Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype

Sandström, Jenny; Antinori, Paola; Zurich, Marie-Gabrielle; Rosset, Robin; Aschner, Michael; Gluck, Florent; Scherl, Alexander; Monnet‐Tschudi, Florianne

doi:10.1016/j.neuro.2014.04.005

Cited by 21 publications

(10 citation statements)

References 55 publications

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“…Neurotoxic astrocytes can, e.g., be induced by activated microglia [18], whereas an alternative activation of astrocytes by microglia via P2Y1 receptor downregulation leads to neuroprotective conditions [19]. Therefore, a more exact characterization of this KE is required [1] Aschner ( 1998 ), [2] Graeber and Streit ( 1990 ), [3] Monnet-Tschudi et al ( 2007 ), [4] Streit et al ( 1999 ), [5] Kraft and Harry ( 2011 ), [6] Claycomb et al ( 2013 ), [7] Brown and Bal-Price ( 2003 ), [8] Nakajima and Kohsaka ( 2004 ), [9] Falsig et al ( 2008 ), [10] Falsig et al ( 2006 ), [11] Monnet-Tschudi et al ( 2011 ), [12] von Tobel et al ( 2014 ), [13] Banati ( 2002 ), [14] Falsig et al ( 2004 ), [15] Eng et al ( 2000 ), [16] Struzynska et al ( 2007 ), [17] Kuegler et al ( 2010 ), [18] Liddelow et al ( 2017 ), [19] Shinozaki et al ( 2017 ) Adverse outcome: Parkinsonian motor deficits Motor information is modulated by the basal ganglia of the extrapyramidal system and returned to the motor cortex from where the processed information is projected to the periphery. The striatum represents the key modulatory site.…”

Section: Key Eventsmentioning

confidence: 99%

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition

et al. 2017

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Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson’s disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor deficits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor deficits are mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson’s disease development.

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Section: Key Eventsmentioning

confidence: 99%

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition

et al. 2017

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“… Pro-and anti-inflammatory cytokine expression (IL-1β; TNF-α, Il-6, IL-4); or expression of immunostimmulatory proteins (e.g. MHC-II)  Itgam, CD86 expression as markers of M1 microglial phenotype  Arg1, MRC1, as markers of M2 microglial phenotype (for descriptions of techniques, see also Falsig 2004;Kuegler 2010;Monnet-Tschudi et al, 2011;Sandström et al, 2014;von Tobel et al, 2014) Regulatory example using the KE:Measurement of glial fibrillary acidic protein (GFAP) in brain tissue, whose increase is a marker of astrocyte reactivity, is required by the US EPA in rodent toxicity studies for fuel additives (40 CFR 79.67), but is optional for other toxicant evaluations.…”

Section: How It Is Measured or Detectedmentioning

confidence: 99%

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

Tschudi-Monnet

FitzGerald

2018

OECD Series on Adverse Outcome Pathways

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This Adverse Outcome Pathway (AOP) on chronic binding of antagonist to N-methyl-Daspartate receptors (NMDARs) during brain development leading to neurodegeneration with impairment in learning and memory in aging, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in June 2018. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP in September 2018. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review].

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“…Ochratoxins are a group of pentaketide mycotoxins found in fruit that are produced mainly by Aspergillus and Penicillium species [ 44 , 45 ]. The most important and most toxic ochratoxin found naturally in foods is ochratoxin A (OTA), which shows hepatotoxicity, teratogenicity, carcinogenicity, cytotoxicity, neurotoxicity, and immunosuppressive properties [ 46 , 47 , 48 , 49 , 50 , 51 ]. Two other forms of ochratoxin—B and C—are less toxic and less common [ 52 , 53 ].…”

Section: Mycotoxins Commonly Found In Fruitmentioning

confidence: 99%

Does the Host Contribute to Modulation of Mycotoxin Production by Fruit Pathogens?

Kumar

Barad

Sionov

et al. 2017

Toxins

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Storage of freshly harvested fruit is a key factor in modulating their supply for several months after harvest; however, their quality can be reduced by pathogen attack. Fruit pathogens may infect their host through damaged surfaces, such as mechanical injuries occurring during growing, harvesting, and packing, leading to increased colonization as the fruit ripens. Of particular concern are fungal pathogens that not only macerate the host tissue but also secrete significant amounts of mycotoxins. Many studies have described the importance of physiological factors, including stage of fruit development, biochemical factors (ripening, C and N content), and environmental factors (humidity, temperature, water deficit) on the occurrence of mycotoxins. However, those factors usually show a correlative effect on fungal growth and mycotoxin accumulation. Recent reports have suggested that host factors can induce fungal metabolism, leading to the synthesis and accumulation of mycotoxins. This review describes the new vision of host-factor impact on the regulation of mycotoxin biosynthetic gene clusters underlying the complex regulation of mycotoxin accumulation in ripening fruit.

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Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype

Cited by 21 publications

References 55 publications

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition

An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

Does the Host Contribute to Modulation of Mycotoxin Production by Fruit Pathogens?

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