Arsenic down-regulates the expression of Camk4, an important gene related to cerebellar LTD in mice

Wang, Yanyan; Li, Sheng; Piao, Fengyuan; Hong, Yan; Liu, Peng; Zhao, Yufeng

doi:10.1016/j.ntt.2009.04.064

Cited by 39 publications

(24 citation statements)

References 32 publications

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“…Experimental studies have shown the alteration of locomotor activity and behavioral disorders in experimental animals exposed to As 12−14) . In our previous studies, an accumulation of As in the brains of mice and a decrease in memory function were also found in the mice exposed to As at the same doses as used in the present study 29,30) . It is well known that the hippocampus is functionally related to vital behaviors and intellectual activities such as memory and learning 20) .…”

Section: Discussionsupporting

confidence: 80%

Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl‐2/Bax pathway

Wang

Bai

Guan

et al. 2015

Journal of Occupational Health

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were found in the hippocampus of As-exposed mice. The expressions of the Bcl-2 gene and its protein in the hippocampus of As-exposed mice were significantly lower than those in the control group (p<0.05). However, the expressions of the Bax gene and its protein, and the expression ratio of Bax/Bcl-2 in the hippocampus were significantly higher in the groups exposed to As than in the control group (p<0.05). Moreover, the activity of caspase-3 in the hippocampus of mice exposed to As was higher than that in the control (p<0.05). Conclusions:These results indicate that subchronic exposure to As induces apoptosis in the hippocampus of mice by disturbing normal Bax/Bcl-2 regulatory pathways. Meanwhile, it is suggested that the induced apoptosis in the hippocampus may be at least partly responsible for As-induced neurotoxicity. (J Occup Health 2015; 57: 212-221) Key words: Apoptosis, Arsenic trioxide, Bax, Bcl-2, Hippocampus, Neurotoxicity Arsenic (As), a naturally occurring toxic metalloid found in both inorganic and organic forms, is ubiquitous in the environment and contaminates water as a result of geological and industrial pollution 1) . Moreover, some kinds of arsenide, such as arsenic trioxide (As 2 O 3 ), are also widely used for the treatment of malignant tumors 2) . In As-contaminated areas, the As concentration in drinking water or groundwater ranges from 0.25 to 2.1 ppm and even reaches >3.0 ppm in some severely contaminated areas 3−5) . Exposure to As has been associated with increasing incidences of various chronic diseases, including peripheral vascular disease, cardiovascular disease, diabetes mellitus, and various cancers 6) . As is also a potent neurotoxicant, and subchronic or chronic As exposure causes severe nervous system Abstract: Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl-2/Bax pathway: Yachen WANG, et al. Department of Occupational and EnvironmentalHealth, Dalian Medical University, P.R. ChinaObjectives: The aim of this study was to identify whether arsenic (As) exposure could induce hippocampal neural apoptosis in vivo. Methods: Sixty-four mice were randomly divided into 4 groups of 16 each. Group 1 orally received drinking water alone as a control. Groups 2−4 were given arsenic trioxide (As 2 O 3 ) orally at the doses of 1 ppm, 2 ppm and 4 ppm, respectively. All the treatments continued for 60 days. Morphological changes in the hippocampus were observed by HE staining. Apoptosis in the hippocampus was examined by TUNEL assay and transmission electron microscopy. The expression levels of Bcl-2 and Bax genes and their proteins in the hippocampus were determined by realtime PCR and Western blotting. The activity of caspase-3 was determined by spectrophotometry. Results: Abnormal histopathological changes and apoptosis

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Section: Discussionsupporting

confidence: 80%

Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl‐2/Bax pathway

Wang

Bai

Guan

et al. 2015

Journal of Occupational Health

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“…In addition, the critical gene expression profiles related to the Creb-dependent phase of cerebellar long-term depression (LTD) were analyzed by GeneChip and showed down-regulated expression of Ca 2+ /calmodulin dependent protein kinase IV (Camk4). Finally, antioxidants such as taurine or vitamin C did not prevent the down-regulation of Camk4, indicating that such down-regulation may be via an oxidation-independent mechanism (Wang et al, 2009a). Additionally, rats exposed to inorganic arsenic in drinking water at 68 mg/L for 3 months showed a significant decrease in their spatial memory, while neurons and endothelial cells presented pathological changes, and the gene expression of aspartate receptors in the hippocampus was down-regulated.…”

Section: Inorganic Arsenicmentioning

confidence: 94%

Scientific Opinion on Arsenic in Food

2009

EFSA Journal

828

220

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The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) assessed the risks to human health related to the presence of arsenic in food. More than 100,000 occurrence data on arsenic in food were considered with approximately 98 % reported as total arsenic. Making a number of assumptions for the contribution of inorganic arsenic to total arsenic, the inorganic arsenic exposure from food and water across 19 European countries, using lower bound and upper bound concentrations, has been estimated to range from 0.13 to 0.56 µg/kg bodyweight (b.w.) per day for average consumers, and from 0.37 to 1.22 µg/kg b.w. per day for 95 th percentile consumers. Dietary exposure to inorganic arsenic for children under three years of age is in general estimated to be from 2 to 3-fold that of adults. The CONTAM Panel concluded that the provisional tolerable weekly intake (PTWI) of 15 µg/kg b.w. established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) is no longer appropriate as data had shown that inorganic arsenic causes cancer of the lung and urinary bladder in addition to skin, and that a range of adverse effects had been reported at exposures lower than those reviewed by the JECFA. The CONTAM Panel modelled the dose-response data from key for providing consumption information and calculating exposure, the partners of the EFSA project on the "Individual food consumption data and exposure" coordinated by Ghent University (Department of Public Health, University Hospital, Ghent University, Belgium), and RIKILT (Institute of Food Safety, Wageningen, The Netherlands) for the accessibility of the exposure assessment tools. 4 Table of contents shows now the fourth level of subheadings. 5 An error in the interpretation of the total number of the population in the study of Rahman et al. (2006a) was discovered (Table 41). The BMDL was recalculated and as a consequence it was not considered a potential reference point. The text in the opinion, Table 43 and Appendix were revised accordingly. In addition, the header of the "total number of cases" was replaced by "total number of individuals" in Tables 40-42 and the erroneous units were corrected to µg/L in the text below SUMMARYArsenic is a metalloid that occurs in different inorganic and organic forms, which are found in the environment both from natural occurrence and from anthropogenic activity. The inorganic forms of arsenic are more toxic as compared to the organic arsenic but so far most of the occurrence data in food collected in the framework of official food control are still reported as total arsenic without differentiating the various arsenic species. The need for speciation data is evident because several investigations have shown that especially in seafood most of the arsenic is present in organic forms that are less toxic. Consequently, a risk assessment not taking into account the different species but considering total arsenic as being present exclusively as inorganic arsenic would lead to a considerable overestimation of the health risk rel...

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“…Our results may be specific to the dentate gyrus: studies demonstrating reduced CREB and BDNF, in response to either prenatal stress or toxins such as lead or mercury, have done so using mRNA expression in the dentate gyrus (similar to our previous observations) or protein quantification in the whole hippocampus, but never protein expression in the dentate gyrus (Onishchenko et al, 2008; Feng et al, 2012; Boersma et al, 2014; Guan et al, 2013; Sanchez-Martin et al, 2013). While arsenic exposure in the parts-per-million range has been shown to reduce CREB and associated proteins (Wang et al, 2009), the arsenic concentration in our study is in the parts-per-billion range, closer to the levels humans are exposed to, and likely too low to impair CREB signaling. Additionally, reduced Nr3c1 and Hdac2 mRNA levels in the hippocampus or reduced Creb1 mRNA in the dentate gyrus may not translate to reduced protein levels, as seen in several other studies.…”

Section: Discussionmentioning

confidence: 42%

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

et al. 2014

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Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism.

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Arsenic down-regulates the expression of Camk4, an important gene related to cerebellar LTD in mice

Cited by 39 publications

References 32 publications

Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl‐2/Bax pathway

Subchronic exposure to arsenic induces apoptosis in the hippocampus of the mouse brains through the Bcl‐2/Bax pathway

Scientific Opinion on Arsenic in Food

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

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