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Home , Mycotoxin, Ochratoxin, Trichothecene

Clinical Therapeutics/Volume 40, Number 6, 2018

Effects of on Neuropsychiatric Symptoms and Immune Processes

Aarane M. Ratnaseelan, MBS1; Irene Tsilioni, PhD2; and Theoharis C. Theoharides, MS, MPhil, PhD, MD1,2,3,4,5 1Graduate Program in Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts; 2Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts; 3Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts; 4Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts; and 5Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts

ABSTRACT (Clin Ther. 2018;40:903–917) & 2018 Elsevier HS Purpose: The effects of air pollutants have been Journals, Inc. All rights reserved. receiving increased attention both clinically and in the Key words: autism, brain, cognition, , in- media. One such pollutant is , fungal growth in flammation, mast cells, mold, mycotoxins. the form of multicellular filaments known as hyphae. The growth of is omnipresent not only in outdoor settings but also in indoor environments containing excessive amounts of moisture. INTRODUCTION Methods: PubMed was searched for relevant ar- Mold is a type of fungus grown in multicellular filaments ticles using terms such as mold, mycotoxins, fungi, on moist and other surfaces. While generally fl immunity, in ammation, neurodevelopment, cogni- thought to be an outdoor problem, mold – tion, Alzheimer's, and autism. in buildings is quite common.1 8 One study from Findings: Exposure to molds is most commonly Harvard University (Cambridge, Massachusetts), in associated with allergies and asthma. However, it is 13,369 white children aged 8 to 12 years from 24 now thought to be associated with many complex communities across , reported that the health problems, since some molds, especially Tricho- prevalence of growth was between 22% to derma, and spp, produce 57%, affecting 450% of households in 5 communities. mycotoxins that are absorbed from the skin, airways, The reported prevalence of asthma symptoms ranged and intestinal lining. People exposed to molds and from about 3% to 11% of the children.9 Another study mycotoxins present with symptoms affecting multiple in 5951 children from 9 cities in Russia reported positive organs, including the lungs, musculoskeletal system, associations between water damage or the presence of as well as the central and peripheral nervous systems. molds in the home and asthma, wheezing, dry cough, Furthermore, evidence has recently implicated expo- bronchitis, and respiratory allergy.10 sure to mycotoxins in the pathogenesis of autism Many studies describe the adverse health consequences spectrum disorder. The effects of mycotoxins can be of mold-contaminated indoor environments, and especially mediated via different pathways that include the mycotoxins,11,12 on the skin and respiratory systems.13 fl secretion of pro-in ammatory cytokines, especially Some indoor molds, including Trichoderma, Fusarium, – from mast cells. and Stachybotrys spp, produce mycotoxins,1 8,14 exposure Implications: The information reviewed indicates that exposure to mold and mycotoxins can affect the Accepted for publication May 14, 2018. nervous system, directly or through immune cell https://doi.org/10.1016/j.clinthera.2018.05.004 activation, thus contributing to neurodevelopmental 0149-2918/$ - see front matter disorders such as autism spectrum disorder. & 2018 Elsevier HS Journals, Inc. All rights reserved.

June 2018 903 to which occurs through dermal contact, inhalation, autism. The reference lists of identified articles were and ingestion.11 Inhabitants of affected dwellings searched manually for additional papers eligible for typically report headaches and respiratory and inclusion. Data from articles that were prior to 1990 – musculoskeletal symptoms.9,15 17 Some studies have and those in languages other than English were excluded also reported that mold-exposed groups had altered from the review. neurologic functioning, including changes in body balance, blink-reflex latency, visual fields, reaction time, – RESULTS and color discrimination, compared with controls.18 21 fi The exposed groups also demonstrated depression.22 A total of 150 articles were identi ed from the data- Increasing evidence has implicated the pathogenic base search. Data from articles that were published potential of nanoparticulate fragments of fungi, and prior to 1990 and those in languages other than – ¼ more specifically mycotoxins.23 26 Moreover, while a English were excluded. Data from 16 articles (N single may not produce any effect, a 1580 patients) were included in the present review. The combination of mycotoxins could induce at Table summarizes most of the key studies reviewed. very low levels.27 The major classes of mycotoxins include (A, B, and C), produced by Neuropsychiatric Effects From Mold Exposure and spp, as well as the Findings in Adults (T2).14 is the most Individuals exposed to mold report an extensive common mycotoxin found in and water- range of symptoms, including malaise, fatigue, and damaged buildings, and has been associated with cognitive impairment, which appear to be related to – serious health problems,28 including severe the duration of exposure.18 21 In one study, patients neurologic issues, in humans.29,30 who had been exposed to mold were impaired on a The mycotoxins are subclassified as variety of cognitive measures, including verbal learn- nonmacrocyclic, produced mostly by Fusarium spp, ing, visuospatial learning and memory, psychomotor and macrocyclic, produced mostly by Myrothecium, speed, and emotional functioning.20 Mold-exposed Stachybotrys, and Trichothecium spp. Trichothecene patients in other studies also displayed similar mycotoxins can be released at 300-fold the concen- symptoms of neurologic dysfunction as compared to tration of .24 These are commonly detected in the controls, including an inability to stand on one's toes, air of contaminated buildings, and exposed persons have inability to walk in a straight line with eyes closed, significantly more T2 mycotoxins in their sera as short-term memory loss, altered blink-reflex latency, – compared to controls.25,31 33 These can cause verbal recall impairments, as well as issues with color multisystemic effects, including gastrointestinal, cardiovas- discrimination and reaction time.38,40 cular, and neuropsychiatric complications.23 One study Another group of researchers assessed the psycholog- reported neurotoxic effects on human cells exposed to ical, neuropsychological, and electrocortical effects of satratoxin A at levels found in water-damaged exposure to mixed colonies of toxigenic molds in 182 buildings.34 Trichothecene mycotoxins released by patients with a confirmed mold-exposure history.19 The Stachylobotrys spp, such as satratoxins G and H, patients reported moderate to severe levels of cognitive, have been shown to produce in physical, and emotional symptoms, mostly depression, humans.35,36 The nonmacrocyclic T2 B1 while quantitative electroencephalography results showed has also been associated with neurotoxicity.37 hypoactivation in the frontal cortex, which could Here we review the risk factors, signs and symptoms, potentially be due to brain stem involvement and diagnoses, and mechanisms of action of mycotoxins, insufficient excitatory input from the reticular-activating especially as they relate to neuropsychiatric effects. system.19 Neuropsychological testing also indicated impairments similar to those seen in mild traumatic brain injury, in which there were findings of impaired MATERIALS AND METHODS functioning on multiple cognitive tasks when compared PubMed was searched for relevant articles using terms to premorbid estimates of intelligence.19 This picture is such as mold, mycotoxins, fungi, immunity, inflamma- consistent with that from another study, in which tion, neurodevelopment, cognition, Alzheimer's, and neuropsychological data from and symptoms in 31

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Table. Summary of important studies reviewed.

Environmental Exposure Species Subjects Controls Results Findings Conclusions Study

Mold in home and Humans 10 10 Compared to The most consistent Mold/mycotoxin Baldo et al20 workplace normative data, deficits were found exposure leads to mold-exposed in visuospatial neuropsychologi- patients were learning/memory, cal detriments. impaired on a verbal learning, and number of cognitive psychomotor measures. speed. Mold Humans 65 Patients 202 Community The mold-exposed Most functions tested Indoor mold Kilburn38 subjects group exhibited were abnormal. exposure is decreased function associated with for balance, neurobehavioral reaction time, blink- deficits. reflex latency, color discrimination, visual fields, and grip, as compared to referents. Mixed mold Humans 209 Patients N/A Many of the exposed Exposure to mixed Mold-exposed Gray et al39 mycotoxicosis; individuals had molds and their patients reported water-damaged increased associated a greater buildings lymphocyte mycotoxins in frequency and

phenotypes and water-damaged intensity of al. et Ratnaseelan A.M. numerous other buildings leads to neurological and immune multiple health inflammatory abnormalities. problems involving symptoms. the CNS. (continued) 905 906 Therapeutics Clinical

Table. (continued).

Environmental Exposure Species Subjects Controls Results Findings Conclusions Study

Mixed molds Humans 182 Mold- N/A Hypoactivation of the A dose–response Mold exposure Crago et al19 exposed frontal cortex and relationship leads to normal insufficient between measures neuropsychologi- excitatory input of mold exposure cal detriments. from the reticular and abnormal activating system. neuropsychological Neuropsychological test results testing also revealed suggested that impairments similar toxic mold causes to mild TBI. significant problems in exposed individuals. Mold/mycotoxins in Humans 100 Patients N/A Immune Objective Mold/mycotoxin Rea et al40 home abnormalities were neuropsychological exposure leads to found in 4 80% of evaluations of 46 of neuropsychologi- the patients and the patients who cal detriments. symptoms of exhibited symptoms neurological of neurological dysfunction in 70% impairment showed of all patients. typical Objective abnormal abnormalities in autonomic nervous short-term memory,

oue4 ubr6 Number 40 Volume system tests were executive function/ positive in all 100 judgment, patients tested. concentration, and hand/eye coordination. (continued) ue2018 June

Table. (continued).

Environmental Exposure Species Subjects Controls Results Findings Conclusions Study

Mold Humans 6 Patients N/A Reports data on six Only 2 patients who No credible Stone et al41 patients claiming were also depressed evidence of harm harm from mold. showed credible due solely to evidence of mold exposure. neuropsychological dysfunction. Toxic mold Humans 53 Patients N/A No concomitant Lack of significant Mold exposure does Reinhard cognitive deficits or evidence for not lead to et al42 a significant cognitive cognitive deficits. reduction in dysfunction intellectual functioning. Mold and Humans 8 ASD boys in 145 Non-ASD in The 6 mold-exposed Neuropsychological Mold exposure Kilburn terbutaline non-chemical nonchemical ASD kids had most. abnormalities were increased et al43 community; community; more frequent in neuropsychologi- 6 ASD mold- 29 non-ASD mold-exposed cal abnormalities exposed mold-exposed children. in ASD children. children children Toxic mold Humans 15 Normal N/A Mold-exposed After 10 sessions of HBOT a possible Ezra et al44 adults subjects show HBOT, a treatment statistically statistically method for mold- significant significant exposed patients.

decreases in improvement was al. et Ratnaseelan A.M. attention span and seen in both significant increases measures. in reaction time to stimuli compared to controls. (continued) 907 908 Therapeutics Clinical

Table. (continued).

Environmental Exposure Species Subjects Controls Results Findings Conclusions Study

Mold-contaminated Humans 277 Normal N/A Long exposures to Early postnatal Mold exposure Jedrychowski homes in early babies indoor molds (42 exposure to indoor negatively et al45 postnatal period y) tripled the risk molds reduced affected for low IQ scoring children's cognitive children's IQ. compared with development. controls. No exposure Humans 57 Patients with N/A Patients with Memory and Mast cells Moura et al46 mastocytosis mastocytosis attention emotionality presented high impairment in affect in levels of cognitive mastocytosis is cognition. impairment frequent, even in (memory and/or young individuals. attention). Home dampness, Humans 482 Children N/A Persistent home Damp room in early Damp housing in Casas et al47 pets and farm dampness in the life can have early life adversely animal contact; child's bedroom adverse effects on affects microbial during early life neuropsychological neuropsychologi- compounds significantly development at 4 cal development. (bacterial decreased the years old. endotoxin and general score on fungal MSCA by 4.9 points extracellular and it decreased the polysaccharides) CPSCS by 6.5

oue4 ubr6 Number 40 Volume points. None of the measured microbial compounds were related with the psychometric test scores. (continued) ue2018 June Table. (continued).

Environmental Exposure Species Subjects Controls Results Findings Conclusions Study

Mold Humans 31 65 Patients with Most participants Mold-exposed Mycotoxins/mold Gordon traumatic TBI were found to have participants exposure et al48 & 26 with reduced cognitive reported contributed to moderate TBI function in multiple significantly more cognitive domains, with symptoms. dysfunction. memory and executive functions the most commonly affected areas. Ochratoxin A N/A N/A N/A Ochratoxin A exerted Proposed - Possible explanation Mezzelani a male-specific environment for the male et al49 neurotoxicity, interaction. prevalence of probably via ASD. microRNA modulation of the neuroligin 4X gene. Mycotoxins Humans 25 Patients 29non-ASD Screened for 87 urinary No urine mycotoxins No association Duringer with ASD mycotoxins, but were associated between urine et al50 only 9 of 54 children with ASD- mycotoxin had detectable diagnosed children. exposure and mycotoxins in their autism. urine. No exposure Humans 54 Patients Healthy, age- Patients displayed High perceived stress TRP Georgin- with matched significantly lower and high depression was altered in Lavialle ..Rtaelne al. et Ratnaseelan A.M. mastocytosis controls levels of TRP and 5- scores were mastocytosis and et al51 HT. associated with low correlates with TRP. perceived stress and depression.

5-HT ¼ serotonin; ASD ¼ autism spectrum disorder; CPSCS ¼ California Preschool Social Competence Scale; HBOT ¼ hyperbaric oxygen treatment; MSCA¼

909 McCarthy Scales of Child Abilities; TBI ¼ traumatic brain injury; TRP ¼ tryptophan. Clinical Therapeutics individuals exposed to toxic mold showed that most associated with poor physical health outcomes, such participants had decreased cognitive functioning in as respiratory and issues, poor multiple domains, with memory and executive functions physical health is another likely contributor to – being the most commonly affected areas.48 These depressive tendencies.52,54,61 63 symptoms were similar to those in matched groups of There is also a concern that some neuropsychiatric 65 individuals with mild traumatic brain injury and 26 symptoms may be associated with socioeconomic persons with moderate traumatic brain injury.48 factors present in individuals living in moldy dwell- One study conducted in patients with confirmed ings. The Health Public Housing Initiative in Boston, exposure to mixed-mold infestation in water-damaged Massachusetts tried to identify and correct such buildings found that exposure to mycotoxins was associations.64,65 One study showed increased expo- associated with multisystem issues involving the nerv- sure to mold in a workplace, especially B1 ous and immune systems.40 and B2, due to contaminated onions.66 Workers at a Other studies used both objective and subjective waste-management company in Portugal were measures and showed that the presence of mold and exposed to increased levels of aflatoxin B1.67 In an dampness was associated with the prevalence of analysis in breast-feeding mothers in Lebanon, the – depression and emotional distress.52 54 This conclu- presence of aflatoxin B1 in breast milk was correlated sion was subsequently confirmed using multivariate with low socioeconomic status.68 A strong association analyses.55 between poverty and exposure to aflatoxin was also There are also some contradictory reports. Unlike reported in a cross-sectional study from Kenya.69 the cognitive impairments suggested in other studies, the results from a study by Reinhard et al42 (N ¼ 50) Findings in Children did not reveal a significant reduction in intellectual Exposure to molds that produce potent toxins has functioning, nor did they show a dose effect of self- been associated with acute pulmonary hemorrhage reported duration of exposure on cognitive outcome. and hemosiderosis among infants.70 One study Another study did not find any association between showed a correlation between exposure to excessive exposure to mold and neuropsychiatric symptoms.56 moisture or mold in a home or school environment It is also possible that symptoms of cognitive and the occurrence of respiratory issues, including impairment are not unique to mold and mycotoxin infections, repeated wheezing, and prolonged – exposure. For instance, researchers examining cough.10,61,64,71 77 neurobehavioral and pulmonary impairment in 105 Some studies in children have focused on cognitive- adults with indoor exposure to molds, as compared to development deficits resulting from exposure to air controls and 100 chemical-exposed adults, found that pollutants both prenatally and during childhood.78,79 the increased neurobehavioral impairments associated In children with long-term exposure to molds, there with mold exposure were comparable to those of were significant neurologic findings on clinical neuro- chemical exposures.57 logic and neurobehavioral questionnaires, as well as It is also unclear whether neuropsychological prob- abnormalities on a series of neurophysiological tests, lems are due to the adverse effects of mycotoxins or including electroencephalography, brain stem evoked the emotional and financial stress of keeping a house potential, visual evoked potential, and somatosensory clean in the face of recurrent mold.52 Investigators evoked potential.80 have also hypothesized that housing is intimately A 6-year follow-up study conducted in Poland linked to an individual's perception of control, so explored cognitive functioning in 277 infants born at those experiencing high demands from a moldy home, term and exposed to mold in contaminated homes in yet a low sense of control, may have an elevated risk the early postnatal period. The presence of visible – for anxiety and depression.58 60 Nonetheless, the mold patches on indoor walls was checked at con- association between mold or dampness in the home sistent time intervals over gestation and after birth, up and depressive symptoms was diminished, but not to the age of 5 years. Longer (42 years) exposure to eliminated, when perception of control over one's indoor molds was associated with deficits in intelli- home or a physical health index was included in the gence quotient compared to that in controls.45 In a model.22 Furthermore, since living in a moldy home is population-based birth-cohort study from Spain, 482

910 Volume 40 Number 6 A.M. Ratnaseelan et al. children underwent psychometric testing at 4 years of diagnosis in children.50 However, serum IgE or IgG age; information on home dampness, pet ownership, levels in those exposed to mycotoxins may be a and farm-animal contact was regularly monitored and more reliable index of long-term exposure, and reported by parents through questionnaires, while detoxification may be required to release mycotoxins bacterial endotoxins and fungal extracellular from fat or other depots into the urine so that they polysaccharides were measured in living-room sofa may be detected. dust collected when the children were 3 months of age.47 The results revealed that persistent home Immune Pathways of Mycotoxin Toxicity dampness in a child's bedroom during early life was Unlike bacterial toxins, which are proteins, myco- associated with a significant decrease in the general toxins have diverse structures.86 Mycotoxins have cognitive score on both the McCarthy Scales of Child different mechanisms through which they exert their Abilities and the California Preschool Social effects,87,88 depending on whether studies are per- Competence Scale.47 formed in vitro or in vivo.89 Mycotoxins may produce Recent epidemiologic studies have reported a sig- their detrimental effects not only by affecting nificant association between exposure to mycotoxins and translation, but also through and autism spectrum disorder (ASD), which now inflammatory responses mediated by cytokines.88 affects an estimated 1 in 59 children81 and remains Mycotoxins could also affect the neuroimmune without a clear pathogenesis despite advances in axis90 via activation of a number of kinases, identifying multiple mutations.82,83 Two studies have including mitogen-activated protein kinase – provided strong evidence of an association between (MAPK).88,91 97 Macrocyclic trichothecenes are po- exposure to mycotoxins and ASD. In the first, data tent activators of MAPKs.98 Exposure to satratoxin H from 52 children with ASD were compared to those leads to the activation of MAPKs, the development of from healthy children (31 siblings and 27 unrelated oxidative stress, and the depletion of reduced subjects), with a significant association between levels glutathione.35 In addition, , a mycotoxin of ochratoxin A in urine and serum found in children produced by a number of Fusarium spp, has been with ASD.84 In a subsequent cross-sectional study, shown to affect immune mediators, MAPK signaling, levels of different mycotoxins (aflatoxin M1, and gene expression.99 ochratoxin A, and ) were shown to be Ochratoxin A exposure reduces mitochondrial func- – significantly higher in serum and urine from 172 tion and could lead to in neurons,100 102 as children with ASD as compared to 61 healthy well as dysfunctional responses in cultured murine controls.85 Another study compared neurobehavioral microglia and astrocytes.103,104 In studies in mice, and pulmonary functioning between mold-exposed satratoxin G was shown to produce apoptosis in boys with ASD, non–mold-exposed boys with ASD, sensory neurons in the olfactory bulb,105 as well as terbutaline-exposed children, and unaffected children encephalitis associated with persistently high levels from a community with no known chemical of pro-inflammatory cytokines in the frontal brain exposures.43 After comparisons were adjusted for region.106 confounding variables and variances, the results Many pro-inflammatory cytokines are secreted – showed that the mold-exposed boys with ASD from mast cells,107 109 which are found perivascularly – averaged significantly more abnormalities than did in all tissues, including the brain.110 114 Recent studies the other groups, especially in balance, vision, and have shown strong associations between the preva- blink-reflex latency.43 Additionally, other studies have lence of mast cells and an increased risk for shown that mold-exposed children experienced ASD.115,116 A case of particular interest is mastocy- cognitive deficits compared to controls, but that the tosis, characterized by the abnormal accumulation of effects were not specific to mold or related to mast cells in one or multiple organs,108 and mast cell– psychometric test scores.47,48 activation syndrome, characterized by unregulated One pilot case–control study, conducted in school- mast cell activation.117 We had reported that the aged children, showed that, of 87 urinary mycotoxins prevalence of ASD is 10-fold higher in children with measured via LC-MS/MS, no singular mycotoxin mastocytosis than in the general population.116 or group of mycotoxins was associated with ASD Moreover, one third of patients with mastocytosis

June 2018 911 Clinical Therapeutics display various neuropsychological symptoms, of the molecular pathways that underlie the link including fatigue,118 cognitive impairment,46 and between mycotoxin exposure and cognitive impair- depression.51 It is of interest that mycotoxins can ment, as well as the impact of mold and mycotoxins – stimulate mast cells119 121 and microglia85 because on the immune and nervous systems, is urgently mast cell–microglia interactions have been implicated needed. in neuropsychiatric disorders, especially "brain – fog."122 125 Increasing evidence suggests the presence of local- ACKNOWLEDGMENTS ized inflammation in the brain in patients with ASD.115 This research was partly supported by an anonymous Environmental triggers, such as mycotoxins, have been grant awarded to T.C. Theoharides. – associated with ASD.126 129 Such triggers could in- A.M. Ratnaseelan searched the literature and wrote crease the permeability of the gut–blood and blood– the original manuscript that was submitted as her – brain barriers through mast cell mediators,130 132 thesis for the Graduate Program in Biomedical Scien- especially cytokines,133 allowing circulating and ces, Tufts University School of Medicine (Boston, environmental toxins to pass into the brain, trigger Massachusetts). I. Tsilioni helped to prepare the final microglia proliferation, and disrupt neuronal manuscript. T.C. Theoharides supervised the develop- connectivity.115,134 For instance, it has been reported ment of A.M. Ratnaseelan's thesis and prepared the that propionic acid and ammonia released by Candida final manuscript. albicans in the gastrointestinal tract135 leads to the generation of β-alanine, which could cross the blood– brain barrier and act as a partial antagonist to REFERENCES γ 135 -aminobutyric acid receptors. 1. Ismaiel AA, Ppapenbrock J. Mycotoxins: Producing fungi Ochratoxin A is one of the major food-contami- and mechanisms of phytotoxicity. . 2015;5: nating mycotoxins, and it may exert a male-specific 492–537. neurotoxicity of a specific target gene through micro- 2. da Rocha ME, da Chagas Oliveira FF, Fietosa Maia FE, RNA modulation both in vitro and in vivo with et al. Mycotoxins and their effects on human and animal respect to ASD. Researchers have focused on the health. Food Control. 2014;36:159–165. neuroligin 4X–encoding gene (NLGN), which is ex- 3. American Academy of Pediatrics, Committee on Envi- pressed on the X chromosome and carries a few ronmental Health. Toxic effects of indoor molds. Pediatrics. – single-nucleotide polymorphisms that have been 1998;101:712 714. 4. Andersson MA, Nikulin M, Koljalg U, et al. Bacteria, linked to ASD.49 Some of these point mutations may molds, and toxins in water-damaged building materials. prevent phosphorylation of the protein encoded by – 136 Appl Environ Microbiol. 1997;63:387 393. NLGN, disrupting proper synaptic functioning. 5. Peltola J, Andersson MA, Haahtela T, et al. Toxic- Most recently, mycotoxins were shown to bind to metabolite-producing bacteria and fungus in an indoor 137 proteins involved in neuronal plasticity. Exposure environment. Appl Environ Microbiol. 2001;67:3269–3274. to satratoxin H was shown to increase susceptibility 6. Etzel RA. Mycotoxins. JAMA. 2002;287:425–427. to other neurotoxic mycotoxins.34,138 7. Fog NK. Mycotoxin production by indoor molds. Fungal Genet Biol. 2003;39:103–117. 8. Gorny RL, Reponen T, Willeke K, et al. Fungal fragments CONCLUSIONS as indoor air biocontaminants. Appl Environ Microbiol. – Exposure to mold and their mycotoxins continues to 2002;68:3522 3531. be a major health problem worldwide. Recent studies 9. Spengler J, Neas LM, Nakai C, et al. Respiratory symptoms and housing characteristics. Indoor Air. 1994; have greatly expanded our understanding of the 4:72–82. systemic impact of mold toxicity on the human body, 10. Spengler JD, Jaakkola JJ, Parise H, et al. Housing including the brain. Exposure to mycotoxins has characteristics and children's respiratory health in the demonstrated positive associations with asthma, Russian Federation. Am J Public Health. 2004;94:657– wheezing, and bronchitis, as well as fatigue, muscu- 662. loskeletal pain, headaches, anxiety, mood, cognitive 11. Fromme H, Gareis M, Volkel W, Gottschalk C. Overall impairments, and depression. A better understanding internal exposure to mycotoxins and their occurrence in

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factors combine to cause autism: a 137. Scafuri B, Varriale A, Facchiano A, 138. Thrasher JD, Crawley S. The bio- redox/methylation hypothesis. Neuro- et al. Binding of mycotoxins to pro- contaminants and complexity of Toxicol. 2008;29:190–201. teins involved in neuronal plasticity: a damp indoor spaces: more than 127. Herbert MR. Contributions of the combined in silico/wet investigation. what meets the eyes. Toxicol Ind environment and environmentally Sci Rep. 2017;7:15156. Health. 2009;25:583–615. vulnerable physiology to autism spectrum disorders. Curr Opin Neu- rol. 2010;23:103–110. 128. Rzhetsky A, Bagley SC, Wang K, et al. Environmental and state-level regula- tory factors affect the incidence of autism and intellectual disability. PLoS Comput Biol. 2014;10:e1003518. 129. Wong CT, Wais J, Crawford DA. Prenatal exposure to common environmental factors affects brain lipids and increases risk of devel- oping autism spectrum disorders. Eur J Neurosci. 2015;42:2742– 2760. 130. Theoharides TC. Mast cells: the immune gate to the brain. Life Sci. 1990;46:607–617. 131. Esposito P, Gheorghe D, Kandere K, et al. Acute stress increases perme- ability of the blood-brain-barrier through activation of brain mast cells. Brain Res. 2001;888:117–127. 132. Theoharides TC, Konstantinidou A. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci. 2007;12:1615–1628. 133. Abbott NJ. Inflammatory media- tors and modulation of blood- brain barrier permeability. Cell Mol Neurobiol. 2000;20:131–147. 134. Rozniecki JJ, Sahagian GG, Kem- puraj D, et al. Brain metastases of mouse mammary adenocarcinoma is increased by acute stress. Brain Res. 2010;1366:204–210. https:// www.ncbi.nlm.nih.gov/pubmed/ 20887716. 135. Burrus CJ. A biochemical rationale for the interaction between gastro- intestinal and autism. Med Hypotheses. 2012;79:784–785. 136. Bemben MA, Nguyen QA, Wang T, et al. Autism-associated mutation inhibits protein kinase C-mediated Address correspondence to: Theoharis C. Theoharides, MS, MPhil, PhD, neuroligin-4X enhancement of ex- MD, Department of Immunology, Tufts University School of Medicine, citatory synapses. Proc Natl Acad Sci 136 Harrison Avenue, Suite J 304, Boston, MA 02111. E-mail: theoharis. USA. 2015;112:2551–2556. [email protected]

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