others 1991).
However, in some studies the immunosuppressive
effects of arsenic were most pronounced at low concentrations of exposure, compared to high concentrations (Blakley and others 1980; Savabieasfahani and
others 1998), and it has even been proposed that in
some situations arsenic may enhance certain immune
responses (Yoshida and others 1987).
Arsenic has been found to increase the expression of
granulocyte macrophage-colony stimulating factor
(GM-CSF), transforming growth factor-a (TGF-a)
and TNFa in human keratinocytes (Germolec and
others 1996), and IL-1a and IL-8 in murine
keratinocytes (Yen and others 1996; Corsini and
others 1999). While arsenic has been shown to induce
expression of IL-1, IL-6 and IL-7 receptors, as well as
inducible nitric oxidase (iNOS) in rat liver epithelial
cells (Chen and others 2001), it has also been shown to
downregulate expression of the IL-2 receptor (Yu and
others 1998), IL-1a, IL-1b, IL-2, IL-8, IL-12A and B,
IL-18, monocyte chemotactic protein-1 (MCP-1),
TGF-b1 and b2 human osteoblasts (Yang and
Frenkel 2002).
Reactive oxygen species (ROS) generated during the
innate respiratory-burst response destroy invading
pathogens; however, they can also cause oxidative
stress and tissue damage and affect signal transduction. The introduction of environmental arsenic may
lead to the increased production of ROS through
various pathways and has been shown in humans
(Pineda-Zavaleta and others 2004). Arsenic can
activate NADPH oxidase and induces the production
of O2 and H2O2 (Chen and others 1998), thereby
increasing the production of the intercellular messenger NO (Gurr and others 1998), and uncoupling
mitochondrial oxidative phosphorylation (Klaassen
1996). Low levels of ROS can modulate gene expression and induce apoptosis (Chen and others 1998),
whereas high levels of ROS can result in oxidative
damage and cell death. DNA damage and micronucleus formation caused by ROS may also potentiate
cancer by enhancing cell proliferation (Hei and others
1998). In addition to increasing the amount of
ROS produced, arsenic disturbs the natural oxidation
and reduction equilibria of proteins, including many
signal molecules such as AP-1, NFkB, IkB, p53 and
p21ras (Simeonova and Luster 2000), by binding to
cysteine-sulfhydryl groups.
Arsenic and disease
Arsenic compounds have been used directly on
humans for treating many diseases including skin
conditions, malaria, ulcers, syphilis, sleeping sickness
and some forms of leukemia (Luh and others 1973;
Nevens and others 1990; Zhang 1999; Miller and
others 2002) although it is now rarely used medicinally (Azcue and Nriagu 1994). Organs most
susceptible to arsenic toxicity are those involved
with absorption, accumulation or excretion, including
the skin, circulatory system, gastrointestinal tract, liver
and kidney (Duker and others 2005). The primary
symptom of arsenic exposure is dermal lesions (Zaloga
and others 1985). Skin localizes and stores arsenic,
presumably due to high levels of sulfhydryl-rich
keratin (Kitchin 2001), potentially explaining this
response. Arsenic is associated with multiple health
effects, including Blackfoot disease (Abernathy and
others 1999), diabetes (Longnecker and Daniels
2001), hypertension (Chen and others 1995), peripheral neuropathy and multiple vascular diseases
(see Duker and others 2005). Other effects include
anemia (ATSDR 2000), liver damage, portal cirrhosis,
hematopoietic depression, anhydremia, sensory
disturbance and weight loss (Webb 1966). It has
been suggested that multiple factors, including
genetics and nutrition, affect susceptibility to arsenic
and disease manifestation (Mandal and others 1996;
Hseuh and others 1998).
1044
In addition to acute toxicity, long-term exposure to
inorganic arsenic is associated with certain forms of
cancer of the skin, lung, colon, bladder, liver and
breast (Nemery 1990; Abernathy and others 1999;
Huang and others 2004; Duker and others 2005)
although effects may not appear until more than
20 years after exposure (Jackson and Grainge 1975). It
has been suggested that arsenic may act as a carcinogen
through DNA hypomethylation and overexpression of
protooncogenes (Zhao and others 1997). Cancer may
induced by alteration of DNA-repair mechanisms,
thus interfering with cell division, differentiation and
tumor suppression (Chen and others 1996; Goering
and others 1999). Additionally, arsenic may induce
certain forms of cancer by enhancing the carcinogenic
effects of other substances and by affecting metabolic
pathways (Huang and others 2004).
In summary, the effects of arsenic on health include
various mechanisms of acute and chronic toxicity,
enzymatic and genetic effects, and/or increasing susceptibility to multiple types of disease, both cancerous
and noncancerous. Although it is clear that exposure
to arsenic alters normal biological functions, resulting
in the direct initiation of disease or, at least, predisposition of an organism to it, studying the impact of
arsenic on the ability to fight viral and bacterial
infections via specific immune responses is particularly important for full understanding of its overall
effects on health.
C. R. Lage et al.
possibly other species, do not develop functional
adaptive immunity until a distinct stage of development, until which time they rely entirely upon
the innate immune response (Willett and others
1997). Because of its importance during development, generality of mechanisms of defense against
pathogens and taxonomically conserved nature, innate
immunity has particularly broad implications for
overall health.
Adaptive immune response
The adaptive immune response is mediated primarily
by B lymphocytes and T lymphocytes. Antigenpresenting cells transport and present antigenic
molecules of pathogens to naı̈ve T lymphocytes,
resulting in their differentiation into effector cells. By
virtue of rearrangeable immune gene segments, this
response can generate a repertoire of lymphocytes
with receptors specific to antigenic components of any
potential pathogen. The mature T cells either migrate
to the site of infection to effect cell-mediated immunity, or circulate in the lymphoid organs to activate
the B lymphocytes and participate in humoral immunity. B cells mature to form plasma cells and memory
cells, which are responsible for producing antibodies
against the pathogen and establishing immune
memory, respectively. The adaptive immune response
eradicates the infectious agent from the host body
and provides an immunological memory against
reinfection by the same pathogen.
Overall immune response
The immune system functions to protect a host from
pathogenic infection. Its complex array of defense
mechanisms relies mainly on the ability to distinguish
between the host and foreign cells. To effectively
manage this, the immune system has 2 separate
responses that work synergistically to fight infection.
The innate immune response uniquely recognizes
molecular patterns, surface structures and cellular
products conserved across a diversity of microbes. It is
activated as the first line of defense, whereas the
secondary adaptive immune response consists of a
complex initiation process, followed by clonal selection and expansion of receptors specific to unique
epitopes on the pathogen. They are mutually
complementary, with the innate system acting as a
prerequisite, potentiating factor for the adaptive
immune response.
All eukaryotic organisms, from amoebae to
mammals, have mechanisms of innate immunity,
whereas adaptive immunity, which appeared
450 million years ago, is present only in jawed
vertebrates (Agrawal and others 1998). Some fish, and
Innate immune response
Innate immunity comprises a collection of defense
mechanisms that protect an organism against infection without depending upon prior exposure and cell
memory. As a rapid first response to assault by
pathogens, the innate immune system halts infection
or keeps it at bay until the adaptive immune response
has sufficient time to develop. In addition to circulating cells, the innate immune system comprises
epithelial barriers such as skin, scales and mucociliary
membranes that separate the organism from the
external environment. If this external barrier is
compromised, receptors on circulating cells recognize
specific molecular signatures and induce an inflammatory response, involving the recruitment and
subsequent activation of leukocytes. Inflammation is
considered to be the first sign of the wound-healing
process and is characterized by localized elevation of
temperature, pain, erythema and edema. Infectious
agents are eliminated primarily by phagocytic cells,
including macrophages, neutrophils and natural killer
cells that migrate to the site of infection and respond
Effects of arsenic on innate immunity
by engulfing and destroying the pathogens. These cells
also secrete effector molecules such as chemokines
and cytokines that function as chemical messengers of
the immune response and facilitate cell-to-cell
communication.
Detection of pathogens by the innate immune
system is dependent on the recognition of invariant
molecules of the microorganism by cell surfaceassociated receptors, the best characterized of which
are the toll-like receptors (TLRs). TLR signaling was
recently reviewed by Akira and Takeda (2004). Tolls
were first discovered in Drosophila, associated
with dorsoventral patterning during development
(Hashimoto and others 1988). Further studies
revealed the essential role of these transmembrane
receptors in innate immunity (Lemaitre and others
1996); they detect conserved molecular patterns
shared by large groups of microorganisms, such as
lipopolysaccharide and double-stranded ribonucleic
acid (RNA) (Akira and Takeda 2004). TLR family
members are differentially expressed among immune
cells and are characterized by the presence of a
leucine-rich, extracellular domain and an intracellular
toll/interleukin 1 receptor (TIR) domain. Ligand
binding results in conformational changes in the TIR
domains that facilitate interactions with downstream
signaling molecules. This cascade results in the activation of cytoplasmic transcription factors, NF-kB or
interferon regulatory factor 3, which subsequently
translocate to the nucleus and begin transcription of
proinflammatory cytokines (Medzhitov 2001).
Chemokines are low molecular weight proteins that
represent a superfamily of about 30 chemoattractants
acting as vital initiators of the inflammatory process.
They are secreted by a wide variety of cells including
monocytes, neutrophils, epithelial cells, smooth
muscle cells and T cells (Rollins 1997). Chemokines
function mainly in leukocyte physiology by controlling inflammatory trafficking, but are also important
for gene transcription, apoptosis and granule exocytosis (Thelen 2001). Some chemokines are inducible
by physiological stress and recruit leukocytes to sites
of injury, whereas others are constitutively active and
are responsible for basal trafficking of leukocytes. All
chemokines are tightly regulated by feedback mechanisms because of their potential for severely damaging
host tissues by uncontrolled persistent expression.
Cytokines are small, soluble, pleiotropic proteins
that are secreted by virtually all cells in the body and
possess both autocrine and paracrine functions. They
act on their targets by binding specific membrane
receptors and signaling through them to commence
the transcription of certain genes, usually those
involved in cellular activation or growth and
1045
differentiation. The central role of cytokines, however,
is to modulate and direct the amplitude of immune
responses. There are 2 major groups of cytokines:
proinflammatory are secreted by activated macrophages, and anti-inflammatory are involved in the
downregulation of inflammatory reactions. Important
antiviral cytokines include certain interferons, whereas
antibacterial cytokines include interleukins and tumor
necrosis factors.
Interferons are a multigene family of inducible
cytokines that possess antiviral activity, broadly
grouped into 2 categories, type I and type II, based
on their biological, biochemical and immunological
properties (Samuel 1991). Type I interferons are
secreted upon viral infection and almost all virusinfected cells can synthesize them. Type II interferons
are upregulated by antigenic stimuli and are secreted
mainly by natural killer cells, CD4þ Th1 cells and
CD8þ cytotoxic suppressor cells (Young 1996). All
interferons act through membrane-associated receptor
complexes. In response to ligand binding, JAK-STAT
members become activated via a series of phosphorylation events, ultimately leading to the translocation
of STATs to the nucleus, and upregulation of
interferon-inducible genes (Stark and others 1998;
Horvath 2000).
Among the genes induced by interferons are
proteins important in anti-RNA virus activity,
including protein kinase (PKR), oligoadenylate synthetase (OAS) and interferon-induced Mx GTPases. PKR
and OAS are essential for inhibition of mRNA
translation and catalyzing RNA degradation, respectively (Jacobs and Langland 1996; Samuel 1998). Mx
GTPases are key components for resisting a wide
range of RNA viruses; produced for short periods of
time, they function by sensing viral nucleocapsids.
Their actions trap essential viral components and
make them unavailable for viral replication, thus
containing the infection (Haller and Kochs 2002). Mx
has strong intrinsic antiviral properties, which makes
it competent to induce an effective antiviral state
independently (Hefti and others 1999).
Interleukins (ILs) were initially considered to be
cytokines essential only for the functioning of
leukocytes, but research has shown that they affect
nearly all cell types. The IL-1 gene family includes
3 members, interleukin-1a, interleukin-1b and an
interleukin-1 receptor antagonist, IL-1Ra. IL-1b is
considered to function as a hormone-like mediator,
intended to be released by cells, whereas IL-1a is
primarily a regulator of intracellular events and of
localized inflammation. At low concentrations, IL-1b
mediates inflammation by increasing synthesis of
cell surface adhesion molecules, thus activating
1046
neutrophils and macrophages and stimulating their
recruitment to the site of injury. At higher concentrations, it exerts systemic effects through the activation
of NFkB, AP-1 and activating transcription factor
(ATF) (Li and others 2001).
Tumor necrosis factor (TNF)a, first discovered for
its ability to induce necrosis of tumor cells, belongs to
a superfamily of proteins that possess a wide range of
proinflammatory functions. TNFa is secreted by
activated macrophages and is critical for the normal
functioning of T cells, natural killer (NK) cells,
macrophages and dendritic cells. TNFa is also
responsible for priming the respiratory-burst response
in activated macrophages by increasing the production of NADPH-oxidase subunits.
Phagocytosis by neutrophils and macrophages is an
essential mechanism for the elimination of invading
microorganisms. Upon initiation of phagocytosis, the
phagosome fuses with lysosomes and destroys the
ingested microbe through the production of reactive
oxygen species and superoxides by a process known as
the respiratory burst. The enzyme responsible for
superoxide production is NADPH oxidase, which has
membrane-bound and cytosolic components. The
cytosolic subunits translocate to the membrane
upon phosphorylation and assist in forming the functional enzyme complex that reduces molecular oxygen
to produce superoxide (Smith and others 1996).
Hydrogen peroxide, hydroxyl radicals and hypochlorites are reactive oxygen species formed from the
superoxide via multiple enzymatic reactions
(Hermann and others 2004).
Zebrafish as a model for
innate immunity
Zebrafish or Danio rerio is a teleost that has become
important as an animal model for studying the
embryo development, genetics and immune system. It
has several advantages over other animal models
currently used. Zebrafish have rapid development, are
small in size and easy to manage, and are highly
fecund compared with other vertebrate models.
Embryos develop externally as transparent larvae,
allowing easy observation of cellular and organ development. Genomic libraries, combined with shotgun
sequencing methods, have permitted the sequencing
of the zebrafish genome, and analyses of genes reveal
significant similarities to higher vertebrates (Amemiya
and others 1999). Forward genetic screens have
identified several mutants with phenotypes comparable to human genetic diseases (Karlovich and others
1998; Leimer and others 1999; Hostetter and others
2003) while reverse genetic approaches have also been
C. R. Lage et al.
designed, allowing knockdown of individual genes
(Nasevicius and Ekker 2000).
Zebrafish have been used as a model for understanding the genetic basis for both viral and bacterial
infectious diseases. Pathogenic viral infections examined in a zebrafish model include the spring viremia
carp virus (Sanders and others 2003), pancreatic
necrosis virus and infectious hematopoietic necrosis
virus (LaPatra and others 2000), and snakehead
rhabdovirus (Phelan, Pressley and others 2005). In
some viral infection models, zebrafish are able to
rapidly clear the pathogen without increased mortality
or clinical symptoms, whereas in other models
infection results in increased mortality, hemorrhaging
and increased expression of genes involved in the
antiviral immune response.
Differences in virulence and host immune response
have been observed among different bacterial strains
used for infection (Menudier and others 1996). In
some cases, one strain of bacterium may cause systemic
infection in all major organ systems (Neely and others
2002), whereas, in other cases, pathogenesis of a
different strain may be restricted to certain tissues
(Miller and Neely 2004). Bacterial infection may result
in mortality corresponding with a dramatic increase in
the amount of bacteria entering the bloodstream
(van der Sar and others 2003). It has also been shown
that bacterial infection by static immersion results in
increased inflammatory cytokine production (Pressley
and others 2005). Infections involving both Grampositive and Gram-negative bacteria in zebrafish have
shown similar gene induction to that observed in
mammalian systems, suggesting conserved immune
mechanisms among fish and mammals (Lin and
others 2006). Mycobacterial infection in the zebrafish
resulted in granuloma-like lesions similar to those
seen in mammals (Prouty and others 2003), while
microarray analysis revealed upregulation of genes
known to be associated with immune function (Meijer
and others 2005).
Functional adaptive immunity is not present in
zebrafish until the 4th day of development (Willett
and others 1997) such that, until this time, mechanisms of infectious defense rely entirely on the innate
immune response. Early zebrafish macrophages
develop and have chemotactic functions similar to
their mammalian counterparts (Herbomel and others
1999). A bioassay to measure the respiratory-burst
response has been developed in the zebrafish
(Hermann and others 2004). Multiple chemokines
(Long and others 2001; David and others 2002) and
cytokines (Altmann and others 2003; Altmann and
others 2004; Pressley and others 2005) have been
characterized in the zebrafish. Additionally, over
1047
Effects of arsenic on innate immunity
20 putative variants of the toll-like receptors (Jault
and others 2004; Meijer and others 2004; Phelan,
Mellon and others 2005) as well as 4 adaptor proteins
(Jault and others 2004) have been identified in
the zebrafish. Thus, the zebrafish provides a unique
model for studying vertebrate biology and, in
particular, for investigating ecotoxicological effects
on innate immunity.
Arsenic and innate immunity in fish
As many components of innate immunity are
evolutionarily conserved (Hoffmann and others
1999; Ulevitch 2000), and as arsenic often accumulates
most rapidly in aquatic habitats, monitoring arsenic
levels and their associated health effects in fish may
not only provide insight into overall ecosystem health
(Zelikoff and others 2000) but may also act as a
sentinel for potential impacts on human health
(Zelikoff 1998; Adams and Greeley 1999). Because
adaptive immunity is developmentally delayed in fish
(Alexander and Ingram 1992), the effects of ecotoxicants on innate immunity may be more significant
and thus easier to measure in fish than in mammals.
The general effects of ecotoxicants (Bols and others
2001) and stress (Fletcher 1986) on innate immunity
in fish have been reviewed.
Arsenic has been shown to induce metallothionein
(MT), part of the oxidative stress response (Schlenk
and others 1997; Hermesz and others 2002; Pedlar and
others 2002) in various species of fish. The duration of
arsenic exposure may affect the generation of a stress
response in some fish, as it has been shown in the
snakehead that after initial arsenic exposure and
reduction in ROS scavenging enzyme production, an
extended exposure upregulated enzymatic activity,
resulting in increased arsenic resistance over time
(Allen and Rana 2004).
Arsenic has been shown to regulate transcriptionfactor activation in zebrafish cell cultures (Carvan and
others 2000). Effects of arsenic on the innate immune
system, including the ability to mount an adequate
respiratory-burst response, express essential antiviral
genes and produce sufficient levels of TNFa, within
the concentration range of arsenic found in contaminated groundwater (Clark and Raven 2004), have
been evaluated in the zebrafish model system
(Hermann and Kim 2005). The ability to mount an
appropriate respiratory burst is an indicator of the
general immune health of an organism and reductions
in respiratory-burst activity were found in zebrafish
on exposure to even low concentrations of arsenic.
In an effort to elucidate the possible mechanism for
this inhibition, examination of TNFa levels revealed
decreased expression upon exposure, supporting the
possibility that arsenic hinders respiratory-burst
activity by reducing the expression of TNFa, which
is essential for priming this response. The antiviral
response of the fish was examined upon arsenic
exposure before and after infection with snakehead
rhabdovirus. Gradual increases in interferon expression were observed over time in arsenic-exposed
zebrafish. However, Mx levels failed to mirror this
trend. The disruption of Mx induction by interferon
indicates arsenic inhibition of interferon signaling.
Upon viral exposure, expression levels of both antiviral
genes were downregulated when compared with
arsenic-unexposed controls. These data suggest that
the ability of the zebrafish to mount an effective innate
immune response is reduced by arsenic exposure,
indicating that the presence of this metalloid in
water has potentially adverse effects on the components of innate immunity essential for an antiviral
response in fish.
Concluding remarks
Mounting evidence of links to human disease underscores the need for in-depth investigations into the
health effects of arsenic. Furthermore, from our
studies and those of others, it is becoming increasingly
evident that fish, and in particular zebrafish, serve as
an ideal animal model for studying the effects of
arsenic. It is now clear that arsenic disrupts the
immune response, potentially playing an important
role in the outcome of infection and of host resistance
to infectious diseases.
Conflict of interest: None declared.
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