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Global Indoor Health Network 

Neurotoxicity

Neurotoxicity
Several studies are presented here which discuss the neurotoxic effects of molds, mycotoxins and other contaminants found in water-damaged buildings.

Fumonisins and Neural Tube Defects (NTD)

The information regarding Fumonisin B1 as a potential teratogen in humans and animals has been fully discussed by Gelineau-van Waes et al, 2006, 1999 and Marasas et al, 2003. 

The major source of exposure to FB 1 is the dietary consumption of contaminated corn crops (i.e., maize), particularly along the Texas-Mexico Border, Guatemala, N. China, Transkei region of Africa and other parts of the world (e.g., Central and South America) where maize is a dietary staple. 

The evidence for NTD will be briefly reviewed below. First, we need to understand the what neural tube defects (NTD) means.

NTD: The nervous system (brain and spinal cord) begins as a fold in the dorsum of the developing animal. This differentiates into the neuroectocerm becoming the neural fold that fuses forming the neural tube.

The anterior region becomes the brain and the posterior portion forms the spinal cord. If the anterior neuropore (groove) fails to close, then a condition called anencephaly (absent of the brain) occurs. Failure of the posterior neural groove to fuse results in spina bifida. The extent of damage that results from spina bifida depends upon the level at which fusion failed, i.e., thoracic vs lumbar.

Anencephaly occurs in about 1 of 1000 births, while all NTD affect approximately ≤ 3 in 1000 births in the U.S.A. 

Let us now review the information available on FB 1 and NTD.

Guatemala, Northern China, Transkei Region of Africa and Texas-Mexico Border

1. Guatemala: The Guatemalans consume maize tortillas which contain from as low as 3.7 µg to 27 µg of Fumonisins per dry weight. In Quetzaltenango, Guatemala, where high consumption of tortillas occurs, the NTB was found at 106 NTD per 1000 births.

2. Transkei, S. Africa: In rural regions where maize is a staple in the diet, NTD ranges from 35 to 78 per 1000 births. In contrast, the rates in urban areas of Africa are: Cape town (1.06/1000); Pretoria (0.99/1000); and Johannesburg (1.18/1000).

3. Northern China: In the northern provinces of China, the NTD rates are from 57 to 73 per 1000.

4. Texas-Mexico Border: The Spanish Americans that inhabit the communities along the Texas-Mexico border were noted in 1990-1991 to have what appeared to be an elevated incidence of NTD. The NTD rates ranged from 15 to 27.1000 births. The inhabitants consumed tortillas that were classified into high consumption during the first trimester of pregnancy. The moderate consumption was classified as moderate (301-400) vs low (≤ 100). The rate of NTD in the two groups was 2.7 vs 1.5 per 1000 live births. After adjusting for confounders, the difference between the two groups was significant with an odds ratio of 2.5, 95% Confidence Intervals, 1.1-5.3. The authors concluded that the results suggest that fumonisin exposure increases the risk of NTD, proportionate to does, up to a threshold level, at which point fetal death may be more likely to occur.

Although the above observations indicate that FB 115 is a risk factor for NTD, estimates of inhalation exposure were not made. The authors assumed that ingestion was the means by which exposure occurred. However, if one considers the fact that maize is ground by hand in order to make flour, particulates most likely would be generated. Moreover, fungal colonies are known to shed particulates ranging from <1 micron up to and through the size of spores and hyphal fragments. This raises the question on who harvested the grain and were the harvesters at higher risk of NTD than non-harvesters? Thus, estimates of exposure via inhalation should have been done and should be incorporated in future investigations of NTD associated with FB1 exposure. 

Mouse Models of NTD and FB1

Mice models have been used to investigate the mechanisms of NTD related to FB1 exposure. The models include the following: embryo cultures of the developing nervous system, intracerebral infusion, and susceptible and non susceptible strains of mice. The results of these experiments demonstrated two things: (1) FB1 is teratogenic in susceptible mouse strains; and 2) that genetic polymorphism is an important issue in susceptibility to the teratogenesis of FB1. 

In addition, FB1 inhibits ceramide, causing upstream increase of precursors of sphingolipid metabolic pathway that are cytotoxic. At the same time, downstream complex sphingolipids that are important components in membrane structure and function, e.g., Ganglioside GM1, sphingomyelin, among others. GM1 is essential to the function the folic acid receptors of the brain. Thus, addition of GM1 and/or folic acid to the experimental protocol alleviates the NTB related to FB1 treatment. 

Dietary maternal supplementation of Folic acid in humans prevents 50-70 % of NTD. 

In conclusion, multiple factors are involved in NTD. These are: (1) genetic polymorphism; (2) upstream and downstream products of sphingolipid metabolism; (3) Folic acid and its membrane receptors in the placenta and fetus; and 4) Pro-inflammatory cytokines released by activated astrocytes. 

Key References for FB and NTD 

Gelineau-van Waes J, Starr L, Maddox J, Aleman F, Voss KA, et al. 2005. Maternal fumonisins exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model. Birth Defects Res (Part A) 73:487- 97. 

Gelineau-van Waes, Voss KA, Stevens VL, Speer MC, Riley RT. 2009. Maternal fumonisin exposure as a risk for neural tube defects. Adv food Nutri Res 56:145-81. 

Marasas WFO, Riley PT, Hendricks KA, Stevens VL, Sadler TW, et al. 2002. Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: A potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J Nutr 134:711-6. 

Missmer SA, Suarez L, Feiner M, Wang E, Merril AH, et al. 2006. Exposure to fumonisins and the occurrence of neural tube defects along the Texas-Mexico border. Environ Health Perspec 114:237-41. 

Osuchowski MF, Edwards GL, Sharma RP. 2006. Fumonisin B1-induced neurodegeneration in mice after intracerebroventricular infusion is concurrent with disruption of sphingolipid metabolism and activation of proinflammatory signaling. Neurotoxicology 26:211-21. 

Macrocyclic Trichothecenes - Intranasal Instillation 

Satratoxin G (SG) was isolated and purified from cultures of S. chartarum instilled intranasally into C57B1/6 mice in two regimens: (1) single dose at 500 pg/kg bw and (2) 100 pg/kg bw once per day for five days. Control animals were saline treated and mice given T-2 toxin, deoxynivalenol, isosatratoxin and verrucarin A. 

The purpose of using other trichothecenes was to determine if damage occurred via the 12-13 epoxide found in trichothecenes and/or other structure characteristics. Apoptosis in the olfactory epithelium occurred with rise of apoptotic genes Fas, FasL, p75NGFR, p53, Bax, Caspase-3 and CAD. Time-course study with single instillation of 500 pg dose showed maximum atrophy of olfactory epithelium at 3 days post installation. 

Exposure of 100 pg for 5 consecutive days showed similar atrophy and apoptosis, demonstrating accumulative effects. 

Other findings were acute neutrophil rhinitis, elevated mRNA for proinflammatory cytokines (TNF-a, IL-6, IL-2 and macrophage inflammatory protein (MIP-2). Marked atrophy of the olfactory nerve, tract and glomerular layers of the olfactory bulb were observed at 7 days post instillation. Apoptosis of olfactory neurons was evident. Mild signs of neutrophilic encephalitis were present (Islam et al, 2006). 


Satratoxin G: The tissue distribution of Satratoxin G (SG) was investigated following intranasal exposure in mice (Amuzie et al, 2010). SG at 500 pg/kg bw was intranasally instilled into the nasal cavity of mice. The distribution of SG to various organs was then followed. SG was observed in the blood and plasma at 5 to 60 minutes, with highest concentration (30 ng/ml) at 5 minutes and 19 ng/ml at 60 minutes. SG was distributed to all organs with levels as follows: kidney (200 ng/g); lung (250 ng/g); spleen (200 ng/g); liver (140 ng/g); thymus (70 ng/g), olfactory bulb (14 ng/g); and brain (3 ng/g). 

It should be noted that this was a single (stat) dose and not a chronic low level exposure as seen in WDB. Nonetheless, the observations demonstrate that nasal deposition of SG leads to systemic distribution of the mycotoxin. Brasel, et al, demonstrated the presence of macrocyclic trichothecenes in sera of symptomatic occupants of WDB where S. chartarum was present. 

In addition, Bloom, et al, have demonstrated the presence of macrocyclic trichothecenes and other mycotoxins in the dust obtained from water-damaged buildings. The absorbed toxins can cause systemic and brain Inflammation.

Block and Calderon-Garciduenas, Amuzie CJ, Islam Z, Kim JK, Seo JH, Pestka JJ. 2010. Kinetics of Satratoxin G tissue distribution and excretion following intranasal exposure in the mouse. Toxicol Sci 116:433-440. 

Block ML, Calderon-Garciduenas L 2009. Air pollution: Mechanisms of neuroinflammation and CNS disease. Trends Neurosci 32:508-16. 

Bloom E, Nyman E, Must A, Pherson C, Larsson L. 2009. Molds and mycotoxins in indoor environments: A survey in water-damaged buildings. J Occup Environ Hygiene 6:671-8. 

Brasel TL, Campbell AW, Demers RE, et al. 2004. Detection of trichothecene mycotoxins in sera from individuals exposed to Stachybotrys chartarum in indoor environments. Arch Environ Health 59:417-23.

Brasel, TL, Douglas DR, Wilson SC, Straus DC. 2005. Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins on particulates smaller than conidia. Appl Environ Microbiol 71:114-122. 

Roridin A

Roridin A (RA) is another macrocyclic trichothecene produced by S. chartarum. It has also been tested by intranasal administration to mice. Needless to say, there was damage to the olfactory epithelium, nerve and bulb along with initiating the inflammatory response. The concentration of SG that caused the damage was 100 pg/kg bw. 

Interestingly, the biosynthetic precursor of RA, Roridin L2, did not cause damage at the same concentration. 

In conclusion, there are at least two macrocyclic trichothecenes (SG and RA) produced by S. chartarum. Roridin A instilled into the nasal cavity does a dose response and persistent damage to the olfactory epithelium and nerve, along with neutrophilic rhinitis and inflammation as seen with SG administration. The dosing regimen of RA was as follows: (1) 0.2, 2, 10 or 50 pug/kg bw over 3 weeks or (2) 250 pg/kg bw over 3 weeks. The observed damage had a dose response finding. 

Finally, Lipopolysaccharides (a contaminant of VVDB) potentiated the adverse affects of RA. 

Corps KN, Islam Zr Pestkall, Harkema JR. 2010. Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene rnycotoxin roridin A: dose-response and persistence of injury. Toxicol Pathol 38:429-51. 

Islam Z, Amuzie CJ, Harkema JR, Pestka JJ. 2007. Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene rinycotoxin roridin a: Kinetics and potentiation by bacterial lipopolysaccharide. Toxicol Sci. 98:526-41_ 

Islam Z, Shinozuka J, Harkema JR, Pestka JJ. 2009. Purification and comparative neurotoxicity of the trichothecenes satratoxin G and Roridin L2. J Toxicol Environ Health A. 72:1242-51. 

In Vitro Models

Two tissue culture neuron models have been employed to test the toxic action of macrocyclic trichothecenes on apoptosis and inflammations. These experimental models are briefly discussed and listed below. 

Islam Z, hegg CC, Bae HK. Pestka JJ. 2008. Satratoxin G-induced apoptosis of PC-12 neuronal cells is mediated by PI R and caspase independent. Toxicol Sci 105:142-52. 

PC-12 pheochromocytoma cells were treated with SG at 10 rig/mi. The treatment induced DNA fragmentation and apoptosis. Expression of apoptotic genes via testing of mRNA occurred for p53, PKR, BA X and caspase were significantly increased. 

Karunaseria E. Larrariaga MD. Simoni JS. Douglas DR, Straus DC. 2010. Building-associated neurological damage model in human cells: A mechanism for neurotoxic effects by exposure to mycotoxins in the indoor environment. Mycopathologia June 10 [Epub ahead of print]. 

Cell cultures were treated with purified satratoxin H (SH) at 1, 10, 100, 1000 and 5000 ng/g. The cells tested were human brain capillary endothelial cells (HBCEC), astrocytes and neural progenitor cells. The HBCEC are the fundamental structures forming the blood brain barrier (BBB); astrocytes act as the macrophages of the CNS, while the neural progenitor cells form the neurons. SH damage the HBCEC cells and interfered with the production of adhesion moledules. SH caused apoptosis of astrocytes and production of reactive oxygen species, production of proinflammatorycytokines and reduction of intracellular glatathione. Finally, SH caused apoptosis of neural progenitor cells. 
Neurotoxicity

Neurotoxicity


The results of the two experimental studies done on neuronal tissue culture cells clearly support the observations on damage to the olfactory mucosa, olfactory neurons, tract and bulbs observed in the above mouse models. 

Ochratoxin A (OTA) 

OTA has been demonstrated to be teratogenic in animal studies. Oral dosing of pregnant hamsters at concentration from 2.0 to 20 mg/kg caused malformations of the brain and head of fetuses as follows: mirognathia, hydrocephalus, short tail, syndactyly , cleft lip and heart defects (Hood et al, 1976). 

An oral dose of 2.75 mg/kg bw to pregnant Wistar rats resulted in maternal toxicity and fetal malformations as follows: external and internal hydrocephaly, incomplete closure of skull, omphalocele, microphthalmia, enlarged renal pelvis and renal hypoplasia. Skeletal defects include the skull bones, sternebrae, vertebrae and ribs. 

Patil et al, 2006. Intraperitoneal injection of 2-4 mg/kg bw of pregnant mice caused craniofacial malformations. Ochratoxin A exacerbated the fetal effects of T-1 toxin (Hood et al, 1978). 

Hood RD, Kuczuk MH, Szczech GM. 1978. Effects in mice of simultaneous prenatal exposure to ochratoxin A and T-2 toxin. Teratology 17:25-9. 

Hood RD, Naughton MJ, Hayes AW. 1976. Prenatal effects of ochratoxin A in hamsters. Toxicol 13:11-4. 

Patil RD, Dwivedi P, Sharma AK. 2006. Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats. Reprod Toxicol 22:679-87. 

Acute neurotoxic effects of OTA in Swiss mice has been examined (Sava et al, 2006). Intraperitoneal injection of 3.5 mg/kg bw (10 % of LD50 of 3.95 mg/kg) caused multiple indications of cerebral damage. The following areas of brain were dissected and tested for presence of damage: cerebellum (CB); pons/medulla (PM; Midbrain (MB); caudate/putamen; Hippocampus (HP); and cerebral cortex (CX). All regions of the brain had toxic findings that included inhibition of repair of oxidative DNA repair; elevated lipid peroxidation products, upregulation of superoxide dismustase, and a decrease in dopamine and its metabolites in the CD region. Thus, OTA caused acute depletion of striatal (CD) dopamine on a background of increased oxidative stress and transient inhibition of oxidative DNA repair. 

In a subsequent experiment, OTA caused a time and dose dependent decrease in viability of both proliferating and differentiating neural stem/progenitor cells isolated from mouse brain (Sava et al, 2007). This resulted from oxidative damage as shown in the previous study. The authors conclude these results lead to speculation that OTA exposure may contribute to impaired hippocampal neurogenesis in vivo, resulting in depression and memory deficits, conditions reported to be linked to mycotoxin exposure in humans. 

Sava V, Reunova 0, Velasquez A, Harbison R, Sanchez-Ramos J. 2006. Acute neurotoxic effects of fungal metabolite ochratoxin A. Neurotoxicol 27:82-92. 

Sava S, Velasqquez A, Song S, Sancehz-Ramos J. 2007. Adult hippocampal neural/progenitor cells in vitro are vulnerable to the mycotoxins ochratoxin A. Toxicol Sci 98:2007. 

Aflatoxin B1 (AFB1) 

Toxic encephalopathy was originally described in children with Reye's syndrome associated with consumption of Aflatoxin B1 and/or salicylates (Trauner, 1984: Dvorackova et al, 1977) and subsequently in cases of aflatoxicosis in canines and Chinese children (Dereszynski etl, 2008; Lye et al, 1995). Thus, these observations suggest that Aflatoxins may be neurotoxic. The peer-reviewed papers briefly reviewed herein are highly suggestive that these mycotoxins are toxic to various aspects of brain chemistry and, thus, brain function. 

Intranasal instillation of AFB1 in rats results in damage to the nasal mucosa resembling that seen with Satratoxin G and Roridin A. The pathology included disorganized undulating olfactory epithelium, with injured neuronal and sustentacular cells. 

Selective destruction of mucous cells also occurred. 

Radioactively (tritium) labeled AFB1 was present in the olfactory tract and olfactory bulbs. (Larsson and Tjalve, 2000). 

Furthermore, depletion of glutathione stores leads to distribution of AFB1 to other organ systems, including the upper and lower respiratory tract in fetal, infant and adult mice (Larsson and Tjalve, 1992). 

If you wish to do an entrez pubmed search of Larsson and Aflatoxin B1, you will find similar results on animals other than mice and rats. 

Cytochrome P450 enzymes and other enzymes that activate xenobiotics as well as AFB1 are present in the nasal mucosa and bronchial cells (Van Vleet RT, Mace K, Coulombe RA. 2002; Zhang et al, 2005). 

AFB1 also alters the levels of various biogenic amines (neurotransmitters) and their precursors in rat and mouse brains. These include a decrease in dopamine, serotonin and alterations in the levels of the precursors tyrosine and tryptophan (Weekley et al, 1989; Coulomre and Sharma, 1985; Jayasekara e tal, 1989; Kimbrough et al, 1992). Deficiencies in both of these neurotransmitter lead to neurological symptoms such as neurocognitive decline and alteration of sleep cycle. 

Columre RA, Sharma RP. 1985. Effect of repeated exposure of aflatoxin B1 on brain biogenic amines and metabolites in the rat. Toxicol Appl Pharmacol 80:496-501. 

Dereszynski DM, Center SA, Randolph JF, Brooks MD, et al. 2008. Clinical and clinicopathologic features of dogs that consumed food borne hepatoxic aflatoxins: 72 cases (2005-2006). J Am Vet Med Assoc 232:1329-37. 

Dvorakova I, Kusak V, Vessely D, Vessela J, Nesidal P. 1977. Aflatoxin and encephalopathy with fatty degeneration of viscera. (Reye) Ann Nutr Aliment 31:977-89. 

Jayasekra S, Drown DB, Coulombe RA, Sharma RP. 1989. Alteration of biogenic amines in mouse brain regions by alkylating agents. Effects of aflatoxin B1 on brain monoamines concentrations and activities of metablozing enzymes. Arch Environ Contam Toxicol 18:396-403. 

Kimbrough TD, Llewellyn GC, Weekley LB. 1992. The effect of aflatoxin B1 on serotonin metabolism: Response to a tryptophan load. Metab Brain Dis. 7:175-82. 

Larsson P, Tjalve H. 1992. Binding of aflatoxin B1 metabolites in extrahepatic tissues in fetal and infant mice and in adult mice with depleted glutathione levels. Cancer Res 52:1267-77. 

Larsson P, Tjalve H. 2000. Intranasal instillation of Aflatoxin B1 in rats: Bioactivation in the nasal mucosa and neuronal transport to the olfactory bulb. Toxicol Sci 55:383-91. 

Lye MS,. Ghazali AA, Mohan J, Nair WN. 1995. An outbreak of acute hepatic encephalopathy due to severe aflatoxicosis in Malaysia. Am J Trop Med Hyg 53:68-72. 

Van Vleet TR, Mace K, Coulombe RA. Comparative aflatoxin B1 and cyotoxicity in human bronchial cells expressing cytochromes P450 1A2 and 3A4. Cander Res, 62:105-12. 

Weekley LB, O'Rear CE, Kimbrough TD, Lewellyn GC. 1989. Differential changes in rat brain tryptophan, serotonin and tyrosine levels following acute aflatoxins B1 treatment. Toxicol Lett 47:173-7. 

Zhang X, Shang QY, Liu C, Xu T, Weng Y, et al. 2005. Expression of cytochrome P450 and other biotransformation genes in fetal and adult human nasal mucosa. Drub Metab Dispos 33:1423-8
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