Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats

Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto

doi:10.1016/j.tox.2015.08.001

Cited by 29 publications

(11 citation statements)

References 48 publications

(56 reference statements)

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“…However, neurogenic capacity declines with age and neurodegenerative diseases such as AD (Perry et al, 2012; Jeong et al, 2014; Tanaka et al, 2015). Given that DMS has been shown to promote hippocampal neurogenesis in stress-induced animal models (Zhang et al, 2014), we performed BrdU injection for five consecutive days to determine whether DMS treatment also promoted hippocampal neurogenesis in AD transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Aβ oligomers are considered a primary cause of impairment of the cholinergic system in the brains of AD patients, which show multiple aspects of cholinergic system dysfunction such as decreases in Ach levels, low activity of choline synthetase, and a reduction in the number of cholinergic receptors (Bao et al, 2012; Yang et al, 2014). In addition, studies have reported that suppression of cholinergic signaling readily exerts a detrimental effect on neurogenesis in the hippocampus of AD models (Perry et al, 2012; Tanaka et al, 2015); however, an effective intervention method for AD in the clinic has not yet been found. Thus, we examined whether DMS exerts its effects by enhancing cholinergic activity in the hippocampus of AD mice.…”

Section: Discussionmentioning

confidence: 99%

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Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer’s Disease

Zhen

Qian

et al. 2017

Front. Neural Circuits

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Alzheimer’s disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer’s Disease

Zhen

Qian

et al. 2017

Front. Neural Circuits

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“…Maternal AFB1 exposure affected hippocampal neurogenesis targeting type-3 progenitor cells at PND 21 which the CONTAM Panel considered to be adverse, whereas no changes in neurogenesis-related parameters were observed at PND 77, implying that this effect is reversible. The no-observed-adverseeffect-level (NOAEL) for offspring neurogenesis was 0.1 mg/kg feed (7.1-13.6 lg/kg bw per day) (Tanaka et al, 2015;Shibutani, 2019).…”

Section: Developmental and Reproductive Toxicitymentioning

confidence: 99%

Risk assessment of aflatoxins in food

Schrenk¹,

Bignami²,

Bodin³

et al. 2020

EFS2

212

179

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EFSA was asked to deliver a scientific opinion on the risks to public health related to the presence of aflatoxins in food. The risk assessment was confined to aflatoxin B1 (AFB1), AFB2, AFG1, AFG2 and AFM1. More than 200,000 analytical results on the occurrence of aflatoxins were used in the evaluation. Grains and grain‐based products made the largest contribution to the mean chronic dietary exposure to AFB1 in all age classes, while ‘liquid milk’ and ‘fermented milk products’ were the main contributors to the AFM1 mean exposure. Aflatoxins are genotoxic and AFB1 can cause hepatocellular carcinomas (HCCs) in humans. The CONTAM Panel selected a benchmark dose lower confidence limit (BMDL) for a benchmark response of 10% of 0.4 μg/kg body weight (bw) per day for the incidence of HCC in male rats following AFB1 exposure to be used in a margin of exposure (MOE) approach. The calculation of a BMDL from the human data was not appropriate; instead, the cancer potencies estimated by the Joint FAO/WHO Expert Committee on Food Additives in 2016 were used. For AFM1, a potency factor of 0.1 relative to AFB1 was used. For AFG1, AFB2 and AFG2, the in vivo data are not sufficient to derive potency factors and equal potency to AFB1 was assumed as in previous assessments. MOE values for AFB1 exposure ranged from 5,000 to 29 and for AFM1 from 100,000 to 508. The calculated MOEs are below 10,000 for AFB1 and also for AFM1 where some surveys, particularly for the younger age groups, have an MOE below 10,000. This raises a health concern. The estimated cancer risks in humans following exposure to AFB1 and AFM1 are in‐line with the conclusion drawn from the MOEs. The conclusions also apply to the combined exposure to all five aflatoxins.

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“…More recently, studies have shown that aflatoxin B1 is able to induce several histopathological alterations in the cerebral cortex and hippocampus in a rat model 12 . Moreover, it has been shown that maternal exposure to aflatoxin B1 and to its metabolite aflatoxin M1 allows the transfer of these toxins to milk and causes alteration in hippocampal neurogenesis with suppression of cholinergic signals in the offsprings 13 .…”

Section: Introductionmentioning

confidence: 99%

Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation

Scafuri

Varriale

Facchiano

et al. 2017

Sci Rep

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We have applied a combined computational procedure based on inverse and direct docking in order to identify putative protein targets of a panel of mycotoxins and xenobiotic compounds that can contaminate food and that are known to have several detrimental effects on human health. This procedure allowed us to identify a panel of human proteins as possible targets for aflatoxins, gliotoxin, ochratoxin A and deoxynivalenol. Steady-state fluorescence and microscale thermophoresis experiments allowed us to confirm the binding of some of these mycotoxins to acetylcholinesterase and X-linked neuroligin 4, two proteins involved in synapse activity and, particularly for the second protein, neuronal plasticity and development. Considering the possible involvement of X-linked neuroligin 4 in the etiopathogenesis of autism spectrum syndrome, this finding opens up a new avenue to explore the hypothetical role of these xenobiotic compounds in the onset of this pathology.

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Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats

Cited by 29 publications

References 48 publications

Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer’s Disease

Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer’s Disease

Risk assessment of aflatoxins in food

Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation

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