Molecular mechanism of action

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Indoor Molds

Indoors, the most common exposure to mycotoxins is through

inhalation. Fungi that produce the most potent mycotoxins are rarely

found in the outdoor ambient

Characteristics

Fate and Transport in the Environment

Methods for Monitoring in the Environment

Exposure Pathways

Methods for Measuring Human Exposure

Strategies for Preventing or Controlling Mold Exposure

http://enhs.umn.edu/current/5103/molds/molecular.html

Harmful Effects

Absorption, distribution, metabolism, and sites of toxicity

Biomarkers

Molecular mechanism of action

Risk Assessment

5103/5104 Home

Molecular mechanism of action

Initial events

Molecular action of mold spores from inhalation exposure starts in

the alveolar regions of the lungs. Mold particles embed themselves

in the alveoli and are attacked by macrophages. Phagocytosis,

engulfing and ingesting particulate matter by macrophages, is the

first step when absorbing or digesting particles. Large numbers of

macrophages are present on the alveolar walls. If particles are

digestible, the macrophages will dissolve the particles and release

the products into the lymph. Initial phases of this process, and the

reactions involved, are not completely understood for mold toxins.

Generally, the receptors on the macrophage cell surface recognize

the particles, which leads to a series of internal cell changes.

Macrophages change metabolic pathways that lead to alteration of the

cell surface characteristics. Due to the changes, a production of a

variety of proteins called cytokines take place. These proteins have

the ability to induce activity in other cell systems. Some of the

agents released by the macrophages are chemotactic and introduce

neutrophils from the blood into the lungs and later into the

airways. A buildup of platelets also occurs in the pulmonary

capillary bed.

Diagram of lungs and alveoli

(www.nlm.nih.gov/medlineplus/ency/imagepages/8675.htm)

Molds produce many substances that can be harmful with excessive

exposure. Generally, these agents fall into two classes:

Secondary products of metabolism (mycotoxins)

Structural components (beta-1,3-D glucans)

Mycotoxins

Most of the toxicological studies related to mold mycotoxin exposure

involves case studies of ingestion exposure. Extrapolation to

realistic indoor inhalation exposure has not been clearly

established. At this time, inadequate data exists to accurately

predict the risk associated with human inhalation exposure to

mycotoxins in indoor environments.

Mycotoxins are by-products of fungal metabolic processes. Their

function has not been clearly established but appear to be related

to competing with other microbes and helping parasitic fungi invade

host tissues. Hundreds of mycotoxins have been identified that are

produced by fungi. Mycotoxins are secondary metabolites because they

are natural products that are not necessary for fungal growth.

Mycotoxins have no molecular features in common and therefore do not

constitute a chemical category. The chemical structures of

mycotoxins include polyketides, terpenes, and indoles. Some

mycotoxins have more toxic effects than others.

Most studies have investigated mycotoxins that are produced by

species of Aspergillus, Fusarium, Penicillium, Stachybotrys, and

Myrothecium. More than one species of fungi may produce a single

mycotoxin, and conversely, one fungus may produce a variety of

mycotoxins. The kinds and amounts of toxins a fungus produces depend

on the following factors:

The fungal strain

The growth substrate it is metabolizing

The presence or absence of other organisms

Environmental conditions (e.g. temperature, pH)

Indoors, the most common exposure to mycotoxins is through

inhalation. Fungi that produce the most potent mycotoxins are rarely

found in the outdoor ambient air.

Cellular effects

Many mycotoxins are potent cytotoxins that cause cell disruption and

interfere with essential cellular processes. Additionally, some

mycotoxins are carcinogens, some are vasoactive, and some penetrate

the blood-brain barrier. Commonly a single mycotoxin can cause more

than one type of toxic effect. There are hundreds of different

mycotoxins and only the most common known mycotoxic effects will be

covered.

Pulmonary macrophage cells, which are part of the immune systems

nonspecific line of defense, actively ingest and remove foreign

particles in the alveolar region of the lungs. Studies have shown

that mycotoxins including patulin, penicillic acid, aflatoxin, T-2

toxin and satratoxins interfere with macrophage functioning or

selectively kill macrophages. Additionally, Aspergillus fumigatus

contains a toxin in the spore wall that diffuses rapidly into water

and inhibits macrophage function. This and other toxins may

facilitate colonization of the airways of asthmatics leading to

allergic bronchopulmonary aspergillosis (ABPA).

Aspergillus

Aflatoxins, produced by several members of the genus Aspergillus are

known carcinogens. Aflatoxin B1 is known as the most potent studied

natural carcinogen. It is a " pro-carcinogen " that must be

transformed to the carcinogenic state within the body. Following

ingestion exposure, this transformation occurs in the liver, and the

result is liver cancer. Additionally, airway epithelium can activate

aflatoxin B1 to the carcinogenic form. Airway instillation also

results in binding both in the lung and in the liver, indicating

translocation of the active form of the toxin.

Gliotoxin is produced during mycelial growth of Aspergillus

fumigatus. This toxin is known to cause fragmentation of DNA. It is

potent immunosuppressive agent that stops phagocytosis actions of

the macrophages and impairs induction of cytotoxic and alloreactive

T-cells. This toxin also disrupts the normal attachment of

epithelial cells and fibroblasts, which allows fungal hyphae to grow

in human tissue, causing a disease called aspergillosis.

Stachybotrys chartarum

Stachybotrys chartarum varies in its ability to produce mycotoxins

depending on the substrate and other environmental factors.

Mycotoxins produced from Stachybotrys chartarum can include the

trichothecene mycotoxins satratoxins G and H. Satratoxins G and H

are potent protein synthesis inhibitors and cause immunosuppression

in laboratory animals. Immunosuppression can lead to secondary

infections. Research has found that trichothecenes affect lymphatic

and hematopoietic tissues as well as skin and mucous membranes.

Acute exposure to large amounts of trichothecene toxins results in a

rapid release of sequestered white blood cells into circulation.

Chronic exposure can destroy granulocytic precursor cells in bone

marrow, which leads to white cell depletion. Cellular effects can

include:

Mitogen B/T lymphocyte blastogenesis suppression

Decrease of IgM, IgG, IgA immunoglobulins

Impaired macrophage activity

Increased spontaneous antibody producing cells in the spleen

Skin reactions have been observed in some asthmatics living or

working in Stachybotrys-contaminated rooms, suggesting

hypersensitivity to the fungus and that the fungal spores may

produce allergenic affects.

Inflammation

Fungi are well-known causes of allergenic disease, stimulating the

production of IgE-mediated response as well as hypersensitivity

pneumonitis (HP). In addition to the allergen-induced release of

inflammatory agents that mediate these responses, some kinds of

fungal spores directly stimulate the release of mediators of

inflammation. Agents that pulmonary macrophages may release in

response to fungal spore exposure include cytokines, reactive oxygen

metabolites, and chemotactic factors. The blood distributes these

agents from the lungs and spreads them throughout the body.

Exposure to fungi and mycotoxins are likely to be associated with

exposure to other agents as well. Organic dust toxic syndrome (ODTS)

is a flu-like illness that may follow exposure to complex mixtures

of organic dusts. The mixtures may include endotoxin, glucans,

antigens, and mycotoxins. Relatively low exposure to complex

mixtures can result in release of mediators of inflammation.

Laboratory animal studies indicate a synergistic effect between

endotoxin and fungal spore components. A family history of

environmental allergies confirmed by skin prick test is a risk

factor for ODTS, possibly indicating a role of antigens in the

disease. The role of mycotoxins in ODTS is still not fully

understood. Deposition of mycotoxins with particles seems to amplify

adverse effects in the lungs, possibly due to increased toxin

retention in the respiratory tract. (Photo: Tomography of the lungs

(www.nhslothian.scot.nhs.uk/.../public_health/2002/09)

Mold as an antigen

Molds are considered to be antigens. Antigens are foreign substances

that can cause a measurable hypersensitivity or immune response. The

immune system is attempting defend the body against a foreign

substance. Inhalation of airborne fungal antigens causes a variety

of immune illnesses generally referred to as hypersensitivity

diseases. An immune response consists of specific antigen

recognition and the recruitment of sensitized cells and antibodies.

An allergic reaction is a specific immune response caused by an

allergen. An allergy is caused by exposure to an allergen, which

produces the immune-mediated state of hypersensitivity.

The primary targets for inhaled antigens are the upper and lower

respiratory tract.

The mechanism of all hypersensitivity diseases involves:

Repeated antigen exposure

Immunological sensitization of a body to an antigen

Immune-mediated damage to the body

A latency period between the initial exposure and the second

exposure in order to develop an immunological sensitization

The immune response depends on the specific antigen and the duration

and intensity of the exposure. Antibodies produced in response to

specific antigens belong to a group of molecules called

immunoglobulins. Immunoglobulins are broken down into five classes:

IgA, IgD, IgE, IgG, and IgM. Antigens produce IgE mediated

responses. People without allergies produce small amounts IgE

antibodies, but allergy sufferers produce abnormally large

quantities as a reaction to allergens.

The IgE antibodies bind to two types of cells. One type of cell is

the basophil, a white blood cell (leukocyte) containing granules

that circulates in blood. Another cell that antibodies bind to is a

mast cell, which is found in the lungs, skin, tongue, lining of the

nose, intestinal tract and connective tissue. Mast cells also

contain basophilic granules. Both types of cells release substances

such as histamine, heparin and other chemicals in response to injury

or inflammation of bodily tissues. These chemicals produce allergic

symptoms.

When the allergic individuals confront the same allergen, it

attaches to the IgE antibodies already bound to basophils and mast

cells, which starts the same chain reaction that results in allergic

symptoms. Allergic reactions become more severe with repeated

exposure because more basophils and mast cells are already bound to

the IgE antibodies.

Diagram of an allergic reaction from

http://www.niaid.nih.gov/final/immds/allergy.htm

Allergic asthma and rhinitis

Exposure to fungal spores or hyphal fragments results in the

formation of IgE antibodies. The IgE antibodies can cause

inflammation mediators and histamine to be released in the blood.

This leads to allergenic rhinitis (hay fever) and/or asthma.

Symptoms for rhinitis are characterized by a runny or congested

nose, sneezing, irritated and inflamed throat and eyes. Allergic

asthma is an inflammation of the airways most likely from acute

reactions.

Allergic bronchopulmonary mycoses and allergenic sinusitis

Fungal colonization of the central airways can occur in individuals

with long-standing, severe asthma. This can lead to a syndrome known

as allergic bronchopulmonary mycoses (ABPM). ABPM is called allergic

bronchopulmonary aspergillosis (ABPA) when the exposure is due to

Aspergillus fumigatus and other Aspergillus species. Symptoms from

this disease include:

Fever

Malaise

Brownish mucus plugs containing fungal hyphae in sputum

An abnormal increase in eosinophils (a type of white blood cell)

Expectoration of blood from the respiratory tract

Allergenic sinusitis can also be caused by localized fungal growth

in the nasal sinuses. This condition is characterized by chronic

sinus symptoms and increased fungal specific serum IgE, most

commonly to Aspergillus fumigatus.

Hypersensitivity pneumonitis (HP)

HP is an inflammatory lung disease caused by continuous or repeated

exposures to various antigenic substances. Once sensitized to the

bioaerosol, individuals respond to very low exposures to

environmental antigens. Although HP is usually a concern for

exposures to dusty environments, HP can be a concern for occupants

of offices and residences, which are not a problem for nonsensitized

occupants. Antigenic bioaerosols have been traced to contaminated

ventilation systems and microbial contamination due to flooding.

SEM of Penicillium (www.cosmiclight.com/ galleries/sem1.htm)

beta-1,3-D glucans

Glucans are glucose polymers, which are structural components of

most fungal cell walls. The structures consist of unbranched or

branched chains that may be chemically bound to chitin. Glucans may

contribute to virulent and opportunistic fungal infections. They may

also be involved in the development of hypersensitivity pneumonitis

(HP) by affecting the inflammation-regulating capacity of airway

macrophages, probably by influencing T cell lymphocytes. In

insoluble form, glucans cause a gradual decrease in the number of

macrophages and lymphocytes in the lung wall and appear to have an

effect on the lung similar to that of endotoxin. In guinea pigs,

exposure to glucans was found to increase breathing rate and

increase in neutrophils, lymphocytes and red blood cells in the

lungs.