Molds_Mycotoxins.html

Jack Dwayne Thrasher, Ph.D.

(505) 937-1150 - Cell

This paper is still in press. The Introduction and Conclusions have been reproduced to give the reader an appreciation of the contents of this paper.

Mold and Mycotoxins: Effects on Neurological and Immune System in Humans. Advances in Applied Microbiology. In: Strauss DC, ed., Sick Building Syndrome, Advances in Applied Microbiology, Volume 55 (in press).

The potential harmful effects of exposure to molds in inhabited buildings were recognized in early biblical times. In the Old Testament (King James Version, Oxford, 1888 edition), King James version, Chaper XIV: Verses 34 through 47, Leviticus put forth a detailed protocol for the remediation of contaminated structures, including the desruction of dwellings and personal belongings if remediation failed. Currently, it is recognized that water intrusion into buildings leads to amplification of molds (Andersson, et al, 1997; Gravesen et al, 1999; Hodgson, et al, 1998; Jaakkola, et al, 2002; Johanning, et al, 1996; Nielson, 2003; Peltola, et al, 2001), which requires remediation.

Fungal fragments occur in indoor air as biocontaminants (Burge 1990; Gorney et al, 2002). Potentially, toxic and immunogenic byproducts of fungi and molds include mycotoxins (Croft et al, 1986; Johanninng et al, 2002; Nielsen et al, 1999; Nieminen et al 2002; Tuomi, et al, 1998, 2000): 1,3-alpha-D-glucans (Andersson, et al, 1997); extracellular polysaccharides (EPS) (Douwes, et al, 1999; Notermans, et al, 1988; Wouters et al, 2002); exodigestive enzymes (EDS)( Monod, et al, 2002); and solvents (Claeson et al, 2002). In addition, trichothecenes, ochratoxin A, sterigmatocystin, and other mycotoxins have been identified in ventilation duct dusts and in the air in buildings where occupants have experienced adverse health effects related to mold exposure (Croft, et al, 1985; Englehardt, et al, 2003; Jarvis, 2002; Johanning et al, 2002; Nieminen et al, 2002; Skaug et al, 2000; Smoradiewicz et al, 1993; Tuomi, et al, 1998). The worst-case senario appears to be repeated episodes of water damage that promotes fungal and mycotoxin production, followed by drier conditions, leading to release of spores and hyphal fragments (Nielsen, 2003).

Occupants of affected structures develop multiple organ symtpoms and have adverse effects of the upper and lower respiratory tract, central and peripheral nervous sytem, skin, gastrointestinal tract, kidneys and urinary tract, connective tissue, and the musculoskeletal system (Anyanwu et al, 2003, Croft, et al, 1986; Gunnbjornsdottir, et al, 2998; Gray, et al, 2003; Hodgson , et al, 1998; Jaakkola, et al, 2002; Johanning ,et al, 1996; Kilburn, 2002; Sailvilaht, et al, 2000). Human illness caused by fungi can result via one or all of the following: (1) mycotic infections (mycoses) (Anaissie et al, 2002, Eucker et al, 2001; Fraser, 1993; Grossi, et al, 2000); (2) fungal rhino-sinusitis (Braun, et al, 2003; Ponikau, et al, 1999; Thrasher and Kingdom, 2004); (3) IgE-mediated sensitivity and asthma (Barnes, et al, 2002; Lander, et al, 1001; Zurreik, et al, 2002); (4) hypersensitivity pneumonitis and related pulmonary inflammatory diseases (Erkinjunttu-Pekkanen, et al, 1999; Ojanen, 1992; Patel, et al, 2001; Sumi, et al, 1994); (5) cytotoxicity (Desai, et al, 2002; Gareis, 1995; Jones, et al, 2002; Nagat, et al, 2001; Poapolathep, et al, 2002); (6) Immune suppression/modulation (Berek, et al, 2001; Bondy and Petska, 2000; Jakab, et al, 1994); (7) Mitochondrial toxicity (Hoehler, et al, 1997; Niranjan, et al, 1982; Pace, 1983, 1988; Sajan, et al, 1987; Wei, et al, 1984); (8) Carcinogenicity (Dominguez-Malagon and Gaytan-Graham, 2001; Schwartz, 2002); (9) Nephrotoxicity (Anyanwu, et al, 2003; Pfohl-Leszkowicz, et al, 2002); (10) The formation of nuclear and mitochondiral DNA adducts (Hsieh and Hsieh, 1993; Petkova-Bochatrova, et al 1998; Pfhol-Leszkowicz, et al, 1993). Finally, in the infectious state, molds secrete EDS that cause tissue destruction, angioinvasion, thrombosis, infarction and other manifestations of mycosis (Ebina, et al, 1985; Kordula, et al, 2002; Kudo, et al, 2002, Monod, et al, 2002; Vesper, et al, 2000).

The pathological and inflammatory conditions associated with Stachybotrys chartarum in infants with pulmonary hemosiderosis have been characterized. S. chartarum isolated from the lungs of an affected infant produced a hemolysin (stachylysin), a siderophore, and a protease (stachyrase A) (Kordula, et al, 2002, Vesper, et al, 2000). Stachylysin has also been demonstrated in the serum of adults ill from building-related exposure (Von Emon, et al, 2003). In rodents, its presence has been demonstrated by an immunocytochemical method following installation of S. chartarum spores into the lungs. The hemolysin increases in concentration from 24 to 72 hours following installation of spores, indicating tht production/release is a relatively slow process (Gregory, et al, 2003). In addition, strains of S chartarum produce different quantities of toxic trichothecenes (Jarvis, et al, 1998). In an earthworm model, stachylysin increased permebility of blood vessels, causing leakage through the vessel endothelium and walls (Vesper and Vesper, 2002). Additionally, patholgy may result from the interference of pulmonary surfactant synthesis by S. chartarum spores and isosatratoxin-F in juvenile mice. Ultrastructual changes in type II alveolar cells - with condensed mitochondria, increases cytoplamic rarefaction, and distended lamellar bodies with irregularly shaped lamellae - have been observed following exposure to S. chartarum (Mason, et al, 1998, 2001; McCrae, et al, 2002, Rand et al, 2001). Thus, hemolysins, siderophores and proteases also appear to have an important role in the pathogenesis of mold infections.

Recognizing the complexity of health problems associated with multiple mold exposure, we have previsously reported a multi-center investigation of patients with chronic health complaints from exposure to mutliple colonies of indoor mold and fungi. We utilized detailed health- and environmental history-gathering questionnaires, environmentl monitoring data, physical examination, pulmonary function testing protocols, routine clinical chemistries, measurements of lymphocyte phenotypic markers (on T, B, and NK cells, antibodies to molds and mycotoxins, neuronal antigen autoantibodies, leukocyte apoptosis, neurocognitive testing, 16-channel quantitative EEGs (QEEG), nerve cvonducton studies (NCS), brainstem auditory evoked potentials (BAER), visual evoked responses (VER) and other neurological testing. The following is a summary of our findings on symtpoms, pulmonary function, alterations in peripheral lymphocyte phenotypes, autoantibodies, and neurological abnormalities observed in patients by us and others. Currently, we refer to the illness of these individuls as a mold mycotoxicosis" involving the immune system, the lungs, the central and peripheral nervous system, and generalized inflammatory and irritatnte responses to exposure to spores, hyphal fragments, mycotoxins, solvents, and other by products (e.g. EPS, EDS).

Forgacs noted in 1962 that mold mycotoxicosis was called "the neglected disease." The manifestations and disroders in humans caused by molds and myctoxins continues to be overlooked or unnoticed by many physicians. Each year studies continue to be published throughout the world medical and scientific literature elucidating and explaining the pathological processes and biomechanisms by which exposure to molds and mycotoxins cause sickness in humans. We have described in this chaper the most recent neuroimmune mechanisms of which disease process in humans of molds and mycotoxins. The exact biological and chemical actions through which these mechanisms unfold is not completely understood. However, molds do produce metabolites (mycotoxins, sovlents) and shed antigenic materials (spores, hyphae, extracellular polysaccharides, and enzymes), which are toxic (mycotoxins) and or cause immunologic respones (antigens). Science and medicine should continue its work in these areas and bring about the much-needed change from "the neglected disease" to "the accepted disease."