INDUCTION OF DEPRESSION BY EXPOSURE TO DAMP ...

UNIVERSITY OF WISCONSIN-LA CROSSE
Graduate Studies
REVIEW: INDUCTION OF DEPRESSION BY EXPOSURE TO DAMP BUILDINGS
A Manuscript Style Thesis Submitted in Partial Fulfillment of the Requirements for the
Degree of Master of Science, Biology
Cassidy Kuchenbecker
College of Science and Health
Microbiology Concentration
December, 2010

ABSTRACT
Damp buildings adversely affect occupant health. Reviews by the World Health
Organization and the United States Institute of Medicine indicated that the strongest
evidence for an association between damp buildings and health is manifested by asthma
and upper respiratory tract symptoms in sensitized persons. A growing body of studies
provides evidence that some occupants of damp buildings also experience neurological
symptoms, such as depression. In this review, depression in sensitive individuals and
exposure to damp buildings is examined. Chronic inflammation and its effects on
synapses and the hypothalamus-pituitary-adrenal axis appears to be linked to damp
conditions and subsequent exposure to microorganisms, such as fungi, bacteria, dust
mites, and mold mites. Mycotoxins produced by fungi may add to a lesser degree to the
inflammatory reaction. Volatile chemicals released by the biological agents and the damp
building materials do not significantly contribute to the inflammatory levels, except in
people who have chemical sensitivities. Thus, exposure to damp buildings may be
affecting the mental health and well-being of occupants. Recognizing and exploring the
potential impact of dampness and water damage on the neurological system is necessary
to further raise awareness of the effects of exposure to these environments.

TABLE OF CONTENTS
Introduction ...................................................................................................................................... 1
Current Understanding of Mechanisms for Depression and Psychological Impairment ................. 2
Hypothalamus-Pituitary-Adrenal Axis Dysregulation Hypothesis .............................................. 4
Immune/Inflammation Mechanism of Depression Hypothesis.................................................... 6
Neuroplasticity and Neurogenesis Depression Hypothesis........................................................ 11
Integration of Three Hypotheses .................................................................................................... 14
Over-activation of the HPA Axis and Neurogenesis/Neuroplasticity ........................................ 14
Immune system activation of the Hypothalamus-Pituitary-Adrenal axis .................................. 15
Immune system reduction of neuroplasticity/neurogenesis ....................................................... 16
Damp Buildings and Inflammation ................................................................................................ 19
Genetic Propensity to Reaction .................................................................................................. 23
Volatile Chemicals from Microbes and Building Materials ...................................................... 26
Dust Mites, Mold Mites, Protozoa and Cockroaches in Damp Buildings ................................. 30
Inflammation Induced by Bacteria and Fungi ............................................................................ 31
Bacterial and Fungal Inflammatory Mechanisms ...................................................................... 34
Fungal PAMPs, Beta-glucan and Their Induction of Inflammation ...................................... 34
Bacterial PAMPS and Their Induction of Inflammation ....................................................... 40
Fungal and Bacterial Hemolysins and Proteinases and Their Induction of Inflammation ..... 42
Interactions between Bacterial and Fungal Debris................................................................. 44
Mycotoxins and Health Effects .................................................................................................. 45
Summary ........................................................................................................................................ 46
References ...................................................................................................................................... 48

Introduction
Damp buildings adversely affect occupant health (IOM, 2004; WHO, 2009). The
term “damp buildings” refers to those that have sustained past or present water damage
that was not properly mitigated and/or have elevated humidity levels. The type and
magnitude of symptoms experienced by occupants of damp buildings appear to depend
both on genetic susceptibility and environmental conditions. Symptoms can vary
significantly, and thus reported health effects vary greatly. The health effects that are
most strongly supported by studies include immediate IgE-mediated hypersensitivity
reactions, asthma, and other upper respiratory tract symptoms (IOM, 2004; WHO, 2009).
A few of the symptoms with less supporting evidence include lower respiratory tract
illnesses, fatigue, headache, and neuropsychiatric symptoms (IOM, 2004; WHO, 2009).
A recent study by Shenassa et al. (Shenassa et al., 2007) focused on reported
symptoms of depression by individuals exposed to damp buildings. The study controlled
for known mediators that induce depressive symptoms that would be relevant with damp
buildings, such as loss of control over one’s environment and the anxiety and depression
that accompanies recurring symptoms. The findings from this study suggested that
exposure to damp buildings, after controlling for other factors, may have a direct
pathological effect on humans, resulting in symptoms of depression. In addition to
depression, other neurological symptoms reported from damp building exposure include
short-term memory impairment, confusion, and inability to concentrate (Kilburn, 2003).
Evidence-supported hypotheses for the mechanisms leading to depressive-like
symptoms include dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis,
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generalized and chronic inflammation, and decreased neurogenesis and neuroplasticity.
The three mechanisms are not mutually exclusive which may help explain variation in
reported symptoms and treatment responses.
Both peripheral and central inflammation may explain the psychiatric symptoms
observed by Shenassa that were reported by some occupants of damp buildings. Chronic
inflammation generalized throughout the body from exposure to damp buildings has been
demonstrated in genetically susceptible people (Shoemaker, et al., 2006; Gray, et al.,
2003; Kilburn, et al., 2003). One proposed mechanism is that susceptible people either
have an inability to clear inflammagens from their systems, or are unable to regulate
inflammatory responses once they are initiated.
This paper will discuss the various hypotheses for the mechanisms leading to
depressive symptoms and their potential induction by exposure to damp buildings. This
review covers in vivo, in vitro, and epidemiological studies that focus both on damp
buildings directly, and on inflammation and psychological impairment in general.
Current Understanding of Mechanisms for Depression and Psychological
Impairment
The term “depression” generically describes a range of emotional states and
disturbances. Some symptoms include a loss of concentration, persistent feelings of
sadness or emptiness, loss of interest in daily activities, and fatigue. The terms “clinical
depression” and “major depression” are used by physicians to describe more severe or
more persistent episodes.
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A popular and previously well-accepted model for depression was the monoamine
hypothesis. The proposed mechanism of the monoamine hypothesis includes a lowering
of neurotransmitters in the synapses of monoaminergic neurons (e.g., serotonin,
dopamine, norepinephrine). Supposedly, this lack of neurotransmitters results in
decreased enervation and the symptoms of depression (Delgado, 2000). Some anti-
depressant drugs, such as selective serotonin reuptake inhibitors (SSRIs; paroxetine,
fluoxeine, sertraline, citalopram), serotonin noradrenaline reuptake inhibitor (SNRIs;
venlaflaxine), tricyclic antidepressants (TCAs; amitriptyline, imipramine), monoamine
oxidase inhibitors (MAOIs; isocarboxazid, moclobemide), and L-tryptophan increase the
level of these neurotransmitters in the synaptic cleft. Mechanisms that increase the
neurotransmitter levels in the synapse include decreased reuptake, increased synthesis,
and decreased breakdown of the neurotransmitters. Antidepressants increase monoamine
levels in the synapse within days. Yet, it takes weeks to months for depressive symptoms
to be lessened. This delay in effect is a major argument against the validity of the
monoamine hypothesis.
The monoamine hypothesis has also been challenged by the variable mechanisms
of action of newer drugs. Some newer antidepressant drugs lower the levels of
neurotransmitters in the synaptic cleft. Specifically, tianeptine enhances serotonin
reuptake, trazodone is an agonist of the 5-HT1A receptor that slows the release of
serotonin into the cleft, and mianserin is an agonist to the α2 receptor that slows the
release of norepinephrine into the cleft (Mennini et al., 1987; Haria et al., 1994; Manier et
al., 1989).
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As support for the monoamine hypothesis waned, other hypothesized mechanisms
for the development of depression emerged. Three of the more studied hypotheses
involved 1) dysregulation of the HPA axis, 2) elevated peripheral and neurogenic
inflammation levels, and 3) decreased neurogenesis and neuroplasticity in various areas
of the brain (Gold and Chrousos, 2002; Nemeroff, 1996; Dantzer et al., 2008;Pittenger
and Duman, 2008). A fourth and newer hypothesis includes dysregulation between the
sympathetic and parasympathetic nervous systems. However, the effects of dysregulation
are thought to include over-activation of the HPA axis and a lessening of anti-
inflammatory effects of acetylcholine release from afferent vagal nerve fibers (Pavlov et
al., 2008). Thus, for the purposes of this paper, dysregulation of autonomic nervous
system will be discussed in context of the other three hypotheses. While these three
hypotheses may be seen as separate, they are not mutually exclusive and there are vast
areas of overlap in mechanisms. The mechanisms explained by all three may be
physiologically relevant and explain various manifestations of depression and related
disorders. In addition, the dysregulation of neurotransmitters is likely still an important
aspect of these disorders, depending on the manifestation, and may be explained by
aspects of the newer hypotheses. While the purpose of this paper is not to elaborate in
detail on these hypotheses, it is important to discuss the basic evidence and ideas and to
relate how they may be induced by exposure to damp buildings.
Hypothalamus-Pituitary-Adrenal Axis Dysregulation Hypothesis
The HPA axis controls many endocrine hormones, including glucocorticoids,
mineralcorticoids, catecholamines (epinephrine and norepinephrine), endorphins, and
melanocyte-stimulating hormone (MSH), to name a few. This axis has significant
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influence on homeostasis, mood, memory, and learning. One mechanism of the HPA
axis directly relating to this discussion is the release of glucocorticoids, specifically
cortisol from the adrenal glands (Fox, 1996). The mechanism for controlling cortisol
release begins with corticotropin-releasing hormone (CRH). First, CRH is released by
the paraventricular nucleus of the hypothalamus due to nervous control. Next, CRH is
transported to the anterior pituitary through a portal system. Corticotropes in the anterior
pituitary are then stimulated by CRH to secrete adrenocorticotropic hormone (ACTH),
which travels through the blood to the adrenal glands. The adrenal cortex is stimulated
by ACTH to release glucocorticoids. Glucocorticoids prepare the body for stress by
facilitating gluconeogenesis and decreasing inflammation and immune cell activity to
conserve energy. Glucocorticoids provide a negative feedback loop by binding to
glucocorticoid receptors (GR) and mineralcorticoids receptors (MR) in the hypothalamus,
lowering the release of CRH (de Kloet, 1991).
Many studies have shown abnormalities in the function of the HPA axis in people
with psychiatric disorders and those that experience psychological events. Both
hypercortisolemia and hypocortisolemia may occur depending on the disorder. Major
depression appears to be related to hypercortisolemia due to impaired HPA negative
feedback (Gold and Chrousos, 2002; Nemeroff, 1996). Hypercorticosolism has been
documented in depressed patients using samples of urine, cerebrospinal fluid and plasma
(Zobel et al., 2001; Carroll et al., 1976; Linkowski et al., 1985). Enlargement of both the
pituitary and adrenal glands have also been documented (Nemeroff, 1996; Nemeroff et
al., 1992; Rubin et al., 1995). Enhanced HPA negative feedback leading to
hypocortisolism is associated with atypical depression and other
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psychological/physiological syndromes, such as chronic fatigue syndrome (Cleare et al.,
2001; Cleare et al., 2001; Gold and Chrousos, 2002; Kellner and Yehuda, 1999).
While cortisol decreases expression of CRH in the hypothalamus due to negative
feedback, it causes increased expression of CRH in the central amygdala and bed nucleus
of the stria terminialis and expression of GABAA neuronal function is increased by
cortisol. The affects of cortisol on amygdala activity is believed to result in increased
anxiety (Schulkin et al., 2005; Schulkin, 2006).
Immune/Inflammation Mechanism of Depression Hypothesis
The association between inflammatory markers and depression, dysthmia,
schizophrenia and other neurocognitive diseases is well documented. Evidence for an
inflammation model of depression is derived from in vivo and in vitro studies on the
levels of peripheral and central inflammatory cytokines and polymorphisms in cytokine
genes. The inflammation model appears to directly relate to and influence the
monoamine, HPA, and neuroplasticity/neurogenesis models.
Inflammation is an immune system response to an infection threat or to bodily
damage. Inflammation is classically defined as a reaction of tissue characterized by
redness, swelling, pain, heat, and sometimes loss of function. However, this definition
only describes a limited range of inflammatory reactions. Now, inflammation is further
described as being either acute or chronic (Kuby, 1997). Acute inflammation occurs over
a matter of seconds, minutes, hours, and days. Typically, acute inflammation affects a
limited area and often results in the classical symptoms listed above. Examples of acute
reactions include allergic responses and the swelling of tissue following damage.
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Chronic inflammation occurs over a period of weeks to years. Many forms of chronic
inflammation have both a local and system-wide impact. Examples of causes of chronic
inflammation are autoimmune diseases and responses to certain parasites (Graham,
Bandeira, Morrell, Butrous, & Tuder, 2010).
For this discussion, the use of the term inflammation refers to chronic
inflammation. The inflammatory pathways that will be described include both innate and
the cellular immune system mediators. During the inflammatory response, many cell
types, both immune and non-immune cells, release cytokines. Cytokines are proteins that
affect the actions and migration of immune cells. Cytokines may either be pro-
inflammatory, anti-inflammatory, or possess both functions. The primary inflammatory
cytokines described in this discussion include interleukin-1 (IL-1), IL-6, interferon-alpha
(IFN-α) and tumor necrosis factor-alpha (TNF-α). The primary anti-inflammatory
cytokines includes IL-4, IL-10 and IFN-β. Unless specifically stated, the use of the term
cytokines in this discussion refers to pro-inflammatory cytokines.
Immune system activation is accompanied by a set of physiological and
behavioral changes. These changes include decreased appetite and activity, depressed
emotions and isolation, among others. In general, these biological changes are termed
“sickness behavior” and they are very similar to those described for depression by the
diagnostic document The Diagnostic and Statistical Manual of Mental Disorders (DSM)
(Lorton et al., 2008). Many believe these sickness-associated symptoms prepare the body
for the exertion that will be required to address an infectious disease or repair damaged
tissue (Kelley et al., 2002).
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The similarities between symptoms of depression and sickness behavior sparked
studies linking inflammation and personality disturbances (Dantzer et al., 2008;
Reichenberg, et al., 2001). Many studies have shown that injection of pro-inflammatory
cytokines in both animals and humans induces depression symptoms. Sub-chronic
injection of IL-1β in mice resulted in altered 5-HT (serotonin) and noradrenaline
utilization in the prefrontal cortex and hippocampus (associated with depression) along
with increased production of IL-1β, IL-6, TNF-α and their receptors in these parts of the
brain (Anisman, 2009). Injection with TNF-α or lipopolysaccharide (LPS), a potent
inducer of inflammation, in rats and mice induced sickness behavior (Dantzer, 2001).
Several studies have focused on the depression symptoms experienced by some cancer
patients receiving IFN-α treatment. IFN-α increases activation of macrophages and
natural killer cells, which then release other inflammatory cytokines and attack cancerous
cells. Expression of the major histocompatibility complex (MHC), and thus T-cell
activation, is also increased by IFN-α. When these patients are pre-treated with the SSRI
paroxetine, the depressive symptoms associated with IFN-α treatment are ameliorated
(Musselman et al., 2001; Capuron et al., 2002). Similar findings have been reported in
studies of IFN-α treatment in patients with viral diseases, such as hepatitis C and HIV
(Laguno et al., 2004; Raison et al., 2009; Raison et al., 2007; Kalyoncu, 2005).
Depressive symptoms are also shown to accompany inflammatory diseases such as
rheumatoid arthritis (Lorton et al., 2008).
Elevated levels of pro-inflammatory cytokines have been repeatedly documented
in patients with depression (Yang et al., 2007; Narita et al., 2006; Tuglu et al., 2003). At
least two studies have shown that increased levels of inflammatory markers in people
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with depression decrease with treatment (Tuglu et al., 2003; Narita et al., 2006).
However, correlations between inflammatory markers and depression may be the result
of improper study design (Haack et al., 1999). Thus, it is not fully understood if the
inflammatory markers are a causative factor or just associated with depression. It is also
possible that inflammation is the causative factor in some, but not all cases of depression.
Adding to the evidence supporting associations (causative or otherwise) between
inflammatory markers and depression, multiple studies comparing genetic mutations
indicated several polymorphisms in the TNF-α and IFN-α genes. The mutations result in
higher productions of those cytokines and conveyed a higher risk for depression or
dysthmia (Jun et al., 2003; Fertuzinhos et al., 2004). However, the dysthmia markers
may not reliably decrease with treatment (Anisman et al., 1999).
In vivo and in vitro studies for several antidepressants have shown either direct or
indirect anti-inflammatory properties (Castanon et al., 2004; Yirmiya et al., 2001; Kenis
& Maes, 2002; Castanon et al., 2002). In vitro studies with TCAs, monoamine oxidase
inhibitors (MOAIs), and SSRIs have shown direct anti-inflammatory effects on immune
cells stimulated with LPS (Xia et al., 1996). One study suggests that TCAs may raise
TNF-α levels (Hinze-Selch et al., 2000). The anti-inflammatory effect may be the result
of an increase in the production of anti-inflammatory cytokines, as demonstrated by
several in vivo studies (Narita et al., 2006; Tuglu et al., 2003; Castanon et al., 2004).
Besides direct anti-inflammatory effects, other studies have shown that
antidepressants have indirect anti-inflammatory properties. A study by O’Sullivan et. al.
(O'Sullivan et al., 2008) showed that the anti-inflammatory effects of noradrenaline
reuptake inhibitors (NRIs) are likely due to the anti-inflammatory affects of the excess
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noradrenaline availability. Noradrenaline, which has anti-inflammatory properties, is
both released by the adrenal gland and is used as a neurotransmitter. Excess
noradrenaline in synapses may decrease local release of pro-inflammatory cytokines by
microglia. Microglia are immune cells that surround neurons in the central nervous
system. In vitro addition of NRIs to LPS-induced immune cells did not have an anti-
inflammatory effect while addition of noradrenaline did, providing more evidence of the
indirect effect on anti-inflammatory action.
Release of acetylcholine by the parasympathetic efferent nerves also appears to
have a direct anti-inflammatory effect that may ameliorate symptoms of depression
(Pavlov et al., 2008). Acetylcholine, which is the primary vagal neurotransmitter, binds
to the alpha7-nicotinic receptor on macrophages. Binding of the receptor results in a
decreased release of inflammatory cytokines from macrophages due to activating the
STAT3 and SOCS3 pathway. This pathway ultimately blocks NF-κβ from inducing the
production of inflammatory cytokines (Jonge et al., 2005). Other immune cells may also
be affected by acetylcholine as the vagus nerve appears to have a tonic effect on CD4 + T-
cells (O'Mahony et al., 2009). One study found an association between symptoms of
depression, colitis, and vagal integrity in a murine model (Ghia et al., 2008). The TCA
antidepressant desmethylimipramine restored vagal integrity and acetylcholine levels,
lowered colitis, and lessened depressive symptoms. A previous study by the same
researcher indicated that colitis induced in vagotomized mice was reduced following
several weeks when other anti-inflammatory mediators, such as IL-10, TGF-ß, and FoxP3
had naturally upregulated (Ghia et al., 2007). Thus, some evidence suggests that
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acetylcholine release is an early and significant anti-inflammatory response, but that other
anti-inflammatory mechanisms may compensate for the lack of this release.
Another study indicated that chronic tianeptine treatment attenuated TNF-α
production in rats injected with LPS (Castanon et al., 2004). The central balance between
pro- and anti-inflammatory cytokines (IL-1ß/IL-10) was also altered. Conversely, at least
one study suggests that elevated inflammatory markers in human studies may be the
result of improperly accounting for confounding factors, such as smoking or recent
infections (Haack et al., 1999). Thus, the evidence strongly supports a role for
inflammation in the pathogenesis of depression. Evidence is supported by several lines
of reasoning using both in vitro and in vivo studies. It is unknown if the primary effects
are caused by directly or indirectly dampening the production of inflammatory cytokines.
Perhaps both direct and indirect anti-inflammatory effects are crucial for the cessation of
depression symptoms.
Neuroplasticity and Neurogenesis Depression Hypothesis
Another well-supported hypothesis for depression involves decreased
neuroplasticity and neurogenesis. Neuroplasticity refers to the ability of the brain to
functionally and structurally adapt to stimuli, and is the basis for learning and
development (Malenka and Nicoll, 1999). Plasticity occurs at both the synaptic and
structural levels. Synapses have the ability to increase or decrease levels of
neurotransmitter receptors (Corera et al., 2009). The dendrites themselves may also
increase in size, complexity, and spine presentation upon repeated stimulation (Malenka
and Nicoll, 1999; Ethell and Pasquale, 2005).
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While neurogenesis is most active in pre-natal development, adult neurogenesis
primarily occurs in the dentate gyrus of the hippocampus and the subventricular zone
lining the lateral ventricles. Decreases in both neuroplasticity and neurogenesis have
been implicated in psychological changes (Pittenger and Duman, 2008).
The neuroplasticity/neurogenesis hypothesis suggests that depression results from
atrophy of neurons, changes in the synapses, and/or decreased neurogenesis in regions of
the brain such as the pre-frontal cortex and hippocampus, as well as through increased
dendritic remodeling in the amygdala (Pittenger and Duman, 2008; Schulkin, 2006;
Kasper and McEwen, 2008). The amygdala is the center for emotional control and
anxiety (Pittenger and Duman, 2008). Deficiencies in the pre-frontal cortex and
hippocampus have the potential to significantly impact emotions and memory. The pre-
frontal cortex is the anterior portion of the frontal lobes. Evidence suggests that this
portion of the brain influences personality expression, social behavior, and decision
making. The hippocampus is located in the medial temporal lobe in the cerebral cortex.
Memory formation, memory storage, and spatial navigation are the primary functions of
the hippocampus. Decreased plasticity and structural changes have been repeatedly
observed in vivo in these regions of the brain using animal depression models, post-
mortem studies, and neuroimaging (Sheline et al., 1996; Stockmeier et al., 2004;
MacQueen et al., 2002; Savitz and Drevets, 2009).
Whether decreased neurogenesis and neuroplasticity in the hippocampus and pre-
frontal cortex and increased amygdala dendritic remodeling is causal to or merely
associated with depression is not completely understood. However, studies with some
antidepressants have shown normalizations in neurogenesis and neuroplasticity in these
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egions (Uzbay, 2008; Kasper and McEwen, 2008; Boldrini et al., 2009). Supporting the
link between antidepressant effects and neurogenesis, an experiment demonstrated that
the effects of antidepressants were nullified when neurogenesis was blocked by
irradiation of hippocampi in mouse model (Santarelli et al., 2003).
Several mechanisms inducing neural atrophy have been elucidated. A well-
supported pathway leading to neural atrophy is a phenomenon termed excitotoxicity.
This phenomenon occurs when neurons receive excessive stimulation, resulting in
neuronal damage and cell death. As reviewed by Forder and Tymianski, excitotoxicity
studies have primarily focused on activation of voltage-gated calcium channels and
glutamate-sensitive channels, such as N-methyl-d-aspartate (NMDA) receptors on
neurons (Forder and Tymianski, 2009). Binding of the NMDA receptor opens its channel
to the influx of calcium ions. The calcium ions bind and activate the intracellular protein
calmodulin. In neurons, calmodulin then activates neuronal nitric oxide synthase
(nNOS). While the free radical nitric oxide (NO) acts as a neurotransmitter, high levels
are toxic to cells. In addition, the influx of calcium results in the production of oxygen
free radicals, such as superoxide. NO reacts with superoxide to create peroxynitrite
(ONOO-). Peroxynitrite is a very toxic chemical that oxidizes lipids, proteins, and DNA.
Peroxynitrite also interferes with important phosphorylation events. Beyond NMDA
receptors, other receptors may also be involved with producing reactive oxygen species
and the resulting toxicity (Forder and Tymianski, 2009).
Several lines of evidence support the NO toxicity hypothesis. One line of
evidence is that several NMDA receptor antagonists have anti-depressant activities and
lessen hippocampal dendrite atrophy in animal screenings and human studies (Oliveira et
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al., 2008). However, increasing NMDA receptor activity decreased neurogenesis in the
rat dentate gyrus (Cameron et al., 1995). Evidence also indicates that it is the
extrasynaptic NMDA receptors (versus the synaptic NMDA receptors) that are involved
in this excitotoxicity reaction (Leveille et al., 2008; Vanhoutte and Bading, 2003).
Integration of Three Hypotheses
While these three hypotheses are often discussed separately, they all share many
common features and may all be relevant. For example, chronic activation of the HPA
axis and the immune system can each directly result in decreased neuroplasticity and
neurogenesis. The HPA axis, in turn, can be induced by stress, decreased neurogenesis,
and by the immune system. Regulation of the immune system may be partly lost due to
decreased activity of the HPA axis or by polymorphisms in immune genes responsible for
recognizing signals by the HPA axis. In the following sections, the various interplays
between these three hypotheses will be addressed.
Over-activation of the HPA Axis and Neurogenesis/Neuroplasticity
Previously, the relationship between over-activity of the HPA axis and symptoms
of depression and anxiety were discussed. The symptoms of anxiety produced by the
actions of glucocorticoids on the body are widely accepted and will not be further
discussed.
Studies suggest that overproduction of glucocorticoids may also result in
decreased neuroplasticity as the synaptic spines regress, resulting in symptoms of
depression (Bennett, 2008). Pittenger and Duman provide a comprehensive review on
the topic of stress and neuroplasticity (Pittenger and Duman, 2008). Chronic stress and
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the associated elevated glucocorticoids have been shown to result in changes at the
synaptic level, reduce dendrite complexity and size in hippocampus and the PFC, and
result in behavioral patterns that mimic depression. These changes are similar to those
experienced with depression. In addition, studies have shown that antidepressants can
attenuate stress-induced behavioral changes (Willner, 2005).
The hippocampus, which is shown to degenerate in depressive individuals, negatively
modulates the HPA axis. Thus, degeneration of the hippocampus may result in increased
HPA axis activation (Pittenger and Duman, 2008).
Immune system activation of the Hypothalamus-Pituitary-Adrenal axis
As discussed previously, activation of the immune system results in release of the
proinflammatory cytokines IL-1β, IL-6, TNF-α, IFN-α, among others. TNF-α, IL-1β, and
IL-6 have all been shown to directly or indirectly activate the HPA axis by stimulating
the release of CRH, ACTH, or glucocorticoids from these tissues (Elenkov et al., 2000;
Zhang et al., 2002). The resulting glucocorticoids then bind to the glucocorticoid
receptors (GRs) on immune cells, turning off the genes producing pro-inflammatory
cytokines. This negative feedback loop is important in regulating immune reactions.
However, chronic production of TNF-α, dysregulation of the central production of
inflammatory molecules (Zhang et. al., 2002), or polymorphisms in the GR may disable
this feedback system. Thus, the mounting inflammatory response may result in
neurogenic inflammation (discussed previously) and the resulting decrease in
neuroplasticity. As a result, the chronic release of glucocorticoids may also increase
decrease neuroplasticity.
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A polymorphism in a chaperone protein for the glucocorticoid receptor was found to
be associated with increased depressive episodes and more response to anti-depressant
drugs (Binder et. al, 2004). There is a strong possibility that other such polymorphisms
may lead to decreased receptor expression, weakening the negative feedback loop of
cortisol (van Rossum et al., 2006). Pro-inflammatory cytokines, specifically IL-6, have
been shown to increase CRH expression. Although no studies have been completed, it is
possible that some people may experience depression due to an inability to dampen
inflammatory reactions that are heightened due to polymorphisms in the genes for the GR
receptor or chaperone proteins in immune cells.
Immune system reduction of neuroplasticity/neurogenesis
While the immune system may induce “sickness behavior” with symptoms
reminiscent of depression, at least one has shown that chronic activation of the immune
system may directly reduce neuroplasticity and neurogenesis, potentially resulting in
depression. The peripheral immune system may induce neurogenic inflammation, which
induces excess neurogenic inflammation. This neurogenic inflammation then results in
atrophy of neural cells (Teeling and Perry, 2009).
Cytokines produced in the periphery have the ability to induce central
inflammatory processes through three proposed mechanisms. The mechanisms include
direct binding of peripherally-produced cytokines to brain tissue, afferent nerve
activation by binding of peripheral cytokines to the vagus nerve, and the production of
prostanoids by endothelial cells of the blood-brain barrier (BBB) following binding of
cytokines or LPS to receptors (Teeling and Perry, 2009).
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Peripherally-produced cytokines may affect brain structures by accessing the
brain through direct transport by endothelial cells or by entering areas of the brain not
protected by the BBB, such as the circumventricular organs (Turrin and Rivest, 2004;
Banks, 2005). Cytokines are too large to cross the BBB without active transport.
However, supportive evidence of this pathway playing a significant role in neurogenic
inflammation is limited.
Peripherally-produced cytokines also bind to the afferent fibers of the vagus
nerve, inducing neurogenic inflammation. Up to 80-90% of the fibers of this nerve are
afferent, providing sensory information to the CNS. Inflammatory cytokines and LPS in
these tissues bind to receptors on the vagal fibers, signaling the CNS that an
inflammatory reaction is occurring. A study by Honsoi et al. (Hosoi et al., 2000) has
shown that electrical stimulation of the afferent fibers results in an elevation of IL-1β in
the hippocampus and the hypothalamus. An elevation of IL-1β was not observed in the
periphery, suggesting central production of the cytokines. In response, the efferent fibers
of the vagus nerve release acetylcholine, an anti-inflammatory molecule as discussed
above. This reaction attenuates peripheral inflammation.
Stimulation of the vagus nerve is currently used to treat depression where
pharmacology has failed to produce results. The effects on depression may be the result
of acetylcholine release from the efferent nerves dampening inflammatory responses
(Rosas-Ballina et al., 2009).
A third mechanism for peripherally-produced cytokines to induce neurogenic
inflammation is by binding to the endothelial cells of the BBB. IL-1ß, TNF-α, and LPS
bind to receptors on the endothelial cells. Once bound, these receptors signal production
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of prostaglandins, thromboxanes, and leukotreines that diffuse into the CNS to exert an
inflammatory signal (Turrin and Rivest, 2004). Prostaglandin E2 (PGE2) appears to be
important in neuronal degeneration and death. While PGE2 is produced by post-synaptic
neurons as a retrograde neurotransmitter, it is the PGE2 produced by non-neuronal cells,
likely astrocytes and endothelial cells, that appear to be responsible for the cellular
degradation (Takemiya et al., 2006; Sang et al., 2005). Binding of one of the PGE2
receptors, EP2, results in the activation of inducible nitric oxide synthase (iNOS), which
may be required to produce the detrimental effects on the neurons (Shie et al., 2005).
One proposed mechanism leading to neural atrophy by the immune system
following its activation by one or more of the pathways previously discussed involves
increased production of neurotoxic compounds from tryptophan degradation (Wichers et
al., 2005). The first step in tryptophan degradation is mediated by the enzyme
indolamine 2,3-dioxygenase (IDO). IDO production is stimulated in immune cells by
IFN- α, IL-2, and TNF-α (Capuron et al., 2002). During the process of tryptophan
degradation, 3-hydroxykynurenine is created. This compound may cross the BBB to
induce neuronal apoptosis from the production of reactive oxygen species (Dantzer and
Kelley, 2007; Okuda et al., 1998). Microglia may also degrade tryptophan to produce
toxic metabolites (Myint et al., 2009). One of two possible end-products of tryptophan
degradation is quinolinic acid, a potent agonist of the NMDA synapse receptors.
Overstimulation of the NMDA receptors results in neuronal damage (Stone and Addae,
2002). Neuronal damage from NMDA overstimulation and the elevated production of
NO was observed during a post-mortem experiment using brain tissue from individuals
affected with major depression (Oliveira et al., 2008).
18

A study assessed the level of neuronal damage in the hippocampus of adult male
rats caused by quinolinic acid, IL-1β, and TNF-α (Stone and Behan, 2007). The study
findings revealed that low doses of quinolinic acid, IL-1β or TNF-α did not induce
neuronal damage, but a combination of quinolinic acid and IL-1β resulted in significant
neuronal damage. Higher doses of these two compounds nearly decimated the pyramidal
cells.
Microglia activation results in the production of quinolinic acid from the breakdown
of tryptophan, which is also a precursor for serotonin. Wichers et al. completed an
elegant study that correlated tryptophan degradation, and thus the production of the
neurotoxic compounds, with increases in depressive symptoms during TNF-α treatment
in patients with chronic hepatitis C (Wichers et al., 2005). This study did not find a
correlation between tryptophan availability and depression, however. Being that
tryptophan is a precursor to serotonin, some studies have concluded that the decrease in
tryptophan availability affects serotonin levels, and thus depressive symptoms (Capuron
et al., 2002). However, studies that suggest a reduction of tryptophan as being causative
for depression must be sure to include measurements of the buildup of neurotoxic
compounds from tryptophan degradation (Bonaccorso et al., 2002).
Damp Buildings and Inflammation
A growing body of studies has assessed neurological symptoms in people exposed to
damp buildings. Most reported only on the presence of mold growth. However, the
findings of these studies cannot be narrowly viewed as evidence that mold was the only
or the most pertinent agent to induce such symptoms, as other agents are also present in
damp environments. The general assertion is that occupant health effects are primarily
19

the result of exposure to chemicals released from damp building materials and from both
the microbial volatile organic compounds (mVOCs) and multiple inflammagens (a
generic term describing a chemical or agent that induces an inflammatory reaction)
produced by biological growth. Secondary metabolites, such as mycotoxins, are also
considered (Seltzer, 2007; Mudarri and Fisk, 2007; Bornehag et al., 2004; Bornehag et
al., 2001).
Inflammation is strongly supported as being a factor in inducing depressive
symptoms, likely through affecting neuroplasticity and neurogenesis. An inducer of the
inflammatory process in the body is exposure to damp environments. It is well
recognized that occupants of damp buildings report a number of symptoms, many being
associated with activation of the immune system (IOM, 2004; WHO, 2009). Damp
buildings release numerous potential inflammagens, both biological and chemical in
nature. Contaminants commonly associated with damp buildings include the increased
release of volatile chemicals from building materials, growth of fungi and bacteria, and
growth of dust mites and cockroaches. While the various contaminants by themselves
may induce inflammation, the potential interactions and synergism and antagonism
between the various potential mixtures may be near infinite.
Several studies have shown that skin, eye, nose, and throat irritation are increased in
people occupying damp buildings and habitats with elevated or distinct mixtures of
volatile chemicals (Saijo et al., 2004; Sunesson et al., 2006). However, studies have also
shown that symptoms in sensitive people beyond general irritation also occur in damp
buildings. Specifically, humans exposed to damp buildings experience increases in
20

allergies and asthma and other inflammation processes (Dales and Dulberg, 1998;
Bornehag et al., 2004; Roponen et al., 2003).
In one study, the levels of inflammatory markers TNF-α, IL-6, and nitric oxide in
nasal lavage fluid were compared between staff members in a fungal-contaminated
school and a reference group (Hirvonen et al., 1999). During the school year, the staff
members from the contaminated building had higher levels of these markers than the
control group, but showed a lower levels of these markers compared to the controls
during the summer break. When the staff went back to the building during the fall
semester, nitric oxide and IL-6 increased again.
Several epidemiological studies have correlated increased inflammatory markers in
serum of people exposed to damp buildings. One study assessed multiple immune
markers in 209 symptomatic patients with self-reported exposures to damp buildings
(Gray et al., 2003). When compared to controls, patients with exposure to moldy
dwellings reported significantly more symptoms, especially those that were neurological
and inflammatory in nature. The research group found significant increases in T-cell
activation, pro-inflammatory cytokines levels, and autoantibodies concentrations to
components of the central and peripheral nervous system.
Another study compared the neurological measurements of 65 patients self-reporting
exposure to damp home environments that supported fungal growth (Kilburn, 2003).
Growth was confirmed via microscopic identification and analysis of air samples. The
patients underwent a battery of neurophysiological and neurobiological tests,
neurological examination, serum antibody measurements to molds and mycotoxins, as
well as respiratory flow and vital capacity testing. When compared to a control group of
21

202 unexposed individuals, the patient group measurably differed with multiple
impairments of neurophysiological and neurobiological markers. Included in these
impairments were reaction time, verbal recall, and grip strength, among many others.
The patient group also had a higher reporting of depression and other mood states. For
biological measurements, the patient group exhibited elevated levels of antibodies
specific for molds and satratoxin (fungal mycotoxin) and reduced pulmonary function
compared to control, indicating activation of the immune system.
A study by Dales and Dulberg compared the activation of T- and B-cells in a group of
school-aged children (Dales and Dulberg, 1998). Four hundred residences in a
community were assessed for levels of fungal growth. The residences were ranked based
on levels of fungal debris present. Thirty-nine homes near the higher end of the range of
the level of fungal debris present and 20 homes towards the lower end were included in
the study. Blood samples from children in these environments were assessed. The
children in the 39 homes with more fungal biomass (indicating more water damage) had a
higher percentage of differentiated T-cells, indicating previous antigen exposure and
activation, and a decreased CD4 + /CD8 + ratio. This difference persisted for 12 months as
shown in a follow-up blood screening.
Another study measured the TNF-α levels secreted by peripheral white blood cells
and the IFN-γ/IL-4 secretion ratio in people exposed to damp buildings (Beijer et al.,
2003). Non-stimulated white blood cells isolated from atopic and non-atopic people
chronically exposed to environments with water damage expressed increased levels of
TNF-α. Non-atopic people also had an increased IFN-γ/IL-4 ratio. Notably, both of
these markers increased as the level of measured fungal exposure increased. An increase
22

in TNF-α secretion indicates an overall increase in inflammation and an increase in the
IFN-γ/IL-4 ratio indicates a shift to a Th1 (versus Th2) response. Another research group
reported similar dominance of Th1 inflammatory pathways in patient exposure to
biological components of damp buildings (Dales and Dulberg, 1998). The finding by
Beijer’s group and others is significant in that delayed-type hypersensitivity (DTH)
reactions are dominated by Th1 responses, especially in non-atopic individual. These
studies provide initial evidence suggesting that exposure to water-damaged and damp
environments may induce or support the inflammatory pattern of DTH reactions, which
result in more chronic inflammatory levels. Since chronic inflammation appears to be an
inducer of depression, the DTH reaction induced by humans exposed to damp buildings
may be crucial in the development of neurological symptoms experienced by sensitive
people in damp buildings. DTH reactions can occur independent a person’s ability to
have immediate, Type 1 allergic reactions.
Genetic Propensity to Reaction
Health reactions to damp buildings have some genetic components, such as
differences in reactions between people with and without allergic tendencies.
Interestingly, an allergic mouse model study displayed an increase in neutrophils,
macrophages, and eosinophils when exposed to fungal spores, while the non-allergic
model displayed only increased macrophages (Leino et al., 2006). The non-allergic
model also experienced a decrease in CD4 + /CD8 + ratio and a Th1 cytokine profile while
the allergic model did not. However, the switch to a favored Th1 profile may be
prevented by the priming of the allergic mouse models with ovalbumin, inducing a Th2
profile prior to spore exposure. The study also indicated a more pronounced
23

inflammatory reaction in allergic mouse models exposed to fungal spores than non-
allergic exposed to fungal spore models and control allergic models. A Th1
inflammatory reaction is a delayed reaction, and as discussed earlier, may result in a more
chronic inflammatory condition. This raises the question as to whether non-atopic
individuals are more prone to the depression-inducing chronic inflammation from
exposure to damp spaces than atopic individuals.
Beyond allergic tendencies, people with underlying conditions that result in
chronic inflammation may be predisposed inflammatory reactions from exposure to damp
buildings and the resulting neurological insult. As an example of such an effect, Teeling
and Perry discuss that people with inflammatory diseases have more depression with
IFN-α treatment (Teeling and Perry, 2009). Teeling goes on to discuss that astrocytes
(which includes microglia) proliferate due to inflammation, which go on to release
additional inflammatory cytokines. Excessive astrocyte numbers are seen in several
CNS-related diseases, such as multiple sclerosis, Alzheimer’s disease, and stroke. Thus,
genetic propensity for poor regulation of astrocyte proliferation due to underlying chronic
inflammation may be a risk factor.
Shoemaker, Hudnell and colleagues have produced several publications reporting
evidence for a genetic component underlining exaggerated and chronic inflammatory
reactions associated with damp buildings. Their work began with documenting
inflammatory reactions in susceptible people caused by the estuarine dinoflagellate,
Pfiesteria piscidia (Hudnell, 2005; Shoemaker and Hudnell, 2001). The susceptible
people experienced multiple symptoms and increased levels of inflammatory markers
with exposure to P. piscidia blooms in estuaries. Because of their work, a disease
24

described as possible estuary-associated syndrome (PEAS) was recognized by the United
States Centers for Disease Control.
Continuing their work on inflammatory diseases from biological exposures, this
group then found the same increase in immune markers and multi-system symptoms in
some individuals exposed to damp buildings (Shoemaker and House, 2006). Abnormal
inflammatory levels and symptoms were alleviated in both PEAS and damp building
exposure through the use of cholestyramine and immune modulating drugs.
Cholestyramine is a chelating agent that is typically used to lower cholesterol, although it
can also remove chemical and biological agents from the intestines. One hypothesis is
that inflammagenic agents from damp buildings are not eliminated from the body in
genetically susceptible individuals. Hypothetically, the agents would eventually be
transported into the intestines by the liver and then migrate through the intestinal wall
back into the body. Cholestyramine in the intestines would act as a chelating agent,
binding and removing the agents.
Genetic data compiled from individuals that reportedly have been successfully
treated using the cholestyramine therapy suggests that certain human leukocyte antigen
(HLA) genes may be responsible for the susceptibility. Specific alleles associated with
susceptibility included certain Class II HLA-DR and –DQ loci (Hudnell, 2005). This
genetic data may partly answer why only a minority of the population appears to be
significantly impacted by exposures to damp buildings.
Beyond HLA genotypes, other genetic factors are also likely involved.
Dysregulation of the body’s systems resulting in depression and immunological
irregularities due to genetic polymorphisms is well documented. Similar polymorphisms
25

may be a factor in chronic inflammatory reactions in damp buildings. A potential for
exaggerated psychological effects due to elevated cytokine levels has been shown in past
experiments where patients were injected with IFN-α as a treatment for tumors that
resisted chemotherapy and radiotherapy. Patients that experienced abnormally increased
HPA axis activity and resulting depressive symptoms had scored higher on a depression
scale prior to treatment (Dantzer et al., 2008). The findings from this study support a
genetic component that may link susceptibility to damp building exposures to an inability
to control inflammatory responses.
Volatile Chemicals from Microbes and Building Materials
Along with biological growth, elevated levels of volatile chemicals are often present
in damp buildings. Volatile chemicals have been hypothesized as inducing symptoms in
people exposed to damp buildings. Building materials often include a multitude of
chemicals from the manufacturing processes. While VOCs will be released during the
lifespan of the various materials and adhesives, an increased release will occur within the
first several weeks to months of installation and when the various materials and adhesives
become damp (Fang et al., 1999; Pasanen et al., 1998; Park and Ikeda, 2006). Microbial
degradation of the materials will also likely release VOCs.
The microbes also produce their own volatile compounds termed microbial volatile
organic compounds (MVOCs). MVOCs are secondary metabolites released by bacteria
and fungi that are dominated by alcohols, but also include ketones, aldehydes, terpenes,
esters, amines, and sulfides (Claeson et al., 2002). A commonly recognized MVOC is
geosmin – the compound that gives soil the characteristic aroma.
26

While it has been shown that VOCs and MVOCs are elevated in damp spaces, it
is unknown if they have an appreciable impact on one’s health or the inflammatory
processes. As for VOCs, relatively few studies have been completed that assess the
potential of domestic levels of these chemicals to induce inflammatory processes. The
studies that have been completed primarily focus on pulmonary inflammation. One study
assessed the individual effects of dampness, VOCs, formaldehyde, and NO2 in homes and
the effect on wheezing in children between the ages of 9 and 11 (Venn et al., 2003).
Their study included a significant sample size of 193 cases and 223 controls. The data
suggested dampness and formaldehyde levels had an effect on wheeze. The data did not,
however, support the contention that indoor levels of VOCs or NO2 measurably affected
wheeze. However, VOC levels in the homes considered damp were not separately
assessed for correlation to wheeze. A recent review by Nielson et al. (Nielsen et al.,
2007) also did not find convincing evidence that VOC levels in damp buildings
significantly aggravated allergic asthma. These findings suggest that VOC release in
damp buildings does not significantly impact health or support inflammatory processes in
the body.
Studies assessing the health impact of MVOCs in damp buildings have been
similarly non-supportive of such a correlation between their presence in typical damp
buildings and adverse health effects (Korpi et al., 2009). One such recent study exposed
participants to filtered air from a chamber of damp building materials inoculated with
mold (Claeson et al., 2009). This study accounted for both VOCs from the materials and
MVOCs from mold. When the volatiles were at levels typically found in damp buildings,
no health symptoms were reported. Even when the levels of the volatiles were increased
27

to 10-100 times greater than that found typically in damp buildings, they did not
significantly induce health effects. However, some studies do provide evidence that
suggest increased incidence of asthma following exposure to certain VOCs, such as
benzene, toluene (Rumchev et al., 2004), and formaldehyde. Whether this increase in
pulmonary inflammation can significantly raise inflammatory levels on a body-wide level
has yet to be determined.
In general, it has been concluded that VOCs at indoor concentrations, with
exception to a few species noted above and some others, do not induce inflammation in
the general population. However, several studies have presented convincing evidence
that some people who report symptoms of multiple chemical sensitivity (MCS) do
experience an increase in inflammatory markers when exposed to domestic levels of
VOCs. Such sensitivities appear to result from neural sensitization due to chemical
exposures, psychological stress, and/or neurogenic inflammation (Bell et al., 1999; Bell
et al., 1998). However, some researchers view MCS as a somatoform disease (Bailer et
al., 2007). One study observed that MCS patients experienced measurable levels of
neurogenic inflammation where cytokines released by nerves increased histamine levels
(Hajime, 2004). The study compared the levels of substance P (SP), vasoactive intestinal
peptide (VIP), nerve growth factor (NGF), and histamine in normal controls, patients
with atopic eczema/dermatitis syndrome (AEDS), and in patients with self-reported
MCS. Baseline plasma levels of SP, VIP, and NGF were elevated in MCS and AEDS
patients, but not in the control group. In addition, histamine was also elevated in AEDS
patients. All participants in the study were found to have normal T-cell levels and were
generally non-atopic, with the exception of the AEDS patients. Exposure to 3.13-3.42
28

mg/m 3 of VOC released from freshly painted walls significantly increased the levels of
SP, VIP, NGF and histamine in MCS patients, but not in control or AEDS patients.
These findings suggest that some people are primed to have exaggerated inflammatory
responses to chemical exposures that are mediated by the nervous system.
Another study showed that formaldehyde exposure was able to induce the
production of NGF in the hippocampus of ovalbumin-sensitized mice, but not in non-
immunized mice (Fujimaki et al., 2004). An extension of that study found evidence to
suggest that formaldehyde binds to vanilloid receptors on glutamatergic nerves of the
trigeminal nerve system, stimulating the increase in some of the proteins required for
long-term potentiation (Ahmed et al., 2007). Other researchers have presented evidence
that indicates prolonged or exaggerated long-term potentiation of these glutamatergic
nerves in susceptible people can induce excitotoxicity and neuron degeneration by the
overproduction of reactive oxygen species of NO, superoxide, and peroxynitrite (Forder
and Tymianski, 2009; Pall, 2007), which could then decrease neurological plasticity by
causing neuron cytotoxicity and the resulting symptoms of depression and cognitive
deficiency. However, the effects of formaldehyde in the two mouse studies required the
induction of inflammation through ovalbumin sensitization, suggesting a required
inflammatory event to induce chemical sensitivity. The peripheral inflammation may
prime a central inflammatory reaction by nerves, allowing for the induction of LTP and
chemical sensitivity. Indeed, a murine study by Afrah et al. (Afrah et al., 2004),
indicated that chemical receptors on the trigeminal nerve may be more sensitive, causing
the increased release of SP in the spinal cord when the body is experiencing peripheral
inflammation.
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While some studies have provided adequate evidence that VOC release increases in
damp environments, the VOCs are still relatively low in concentration. Currently, studies
do not support an effect of VOCs release damp buildings on human health. However,
some people may be exquisitely sensitive to chemicals and may react in damp buildings
from VOC release.
Dust Mites, Mold Mites, Protozoa and Cockroaches in Damp Buildings
Beyond bacteria and fungi, dust and mold mites, protozoa, and cockroaches may
grow in damp buildings. Dust mites (Dermatophagoides farinae and D. pteronyssinus)
and mold mites (Tyrophagus putrescentiae) are arachnids. Studies generally indicate that
mites require a minimum relative humidity over 45-50% (WHO, 2009). Dust mites are
found in house dust, mattress dust, and bedding in damp buildings (WHO, 2009). These
mites feed primarily on human skin scales. Mold mites, as their common name suggests,
feed on fungal growth and sometimes the substrate supporting the growth. Dust mites
produce allergens and may significantly affect sensitive occupants (Wraith et al., 1979;
Bornehag et al., 2004). The major antigen in D. farinae is Der f I, which is a protease
found in mite feces. Major antigens in D. pteronyssinus are Der p I and Der P II. In
addition, a recent study has isolated a potentially allergenic component from T.
putrescentiae as well (Jeong et al., 2009).
Protozoa are unicellular eukaryotic cells that can be found in improperly draining
condensate pans and other areas of standing water. Very few studies have been conducted
to assess the potential health impact of protozoa in damp buildings (WHO, 2009).
Cockroaches produce the allergen Bla g 1, which is commonly present in concentrations
that can induce allergic sensitization and asthma morbidity (Cohn et al., 2006).
30

Cockroaches are attracted to standing water (WHO, 2009) and may be more prevalent in
damp buildings.
The deleterious effects of exposure to dust mites, mold mites, and cockroaches are
well documented as these organisms produce known allergens (WHO, 2009). Chronic
exposure and inflammatory reactions elicited to these allergens may impact neurogenic
inflammatory levels, resulting in symptoms of depression. However, the long-term effect
of exposure to these organisms and induction of depression have not been studied.
Additional studies using common allergens and their relationship to depression would be
beneficial.
Inflammation Induced by Bacteria and Fungi
Inflammatory reactions in the form of immediate and delayed-type reactions to fungi
and bacteria are well established. Bacterial cells and membrane fragments can cause
shock when released into the bloodstream. Significant localized tissue inflammation is
also a well-recognized reaction to bacterial growth in tissue. Approximately 10% of
emergency room admissions for asthma are the result of outdoor fungal spore exposure
(Rand et al., 2005). Three to thirty percent of Europeans tested positive for IgE-mediated
sensitivity to Cladosporium or Alternaria, common fungal spore types in outdoor air
(Bavbek et al., 2006). Other commonly encountered fungi that can elicit an exacerbation
of allergy symptoms include Penicillium, Aspergillus, and Epicoccum.
Elevated levels of fungal and bacterial growth are commonly found in damp
buildings. Due to the disparate environmental conditions between indoors and outdoors,
stark differences in the fungal biota between these two habitats are recognized. With a
31

few exceptions, many of the genera found dominating damp spaces are rarely elevated in
outdoor air samples. For some genera found in both indoor and outdoor habitats, the
dominant species between indoors and outdoors differ. As an example, Cladosporium
herbarum and occasionally Cladosporium cladosporioides dominate in outdoor samples,
while C. cladosporioides and sometimes Cladosporium sphaerospermum dominate
indoors when conditions supporting Cladosporium are present (Bush and Portnoy, 2001;
Kuchenbecker, unpublished). Because fungal genera vary in their allergenic properties,
an individual’s reaction to indoor versus outdoor fungal growth may differ.
Many different Gram-positive and Gram-negative bacteria are isolated from water-
damaged materials. In addition, filamentous Gram-positive bacteria in a group termed
actinomycetes, most notably thermophilic actinomycetes and Streptomyces, are also
isolated (Hirvonen, et al., 1997; Andersson, et al., 1997; Thrasher, 2009). Actinomycetes
are potent stimulators of the innate immune system (Hirvonen et al., 1997). An unusual
percentage of the bacteria in damp buildings are Gram-negative, often dominating Gram-
positive organisms (Kuchenbecker, unpublished). Because Gram-negative bacteria have
a thinner peptidoglycan cell wall, they are more susceptible to dessication and UV
irradiation, and thus are normally less abundant than Gram-positive organisms on
inanimate surfaces.
Airborne exposures to fungi and bacteria produce inflammation involving both
the acquired and innate immune systems through multiple mechanisms. Exposures of
whole fungal spores and components from multiple genera that are common in damp
buildings have induced inflammation in in vivo and in vitro rodent models using
RAW264.7 mouse macrophages (Leino et al., 2006; Chung et al., 2005; Jussila and
32

Komulainen, 2002; Huttunen et al., 2003). Exposure of this cell line to fungal spores of
indoor-associated genera, such as Aspergillus, Penicillium, and Stachybotrys, induces the
production of pro-inflammatory cytokines IL-1, IL-6, and TNF-α (Murtoniemi et al.,
2003; Huttunen et al., 2003). Studies show that bacteria have an even higher
inflammatory potential than fungi, with actinomycetes being the most reactive (Huttunen
et al., 2003; Jussila and Komulainen, 2002; Jussila et al., 2002; Jussila J. et al., 2001;
Hirvonen et al., 2005).
Many in vivo experiments include either aspiration or instillation of fungal spores
or extracts from the spores in either the trachea or nasal passages. In most studies, the
bronchial alveolar lavage fluid (BALF) was analyzed either for immune cell presence or
levels of pro-inflammatory cytokines. Studies did show an appreciable inflammatory
effect on pulmonary tissue (Viana et al., 2002; Flemming et al., 2004; Chung et al., 2005;
Chung et al., 2007).
Going beyond animal models, several surveys have been completed that measured
antibody levels in serum of healthy control individuals and those that were exposed to
moldy environments. One such study compared the antibody levels of three cohorts: 500
patients exposed to moldy indoor environments who had reported neurological and other
symptoms, 500 healthy control subjects, and 500 random blood samples of patients
whose blood had been sampled for reasons other than mold exposure (Vojdani et al.,
2003B). Approximately sixty of the exposure buildings were verified by environmental
engineers and found to have elevated levels of fungal growth. The patients lived in these
environments for periods from two weeks to two years. Their findings indicated a
significant difference in elevated IgG, IgM, and IgA antibodies to antigens from
33

Penicillium notatum, Aspergillus niger, Stachybotrys chartarum, and to the mycotoxin
satratoxin H produced by Stachybotrys from the patients exposed to moldy environments
compared to the healthy group. The randomly sampled patient group (some whom may
have had exposure to moldy environments) had elevated antibody levels compared to the
healthy control group, but lower than the mold exposure group. This study strongly
suggests that people reporting symptoms following exposure to moldy buildings are
experiencing immune activation as evident by antibody production. However, this study
does not necessarily indicate that exposure to moldy buildings automatically results in
inflammation in all people as that aspect was not controlled or tested for in this study.
Another study surveyed IgA antibodies levels in the saliva of forty occupants in a
heavily water-damaged commercial building where neurological symptoms were reported
by occupants (Vojdani et al., 2003A). Forty matched controls with no history of
exposure to water-damaged buildings were also assessed. The saliva of the 40 occupants
had significantly higher levels of IgA to multiple water damage-associated molds and to
two mycotoxins. This study presents additional evidence of activation of inflammatory
processes from exposure to damp buildings.
Bacterial and Fungal Inflammatory Mechanisms
Fungal PAMPs, Beta-glucan and Their Induction of Inflammation
Perhaps the most prominent inflammatory pathway involving microorganisms and
damp buildings includes the binding of cell membrane components, cell wall
polysaccharides, and proteins by immune cells. Innate and acquired immune cells, some
epithelial cells, and fibroblasts have specific receptors that recognize critical components
of fungi and bacteria, such as cell membrane and cell wall components. These receptors
34

are termed pattern recognition receptors (PRRs). PRRs are found both on the membranes
of innate immune cells and in soluble form. The highly conserved microbial structures
that are recognized by these PRRs are termed pathogen-associated molecular patterns
(PAMPs). PAMPs are structures that are widespread among microbes and are essential
for survival of the microbes. These structures are not easily changed or eliminated to
evade immune recognition.
Some bacterial PAMPs include lipotechoic acid, lipopolysaccharide (LPS), and
peptidoglycan. An important fungal PAMP is β-glucan. Many of these bind to a class of
membrane spanning receptors termed Toll-like receptors (TLRs). To date, thirteen
mammalian TLRs have been characterized (TLR-1 to TLR-13). However, the TLR
repertoire differs among animal species. For example, humans and mice both express
several of the same TLRs, but mice also express TLR-11 to TLR-13, while humans do
not. These receptors function as either homodimers or as heterodimers. TLRs share a
similar domain with the receptor for IL-1 (IL-1R). For this reason, TLRs activate many
of the same pathways of accessory proteins and immune modulation as IL-1R. Other
classes of PRRs are also important in the recognition of bacteria and fungi and are briefly
discussed below.
TABLE 1: PAMPs and their corresponding PRRs.
Organism PAMP PRR
Gram-positive
bacteria
Peptidoglycan TLR-1/TLR-2
heterodimer
Viruses Double-stranded RNA TLR-3 in endosomes
Gram-negative
bacteria
LPS TLR-4
35

Motile bacteria Flagellin TLR-5
Gram-positive and
Gram-negative
bacteria
Peptidoglycan and
some lipoproteins
36
TLR-6
Viruses Single-stranded RNA TLR-7/TLR-8
heterodimer
Bacteria Unmethylated CpG of
DNA
TLR-9 in endosomes
Fungi B-glucan TLR-2/TLR-6
heterodimer, CR3,
lactosylceramide,
scavenger receptors,
Dectin-1
PAMP = Pathogen-associated molecular pattern; PRR = Pattern recognition receptor
Of the microbial cell membrane and cell wall components, β-glucans may be the
most widely studied in their relation to damp building exposures. β-glucans are an
integral part of the fungal cell wall and consist of a heterogenous group of glucose
polymers made of linear (13)-β-D-linked glucose chain backbones with (16)-β-D-
linked side chains of various sizes and length. While β-glucans are also found in plants
and bacteria, their relation to immune activation has been most studied in fungi where
they are more relevant. Vertebrates lack enzymatic glucanases to degrade these
structures, making β-glucans long lasting in the body. β-glucans are removed through
oxidation in the liver, secreted in the urine, or by clearance by antibodies (Suda et al.,
1996).
In general, β-glucans stimulate complement and the activities of innate immune
cells, such as macrophages, neutrophils, dendritic cells, and potentially eosinophils
(Douwes, 2005; Hohl et al., 2005) by binding to receptors on these cells (Harada and
Ohno, 2008). TLR-2 combines with TLR-6 to bind the β-glucan in the cell wall of fungi,

esulting in the activation on NF-κβ for the production of inflammatory cytokines (Hohl
et al., 2005; Underhill et al., 1999; Ozinsky et al., 2000). Other receptors have also been
identified that recognize β-glucans, including the C-type lectin receptor called dectin-1
(Steele et al., 2005), CR3 (Brown, 2006), lactosylceramide (Zimmerman et al., 1998),
and scavenger receptors (Brown, 2006).
Many studies have shown cytokine release by immune cells exposed to non-
purified β-glucan, which includes other membrane antigens (Olsson and Sundler, 2007).
Some studies suggest that the binding of β-glucans alone does not induce the release of
inflammatory cytokines (Li et al., 2007), but that they act only in an adjuvant capacity by
potentiating the effects of other agents (Williams, 1987). However, some studies have
shown that purified β-glucan can induce significant inflammatory reactions (Young et al.,
2003). These apparent conflicting findings are likely due to differences in physical
characteristics of the β-glucan used, such as size, complexity, and solubility. These
variations appear to affect their immunostimulatory properties by modulating their ability
to bind to receptors that recognize β-glucan (Bohn and BeMiller, 1995; Young et al.,
2003; Okazaki et al., 1995). In general, studies indicate that particulate glucans induce
more potent inflammatory responses than soluble glucans (Young et al., 2003), and large
particles are more inflammagenic than small particles (Suzuki et al., 1992).
Significant differences between soluble and particulate forms of β-glucans have
been realized. Particulate β-glucan from multiple fungal sources has been shown to
stimulate production of proinflammatory cytokines (Ishibashi et al., 2001), lower the
CD4 + /CD8 + ratio (Young et al., 2006; Kimura et al., 2007) and shift the immune reaction
to Th1 dominance as demonstrated by increased IFN-γ/IL-4 production ratio (Kimura et
37

al., 2007). One study exposed mice to the allergen ovalbumin by feeding 0.25%, 0.5%,
and 1.0% mixtures of low molecular weight β-glucan from the mold Aureobasidium
pullulans (Kimura et al., 2007). Control mice that were exposed to ovalbumin, but not fed
the β-glucan, displayed lower IL-12 and IFN-γ production in the small intestines and a
lowering of CD8 + and IFN-γ-producing cells in the spleen, while IgE production to
ovalbumin increased. From this analysis, there appears to be a dominant Th2 response in
mice exposed only to the allergen, ovalbumin. However, mice fed 0.5% or 1.0% β-
glucan feed experienced a decrease in IgE production and more production of IL-12 and
IFN-γ production in the small intestines and CD8 + and IFN-γ producing cell populations
in the spleen compared to the control mice. These findings suggest that β-glucan may
stimulate dendritic cells and macrophages to produce IL-12, which then stimulates the
production of IFN-γ from T-cells, producing a Th1 T-cell response. Increases in release
of IL-12 from β-glucan stimulation has been observed research using human whole blood
and other mouse models (Nameda et al., 2003; Netea et al., 2006B; Tada et al., 2008).
Release of IFN-γ by peripheral monocytes through stimulation of the β-glucan receptor
Dectin-1 has been shown to result in the direct release of IFN-γ by the monocytes (Gow
et al., 2007). Th1 and CD8 + T-cell response are more associated with DTH reactions
than Th2 cells (Mori et al., 2008; Jacysyn et al., 2003), which may be more dominant in
chronic inflammation from damp building exposure.
While particulate β-glucans from some fungi have shown immunostimulatory
effects, some evidence has suggested that the soluble form lowers cytokine production,
possibly by binding and blocking β-glucan receptors without activation (Olsson and
Sundler, 2007; Nakagawa et al., 2003; Ishibashi et al., 2001). Although evidence does
38

suggest that the higher molecular weight soluble β-glucan may still have
immunostimulatory properties (Okazaki et al., 1995). However, one study has provided
evidence that soluble β-glucan from pathogenic yeast, but not two other non-pathogenic
fungi, resulted in neutrophil chemotaxis (Sato et al., 2006). Chemotaxis of neutrophils to
the site of a fungal infection is an important aspect of the immune defense against fungal
pathogens. Besides complexity and solubility, these findings may indicate that the β-
glucans of pathogenic fungi may be specifically recognized by immune cells. Also, an
initial study suggests that more elevated levels of soluble β-glucan in the blood of
patients with fungal and bacterial infections may suppress pro-inflammatory cytokine
release (Gonzalez et al., 2004). This may be a biological attempt to prevent systemic
shock.
In addition to physical characteristics dictating inflammagenicity of β-glucans,
vast differences in the levels of cytokine production have also been realized between
humans when exposed to β-glucans, likely due to genetic differences (Nameda et al.,
2003; Beijer et al., 2002). This fact is important when considering why some people
appear to react to damp buildings, while others do not.
Another study design element that confounds results is the addition of human
plasma in in vitro studies. In a preliminary study, polymorphonuclear granulocytes and
peripheral blood mononuclear cells isolated from volunteers were exposed to a purified
soluble mushroom β-glucan, SCG (Nameda et al., 2003). Exposure to SCG was able to
directly induce production of several pro-inflammatory cytokines in these cells only
when human plasma was included. The cytokine production may be due to activation of
39

complement present in the plasma as has been shown as an effect by some β-glucans
(Suzuki et al., 1992).
Many studies completed that did not consider the adjuvant effect by β-glucan and
the effect of plasma where exposure of pure β-glucan without plasma either did not
induce a significant inflammatory effect or lowered the release of cytokines from immune
cells (Thorn et al., 2001; Beijer et al., 2002; Beijer and Rylander, 2005). Thus, any
conclusions that support an absence of immunostimulatory effect using only purified β-
glucan without plasma may be suspect.
Bacterial PAMPS and Their Induction of Inflammation
Bacterial PAMPs include teichoic acid, lipoteichoic acid, lipoproteins,
lipopolysaccharide (LPS), peptidoglycan, flagellin, lipoarabinomannan, and
unmethylated bacterial DNA (Netea et al., 2006A; Takeuchi et al., 1999; Schwandner et
al., 1999; Akira et al., 2006; Chow et al., 1999; Caron et al., 2005; Hemmi et al., 2000;
Kreig, 2002). The bacterial PAMPs primarily stimulate immune cells through binding
the TLRs. Most TLR activation stimulates the Th1 response, with exception to TLR-2
activation, which favors the Th2 response (Agrawal et al., 2003, Weiss et al., 1999). As
discussed previously, the Th1 response may play an important role in induction of
inflammation in damp buildigns.
Studies suggest that inhalation exposure to Gram-negative bacteria results in a
more adverse inflammatory reaction than exposures to Gram-positive bacteria. This
differential reaction is due to the presence of the LPS layer of Gram-negative bacteria.
Liberated LPS first binds to LPS binding protein (LBP), which then binds to
glycosylphosphoinositol-anchored cell protein, CD14. Once bound to CD14, LPS is
40

transferred to the protein MD-2 and then associates with the homodimer of TLR-4 (Akira
et al., 2006). This results in the activation of the mitogen-activated protein kinase
(MAPK) that influences growth and expression of inflammatory-related genes by
activation of NF-kβ. In the pulmonary tissue, activation of alveolar macrophages by LPS
results in infiltration of neutrophils and eosinophils and damage to the alveolar cells from
the inflammatory process (Dong et al., 2009). Indeed, LPS may be the most important
activator of the inflammatory process in damp buildings. One study assessed healthy
volunteers injected with very low levels of LPS (Reichenberg et al., 2001). The
volunteers developed symptoms of depression and anxiety. In addition, verbal and non-
verbal memory was also significantly impaired. As previously indicated, LPS has also
been shown to directly bind to receptors on the vagus nerve, stimulating an inflammatory
response in various areas of the central nervous system. Thus, the initial symptoms of
depression experienced by sensitive individuals in damp buildings may be the result of
sickness behavior caused by exposure to inflammagens such as LPS. Chronic exposure
to the inflammagens would then result in symptoms of depression through classical
methods, such as decreased neuroplasticity.
Peptidoglycan is the major component of Gram-positive bacterial cell walls,
although it is also present in lesser amounts in Gram-negative cell walls. This structure
consists of long chains of alternating N-acetyl glucosamine and N-acetyl muramic acid
subunits. The long chains are linked together by peptide bridges. While it is generally
believed that TLR-2 recognizes peptidioglycan, controversy exists due to the potential of
contaminants in the studies (Akira et al., 2006).
41

Fungal and Bacterial Hemolysins and Proteinases and Their Induction of
Inflammation
A less frequently studied and discussed factor that may contribute to health effects
in damp buildings is exposure to the hemolysins and proteinases from fungi and bacteria.
Evidence suggests that these agents induce inflammation both through antigenic and
cytotoxic effects.
Proteinases and Inflammation
One method by which proteinases produce health effects is by signaling the
immune and epithelial cells to produce inflammatory cytokines by activating or
potentially deactivating proteinase-activated receptors (PARs) that are coupled to G-
proteins. These receptors have seven transmembrane domains with an extracellular N-
terminal end. Within this N-terminal end is a ligand that can bind back onto the
transmembrane portion of the receptor. Proteinases cleave PARs within the extracellular
N-terminal domain, exposing the tethered ligand. Four PARs (PAR1-4) have been
identified. They are present on several cell types such as respiratory epithelium cells,
glandular cells, smooth muscle cells, and macrophages (Lan et al., 2002; Miotto et al.,
2002; Ostrowska et al., 2007). Proteinases exogenously produced by bacteria and fungi
and endogenously produced by mast cells, neutrophils, and others may cleave the N-
terminal end, thus activating the receptor and alerting the immune system to the potential
presence of the microbes.
Activation of PAR2 may induce contraction of airways and other factors that are
involved with asthma (Chambers et al., 2001). Activation of PAR2 also appears to
enhance phagocytosis, assisting in increased clearance of bacterial cells and
42

inflammagens. However, deactivating PAR2 slows phagocytosis, and thus may allow
inflammatory mediators and bacteria to remain in the pulmonary tissue longer, resulting
in more pronounced inflammatory reactions (Moraes et al., 2008). Thus, inhalation of
proteinases in damp buildings may result in either activation or deactivation of PAR2,
depending on which microbes and proteinases are present. While both activation or
deactivation may have detrimental inflammatory consequences, the latter may result in
more health effects from the decreased clearance of debris. The lingering debris may
potentially have a greater ability to cross the epithelial lining and enter into circulation.
Hemolysins and Inflammation
Hemolysins are proteins produced by microbes that lyse immune cells and red
blood cells. Lysing of red blood cells releases iron, a limiting nutrient in most
environments, including the body. Hemolysin production by bacteria infecting tissue is
relatively common. However, studies suggest that hemolysin production may also be
fairly common among species of certain fungal genera. Hemolysins have been identified
in a number of fungi that are commonly encountered in damp buildings. Stachylysin has
been isolated from S. chartarum, asp-hemolysin from Aspergillus fumigatus, chrysolysin
from Penicillium spp., and nigerlysin from Aspergillus niger (Donohue et al., 2005;
Donohue et al., 2006; Vesper and Vesper, 2002).
In a 2006 publication by Donohue and colleagues, six strains of A. niger tested
positive for producing nigerlysin at 37°C and at 23°C (Donohue et al., 2006). Although
further testing is needed, these findings suggest the potential for production of
hemolysins by some fungi present in damp buildings on surfaces. If so, inhalation of
hemolysins produced by fungi in damp buildings may be possible.
43

Donohue and colleagues found that 14 of 19 strains of Penicillium chrysogenum
produced chrysolysin (Donohue et al., 2005). Interestingly, 10 of the 11 strains isolated
from indoor air produced chrysolysin, and all strains that produced chrysolysin did so at
37°C but not 23°C, suggesting a role in pathogenicity. This suggests that many of the P.
chrysogenum strains found in damp buildings may be able to act as opportunistic
colonizers of human tissue or the airways. Undetected or unresolved colonization could
lead to chronic, low-level inflammatory reactions. Such colonization has been shown to
be an important factor in several forms of sinusitis (Schubert, 2004).
Interactions between Bacterial and Fungal Debris
While exposure to fungi or bacteria can induce an inflammatory effect, co-
exposure results in a potentiating synergy with more pronounced and modulated
inflammatory effects. This effect appears to be the result of LPS priming the immune
system by alerting immune cells that an inflammatory reaction may be required to ward
off a potential microbial infection. Mice that were exposed to airborne LPS produced a
much greater IgE-mediated sensitivity to the allergen ovalbumin than mice that were not
exposed to LPS (Wan et al., 2000). One study exposed mice to both ovalbumin and a
low or high level of LPS (Dong et al., 2009). They found that the lower LPS dose
resulted in recruitment of both eosinophils and neutrophils into the lung tissue and
secretion of Th2 cytokines. However, a Th1 associated response with neutrophil
recruitment was observed using higher LPS levels.
Co-exposure to fungal allergens along with LPS also results in a modulated
immune response. One study that examined the effects of co-exposure characterized the
pulmonary inflammatory reaction in a mouse model using lysates of either Candida
44

albicans, A. fumigatus, or Gram-negative bacterium Pseudomonas aeruginosa (Allard et
al., 2009). When either fungal lysate was administered, a Th2 cytokine response with
airway eosinophilia and mucus cell metaplasia was observed. Administration of the P.
aeruginosa lysate resulted in neutrophil influx with Th1 cytokine secretion and no mucus
production. However, administration of the bacterial lysate with the fungal lysates
resulted in Th1-associated cytokine profiles with neutrophilia and diminished mucous
production. Additional studies using varied amounts and types of fungi and bacteria will
further elucidate the potential synergies and deviations of inflammatory reactions that
may occur in exposures to damp buildings. However, studies currently indicate that such
reactions do occur. These interactions due to co-exposure of bacteria and fungi are
important to consider in exposure studies since both organisms exist in damp buildings.
Mycotoxins and Health Effects
Exposures to mycotoxins in damp buildings and their potential effects on human
health are frequently explored in research. Mycotoxins are secondary metabolites created
by fungal organisms. It is widely believed that some of these mycotoxins are produced as
a defense mechanism to limit the growth of competing organisms. This is the case with
P. chrysogenum which produces penicillin. Mycotoxins are primarily maintained in or on
the cell wall of the spores and hyphae and are readily released into the surrounding
materials (Hinkley and Jarvis, 2000; Curtis et al., 2004; Islam et al., 2007). These
compounds are large enough to not be highly volatile and thus require active agitation or
air currents to become airborne (Kelman et al., 2004).
Mycotoxins have been frequently studied for their ability to induce adverse health
effects (Etzel, 1998; Bunger, 2004; Bondy and Pestka, 2000). The importance of fungal
45

mycotoxins in relation to health has been long recognized by studies addressing animal
toxicity from mold-infested feed (Coppock and Jacobsen, 2009; Porter et al., 1995).
Studies have shown that mycotoxins, at sufficiently elevated levels, can induce
cytotoxicity and inflammatory reactions (Ruotsalainen et al., 1998; Rand et al., 2006;
Nielsen et al., 2001; Flemming et al., 2004; Rand et al., 2005). However, these studies
use exposure levels that are atypically elevated and are not representative of real-world
exposures (Kelman et al., 2004). A more recent study by Miller and colleagues has
utilized lower levels of mycotoxins and showed inflammatory reactions (Miller et al.,
2010). However, the levels in that study may still not be attained in typical damp
building exposures. Thus, sufficient evidence has not been provided that suggests typical
exposures to mycotoxins in damp buildings significantly enhances inflammatory
reactions in humans. Still, some people may be exquisitely sensitive to certain
mycotoxins, although this has not yet been demonstrated.
Summary
Evidence supports the hypotheses that exposure to damp buildings, including wheeze,
exacerbation of asthma and allergies, and other respiratory symptoms (IOM, 2004; WHO,
2009). Neurological symptoms, such as depression and neurological impairment, are also
reported by some individuals following exposure to damp indoor environments (Shenassa
et al., 2007; Kilburn, 2003; Gray et al., 2003). One study suggested that damp buildings
exert a pathological effect on the human system, resulting in symptoms of depression
(Shenassa et al., 2007). In addition to depression, sensitive individuals report other
neurological symptoms, such as short-term memory impairment, confusion, and inability
to concentrate (Kilburn, 2003).
46

Occupants in damp buildings show increased reactivity of inflammatory cells and
increased levels of inflammatory markers in their blood (Shoemaker and House, 2006;
Beijer et al., 2003). Initial inflammatory responses from damp building exposure may
result in symptoms of “sickness behavior”, which includes symptoms similar to
depression. Sickness behavior would likely be from exposure to biological
inflammagens, such as LPS (Reichenberg et al., 2001). Exposures to VOCs and
mycotoxins may also induce inflammation, but likely to a much lesser degree. Longer
exposures to damp buildings may result in chronic activation of immune processes in the
periphery. Inflammatory markers in the periphery may then activate microglia in the
CNS, resulting neurogenic inflammation and changes in neuroplasticity and neurogenesis
in the pre-frontal cortex, hippocampus, and amygdala (Wichers et al., 2005; Oliveira et
al., 2008; Stone and Behan, 2007). The changes in neuroplasticity and neurogenesis may
then induce classical symptoms of depression and other neurological syndromes.
body, resulting in a more pronounced overall inflammatory reaction (Moraes et al.,
2008).
Future work to further elucidate an association between damp buildings
exposures, inflammation, and depression is needed. Researchers should consider
furthering the exposure studies completed by House, Hudnell, and Shoemaker
(Shoemaker and House, 2006; Shoemaker and Hudnell, 2001) while including a complete
neurological assessment throughout the process.
47

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