Biomonitoring Of Mycotoxins in Plasma Of Patients With Alzheimer’s And Parkinson’s DiseaseⅠ
Apr 12, 2023
Abstract: Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from the La Rioja region were analyzed.
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The studied mycotoxins were aflatoxins B1, B2, G1, G2, and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyl deoxynivalenol, 15-acetyl deoxynivalenol, de epoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol, and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase to detect potential metabolites.
Only OTA, OTB, and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, p-value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER showed distributions always different between healthy controls and patients (patients’ group > controls, p-value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = −0.4643).
Keywords: mycotoxins; ochratoxin A; sterigmatocystin; human exposure; Parkinson´s disease; Alzheimer´s disease; neurodegenerative disease
Key Contribution: Data on the presence of 19 mycotoxins in plasma from healthy adults and neurodegenerative disease patients (Parkinson’s and Alzheimer's) are presented. Only ochratoxin A (OTA) and B and sterigmatocystin (STER) were detected. Differences in OTA levels between control and patients appear to be driven by sex (men > women). For STER higher levels were found in patients. STER levels correlated positively with age in women, while OTA decreased with age, especially in men with PD.
1 Introduction
Neurodegenerative diseases are one of the most frequent pathologies associated with aging, Alzheimer’s disease (AD) being the most common, and Parkinson’s disease (PD) the second most common. AD is the most prevalent form of dementia causing a progressive impairment in memory and other cognitive functions. AD is characterized pathologically by the presence of neurofibrillary tangles which contain hyperphosphorylated Tau, extracellular aggregates of amyloid β, and severe neuronal loss in the brain [1].
PD is characterized clinically by motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability, and non-motor symptoms such as olfactory dysfunction, constipation, depression, sleep disorders, pain, and fatigue. PD is characterized pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies that contain aggregates of alpha-synuclein protein [2].
Despite extensive research, the mechanism underlying the cause in the majority of AD and PD cases remains unknown. Dominantly inherited Alzheimer’s disease is relatively rare and in more than 90% of patients AD etiology is driven by a combination of genetic and environmental factors [3]. The majority of PD cases are sporadic and the familial monogenic PD forms represent about 10% of PD cases [4].
Although the precise mechanism of neurodegeneration in AD and PD is not clear, there is likely a complex etiology involving multiple environmental, age-related, genetic, epigenetic, and inflammatory factors [5,6]. It is widely accepted that the etiology of AD is multifactorial and its pathogenesis is influenced by the interaction of numerous factors, including environmental factors, lifestyle, and genetic elements [7,8].
The association between environmental factors and AD has attracted considerable attention recently. Certain environmental factors, such as metals [9], air pollution [10], pesticides [11], or biotoxins produced by bacteria, molds, and viruses [12], have been reported to increase the risk of AD and play a crucial role in the onset and progression of AD through several pathological mechanisms [7,8,13]. In the case of PD, the fact that the disease is accompanied by other non-motor symptoms in organs highly exposed to the environment (olfactory and gastrointestinal systems) reinforces the hypotheses of the role of environmental factors in the etiology of PD. Many chemicals such as pesticides, metals (iron and lead), polychlorinated biphenyls, solvents such as trichloroethylene, perchloroethylene as well traffic particles have been linked to PD [14,15].
Among them, the stronger evidence points to pesticides [16]. Indeed, it is known that people living in rural areas, exposed to neurotoxins present in crops, well and spring waters are at higher risk of developing PD [17,18]. Another group of compounds present in rural areas long before pesticides are mycotoxins. Mycotoxins are naturally-occurring contaminants produced by different fungal species such as Aspergillus, Penicillium, and Fusarium, that contaminate crops, mainly cereals, nuts, and vegetables worldwide.
The economical agricultural losses are huge [19]; however, the main concern is related to human and farm animal health. They are known to cause severe and long-term diseases related to their hepatotoxic, nephrotoxic, immunotoxic, genotoxic, and carcinogenic properties as well as their deleterious effects on the endocrine or reproductive systems [20–22]. Indeed, due to their toxic effects maximum limits on different foodstuffs, foods, and feed have been laid down at the EU level [23–25].
Nowadays there is increasing awareness for minimizing mycotoxins exposure [22] because (i) the general population is widely exposed to mycotoxins mainly through diet, with a worldwide occurrence in foodstuffs above the detectable levels, being up to 60–80% [26], (ii) human and animal are exposed to more than one mycotoxin (cocktails of mycotoxins) and (iii) climate change might increase the risk for mycotoxin contamination in some areas.
This awareness has also led to an increased need to carry out analysis of mycotoxins in biological fluids through human biomonitoring (HBM) to know the real exposure of animals and humans. Indeed, HBM is promoted as an essential complement to direct mycotoxin determination in food [27,28]. Although, as mentioned, the scientific literature has many publications describing the several deleterious effects of the different mycotoxins or quantifying the levels of mycotoxins in foods, little has been done regarding its quantification in human samples and they have been practically unexplored as etiological agents of neurodegenerative diseases.
Very few studies have focused on this purpose. Some case studies from patients diagnosed with AD and related to chronic inflammatory response syndrome (CIRS) have directly pointed to mycotoxin exposure via inhalation in moldy environments as the cause of the disease [29]. Some authors have also hypothesized a link between diet and neurodegeneration with the involvement of bacterial lipopolysaccharides and fungal mycotoxins in amyloid beta (Aβ) homeostasis, a process related to AD [30].
More recently, in vitro and in vivo studies carried out by our group [31] demonstrated that subchronic exposure to the mycotoxin ochratoxin A (OTA) induced some of the key pathological features of PD such as loss of striatal dopaminergic innervation and dopaminergic cell dysfunction accompanied with motor impairments and increased phosphorylated alpha-synuclein levels. All this information as well as the need for continuous HBM led us to quantify the levels of mycotoxins in healthy donors and patients with neurodegenerative diseases such as PD or AD, from a region of Northern Spain: La Rioja.
Therefore, in the present study, the levels of 19 mycotoxins of major risk for human health and some of their metabolites have been quantitatively analyzed by high-performance liquid chromatography-mass spectrometry (LC-MS/MS): aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1), G2 (AFG2), M1 (AFM1), ochratoxin A (OTA) and B (OTB), sterigmatocystin (STER), deoxynivalenol (DON), 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), de epoxy-deoxynivalenol (DOM-1), diacetoxyscirpenol (DAS), nivalenol (NIV), fusarenon-X (FUS-X), neosolaniol (NEO), zearalenone (ZEA), T-2 and HT-2. Moreover, because mycotoxins can be metabolized, plasma samples have been analyzed before and after treatment with a mixture of β-glucuronidase and arylsulfatase to study, in an indirect way, the presence of glucuronide or sulfate conjugate metabolites of the studied mycotoxins.
This is the first time that this analysis has been conducted on plasma from patients diagnosed with AD or PD. Data from healthy donors, and companions of the patients, are also included. The age of the patients and the disease stage, diagnosed by experienced neurologists and based on Hoehn and Yahr (HY) scale for PD and Global Deterioration Scale (GDS) for AD, have been matched with the samples.
The mechanism of Cistanche treats Alzheimer's disease & Parkinson's disease
Cistanche is a traditional Chinese herb that has been used for many years for its potential health benefits. In recent studies, it has been found that Cistanche may have neuroprotective effects and may be effective in treating Alzheimer's disease (AD) and Parkinson's disease (PD).
The mechanism of Cistanche in treating AD and PD effectively is attributed to its active components, such as echinacoside, acteoside, and cistanosides. These compounds are believed to have antioxidant and anti-inflammatory properties that can reduce oxidative stress and inflammation in the brain, which are associated with the development and progression of neurodegenerative diseases.
Cistanche can also promote the growth of nerve cells and improve cognitive function by increasing the levels of brain-derived neurotrophic factor (BDNF), a protein that plays a crucial role in the growth and maintenance of neurons. In addition, Cistanche has been shown to reduce β-amyloid plaques, which are hallmark features of Alzheimer's disease, and decrease the accumulation of α-synuclein in the brain, which is associated with Parkinson's disease.
Overall, the potential therapeutic benefits of Cistanche in treating AD and PD are promising, but further studies are needed to elucidate its exact mechanisms of action and confirm its efficacy and safety in clinical settings.
to be continued...
Beatriz Arce-López 1 , Lydia Alvarez-Erviti 2 , Barbara De Santis 3 , María Izco 2 , Silvia López-Calvo 4 , Maria Eugenia Marzo-Sola 4 , Francesca Debegnach 3 , Elena Lizarraga 1 , Adela López de Cerain 5,6 , Elena González-Peñas 1,† and Ariane Vettorazzi 5,6,* ,†
1 Department of Pharmaceutical Technology and Chemistry, Research Group MITOX, School of Pharmacy and Nutrition, Universidad de Navarra, 31008 Pamplona, Spain; barce@alumni.unav.es (B.A.-L.); elizarraga@unav.es (E.L.); mgpenas@unav.es (E.G.-P.)
2 Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 3rd Floor, 26006 Logroño, Spain; laerviti@riojasalud.es (L.A.-E.); mizco@riojasalud.es (M.I.)
3 National Reference Laboratory for Mycotoxins and Plant Toxins, Istituto Superiore di Sanità, 00161 Roma, Italy; barbara.desantis@iss.it (B.D.S.); francesca.debegnach@iss.it (F.D.)
4 Servicio de Neurología, Hospital San Pedro, Piqueras 98, 26006 Logroño, Spain; slcalvo@riojasalud.es (S.L.-C.); memarzo@riojasalud.es (M.E.M.-S.)
5 Department of Pharmacology and Toxicology, Research Group MITOX, School of Pharmacy and Nutrition, Universidad de Navarra, 31008 Pamplona, Spain; acerain@unav.es 6 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
