Alterations in UPR Signaling by Methylmercury Trigger Neuronal Cell Death in the Mouse Brain

Takasugi, Nobumasa; Hiraoka, Hideki; Iijima, Yuta; Kumagai, Yoshito; Fujimura, Masatake; Uehara, Takashi

doi:10.3390/ijms232315412

Cited by 4 publications

(7 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 a–c). MeHg exposure induces endoplasmic reticulum (ER) stress, C/EBP homologous protein (CHOP) expression, and apoptosis in the cerebral cortex of mice (Hiraoka et al 2021 ; Nomura et al 2022 ), suggesting that the Gr and Mi might be sensitive to ER stress. Intriguingly, intrabulbar infusion with tunicamycin, an N-glycosylation inhibitor and ER stress inducer, into rat pups upregulated the expression of CHOP, an ER stress-mediated pro-apoptotic transcription factor, in the Mi and Gr (Tong et al 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hindlimb impairment is a marker of disease progression in rodent models of MeHg poisoning (Fujimura and Usuki 2020 ; Nomura et al 2022 ). To evaluate hindlimb impairment by MeHg poisoning, the mice were suspended by their tail and the extent of hindlimb extension was observed for 15 s. If both hindlimbs spread widely outward from the abdomen, a score of 0 was assigned (normal phenotype).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of pathological changes in the olfactory system of mice exposed to methylmercury

Iijima,

Miki,

Takasugi

et al. 2024

Arch Toxicol

Self Cite

View full text Add to dashboard Cite

Methylmercury (MeHg) is a well-known environmental neurotoxicant that causes severe brain disorders such as Minamata disease. Although some patients with Minamata disease develop olfactory dysfunction, the underlying pathomechanism is largely unknown. We examined the effects of MeHg on the olfactory system using a model of MeHg poisoning in which mice were administered 30 ppm MeHg in drinking water for 8 weeks. Mice exposed to MeHg displayed significant mercury accumulation in the olfactory pathway, including the nasal mucosa, olfactory bulb, and olfactory cortex. The olfactory epithelium was partially atrophied, and olfactory sensory neurons were diminished. The olfactory bulb exhibited an increase in apoptotic cells, hypertrophic astrocytes, and amoeboid microglia, mainly in the granular cell layer. Neuronal cell death was observed in the olfactory cortex, particularly in the ventral tenia tecta. Neuronal cell death was also remarkable in higher-order areas such as the orbitofrontal cortex. Correlation analysis showed that neuronal loss in the olfactory cortex was strongly correlated with the plasma mercury concentration. Our results indicate that MeHg is an olfactory toxicant that damages the central regions involved in odor perception. The model described herein is useful for analyzing the mechanisms and treatments of olfactory dysfunction in MeHg-intoxicated patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterization of pathological changes in the olfactory system of mice exposed to methylmercury

Iijima,

Miki,

Takasugi

et al. 2024

Arch Toxicol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Numerous pathways are involved in MeHg neurotoxicity, including endoplasmic reticulum stress 24 and oxidative stress 25–27 . However, the detailed molecular mechanisms underlying MeHg‐induced neurotoxicity remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Numerous pathways are involved in MeHg neurotoxicity, including endoplasmic reticulum stress 24 and oxidative stress. [25][26][27] However, the detailed molecular mechanisms underlying MeHg-induced neurotoxicity remain unclear. It is now known that intracellular kinase activation and subsequent neuronal activation play an important role in MeHg neurotoxicity.…”

mentioning

confidence: 99%

BDNF specifically expressed in hippocampal neurons is involved in methylmercury neurotoxicity resistance

Fujimura,

Unoki

2024

Environmental Toxicology

Self Cite

View full text Add to dashboard Cite

Methylmercury (MeHg) causes selective neuronal damage to cerebrocortical neurons (CCNs) in the central nervous system, but not to hippocampal neurons (HiNs), which are highly vulnerable to neurodegenerative diseases. In our previous study using cultured rat neurons, we performed a comprehensive gene expression analysis and found that the brain‐derived neurotrophic factor (BDNF), a neurotrophin (NT), was specifically expressed in HiNs. Therefore, to elucidate the causal factors of MeHg toxicity resistance in HiNs, we conducted a comparative study of the protein expression and function of several NTs, including BDNF, using CCNs showing vulnerability to MeHg toxicity and HiNs showing resistance. BDNF was specifically expressed in HiNs, whereas nerve growth factor was barely detectable in either neuron type. In addition, other NTs, NT3 and NT4/5, were expressed in small but nearly equal amounts in both neuron types. Furthermore, among the various pathways involved in MeHg neurotoxicity, the p44/42 MAPK pathway was specifically activated in HiNs, even without MeHg treatment. siRNAs were used to reduce NTs in both neuron types. Only a specific reduction in BDNF attenuated the resistance to MeHg toxicity and p44/42 MAPK activation in HiNs. In addition, the external addition of BDNF and NT4/5, which act on the same tyrosine receptor kinase (Trk), TrkB, suppressed MeHg neurotoxicity in both neuron types. These results suggest that BDNF, expressed specifically in HiNs, is involved in the resistance to MeHg neurotoxicity via TrkB. Additionally, the activation of the p44/42 MAPK pathway may contribute to the inhibitory effect of BDNF on MeHg neurotoxicity.

show abstract

“…In vitro studies have shown that MeHg activates PERK and ATF6, respectively (Hiraoka et al, 2017) and induces the expression of C/EBP homologous protein (CHOP), a downstream apoptosis-promoting factor (Makino et al, 2015). Furthermore, the PERK-CHOP pathway is activated in the brains of MeHg-exposed mice and correlates with increased apoptosis (Nomura et al, 2022). Therefore, CHOP might mediate MeHg-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Methylmercury-induced brain neuronal death in CHOP-knockout mice

Iijima,

Miki,

Fujimura

et al. 2024

J. Toxicol. Sci.

Self Cite

View full text Add to dashboard Cite

Apoptosis is one of the hallmarks of MeHg-induced neuronal cell death; however, its molecular mechanism remains unclear. We previously reported that MeHg exposure induces neuron-specific ER stress in the mouse brain. Excessive ER stress contributes to apoptosis, and CHOP induction is considered to be one of the major mechanisms. CHOP is also increased by MeHg exposure in the mouse brain, suggesting that it correlates with increased apoptosis. In this study, to clarify whether CHOP mediates MeHg-induced apoptosis, we examined the effect of CHOP deletion on MeHg exposure in CHOPknockout mice. Our data showed that CHOP deletion had no effect on MeHg exposure-induced weight loss or hindlimb impairment in mice, nor did it increase apoptosis or inhibit neuronal cell loss. Hence, CHOP plays little role in MeHg toxicity, and other apoptotic pathways coupled with ER stress may be involved in MeHg-induced cell death.

show abstract

Alterations in UPR Signaling by Methylmercury Trigger Neuronal Cell Death in the Mouse Brain

Cited by 4 publications

References 36 publications

Characterization of pathological changes in the olfactory system of mice exposed to methylmercury

Characterization of pathological changes in the olfactory system of mice exposed to methylmercury

BDNF specifically expressed in hippocampal neurons is involved in methylmercury neurotoxicity resistance

Methylmercury-induced brain neuronal death in CHOP-knockout mice

Contact Info

Product

Resources

About