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Endotoxins are lipopolysaccharide (LPS) complexes of the outer cell wall of gram-negative bacteria, usually pathogens such as E. coli, Salmonella, Shigella and Pseudomonas, etc.

The LPS are maintained within the outer cell wall until autolysis of the bacteria which releases them into the surrounding environment. They are pyrogenic (fever producing), antigenic and cause inflammation through the activation of the complement system via CD14 protein, the TLR4-signaling pathway and release of inflammatory cytokines, e.g., TNF-a. CD14 protein binds LPS and transfers them to the TLR4 receptor. 

Clinical or experimental outcome include fever, leukopenia, hypoglycemia, hypotension, impaired perfusion of essential organs (brain, heart, kidney), activation of C3 and the complement cascade, bleeding, intravascular coagulation, septic shock and death. 

In addition, LPS also causes an increased production of the long pentraxin PTX3 (Cunningham et al, 2005; Imamura et al, 2007) and in the maturation of dendritic cells evoking Th1 and Th17 responses (Iwamoto et al, 2007). 

LPS are present in the indoor environment of normal and water-damaged homes and buildings (Douwes et al, 2006; Gorny, 2004; Gorny et al, 2002; Park et al, 2000, 2006; Rao et al, 2007b).

In transgenic mouse models, endotoxins interact with the TLR4-signaling pathway, CD14 phenotype, TNF-a and other factors leading to increased airway inflammation (Jung et al, 2006; Martinez, 2007a,b; Togbe et al, 2007). 

In addition, in vitro and in vivo animal models of neurological diseases have shown that intra-peritoneal (i.p.), i.v. and intracerebral administration cause expression of pro-inflammatory markers of microglia (Qin et al, 2004), as well as the induction of oligodendrocyte injury via TLR4 (Lehnardt et al, 2002). 

Intracerebral or systemic administration of endotoxin exacerbates microglial inflammatory response and increases neuronal cell death in ME7 prion mouse model (Cunningham et al, 2005). 

Moreover, systemic inflammation (e.g., infectious states) appears to be involved in chronic neurodegenerative disease (e.g., Alzheimer, Parkinson). The increased synthesis of inflammatory cytokines and other mediators during infections and/or systemic LPS challenge promote an inflammatory
response that may contribute to the progression of chronic neurological disease (Cunningham et al, 2005; Godbout et al, 2005; Perry, 2004; Polentarutti et al, 2000). 

Co-exposure of mice to vomitoxin and LPS caused a synergistic increase in TNF-a messenger RNA (mRNA) as well as plasma TNF-a and IL-6. Marked cell death (apoptosis) and loss occurred
in the lymphatic organs, thymus, Peyer’s patches, spleen and bone marrow (Islam et al, 2002; Zhou et al, 1999, 2000). The priming of mice with LPS lowered the dosage of deoxynivalenol causing upregulation of inflammatory cytokines (IL-a and -b, IL6 and TNF-a) and massively increased the thymus apoptosis (Islam et al, 2002). 

Similarly, in vitro priming of TLR of murine macrophages and human whole blood cultures renders macrophages sensitive to exposure to mycotoxins and other xenobiotics. The LPS-sensitized macrophages have an increased production of mRNA of IL-1b, IL-6 and TNF-a after exposure to deoxynivalenol (DON), satratoxin G and zeralenone (Pestka and Zhou, 2006). 

Also, administration of aflatoxin B1 and endotoxin to rats augments liver sinusoidal damage and clotting by converting soluble fibrinogen to insoluble fibrin clots (Luyendyk et al, 2003). 

Finally, nasal inflammation, inflammatory cytokine production and atrophy of the olfactory nerve and olfactory bulbs in mice are enhanced by the co-administration of LPS and roridin A (Islam et al, 2007). 

In conclusion, mold agents and LPS exposure are synergistic with adverse effects on organ systems, including the brain, leading to a systemic inflammatory response.
Gram negative endotoxin LPS

Gram negative bacterial endotoxin lipopolysaccharide

Inhaled LPS causes adverse airway responses in healthy individuals as well as individuals with asthma and other respiratory conditions. Healthy volunteers challenged with LPS had variable airway responsiveness (Kline et al, 1999). Eight sensitive subjects had at least a 20% decline in the FEV1, at a dose of 6.5 mg or less, while 11 hyporesponsive subjects maintained an FEV1 at least 90% after inhaling 41 mg of LPS. Peripheral monocytes from the hyporesponsive individuals released fewer IL-6 and IL-8 than the sensitive subjects.

The interaction between the environment and lung responsiveness is a complicated gene-environment interaction (Martinez, 2007a). The interactions involve TLR2 and -4 and IL-1 receptors as well as polymorphism of CD14 protein (Liebers et al, 2008; Martinez, 2007b; Simpson et al, 2006). In addition, down-stream adaptor molecules, e.g., My88 and TRAM, are also involved (Tanimura et al, 2008). Furthermore, other genes (e.g, IL-13, DEFB1, TLR2, TRL4) seem to have a role in the phenotypic complex condition referred to as asthma. 

Apparently, IgEmediated conditions are not the norm, while the role of IL-4, IL-5, eosinophils and neutrophils are difficult to control (Martinez, 2007a,b). Thus, children with CC genotype at –159 of CD14 have a decreased risk of allergic sensitization to endotoxins while having an increased risk of non-atopic wheezing (Simpson et al, 2006). 

Also, it has been shown that the CC allele of CD14 is a risk factor for allergic phenotypes at a low concentration of endotoxins, whereas the TT allele is a risk factor for higher concentrations of LPS (Martinez, 2007b). In conclusion, gene and air pollution interactions in asthma and endotoxins are complex and require more genome-associated studies with better assessment of exposure and phenotype (London, 2007).

In conclusion, synergism between endotoxins and mycotoxins has been demonstrated in vitro and in animal models. As discussed above, LPS enhance the damage to the olfactory epithelium, tract and bulb of roridin A in mice. 

In addition, exposure to LPS and aflatoxin B1 enhances liver toxicity in rats. Treated animals had damage to sinusoidal cells and hepatocytes with increased alanine aminotranserase and fibrin deposition (Barton et al, 2001; Luyendyk et al, 2002, 2003). 

Oral administration of vomitoxin with simultaneously injected LPS in mice produced a significant enhancement of TNF-a, IL-6 and IL-1b in spleen cells (Zhou et al, 1999). A similarly designed study resulted in an increase of apoptosis of lymphocytes in the spleen, thymus and Peyer’s patches (Zhou et al, 2000). 

Finally, in vitro priming of murine and human whole blood macrophages enhances the proinflammatory cytokine production (Pestka and Zhou, 2006). 

Two questions arise from these observations: 

(1) What role does the genetic polymorphism CD14 protein have in synergism of LPS and mycotoxins? 

(2) Are the children with CD14 CC genotypes more or less sensitive to the inflammatory conditions caused by mycotoxins?

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