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. 2021 Feb 17;10(2):277-283.
doi: 10.1093/toxres/tfab007. eCollection 2021 Mar.

Sodium arsenite induces spatial learning and memory impairment associated with oxidative stress and activates the Nrf2/PPARγ pathway against oxidative injury in mice hippocampus

Liang Xiong  1 , Jinyu Huang  1 , Ying Gao  2 , Yanfang Gao  1 , Chunmei Wu  1 , Shengfa He  3 , Lijun Zou  3 , Dongmei Yang  3 , Yuhao Han  3 , Qiong Yuan  3 , Zuobing Zheng  1 , Gonghua Hu  1
Affiliations

Sodium arsenite induces spatial learning and memory impairment associated with oxidative stress and activates the Nrf2/PPARγ pathway against oxidative injury in mice hippocampus

Liang Xiong et al. Toxicol Res (Camb). .

Abstract

Arsenic (As) is a ubiquitous environmental and industrial toxin with known correlates of oxidative stress and cognitive deficits in the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that represents a central cellular antioxidant defense mechanism and transcribes many antioxidant genes. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a well-known nuclear receptor to regulate lipid metabolism in many tissues, and it has been also associated with the control of oxidative stress, neuronal death, neurogenesis and differentiation. The role of Nrf2 and PPARγ in As-induced neurotoxicity is still debated. The present study was designed to investigate the neurobehavioral toxic effect of sub-chronic and middle-dose sodium arsenite exposure in mice hippocampus, as well as the response of Nrf2/PPARγ expression and influence on protein expression levels of their downstream antioxidant genes. Our results showed that mice treated with intraperitoneal injection of sodium arsenite (50 mg/kg body wt.) twice a week for 7 weeks resulted in increased generation of reactive oxygen species and impairment of spatial cognitive function. The present study also found a positive association between Nrf2/PPARγ expression in hippocampus of mice, and activation of antioxidant defenses by the evidently upregulated expression of their downstream genes, including superoxide dismutase, heme oxygenase-1 and glutathione peroxidase-3. Therefore, our findings were helpful for further understanding the role of Nrf2/PPARγ feedback loop in As-induced neurobehavioral toxicity.

Keywords: Nrf2; PPARγ; arsenic; neurobehavioral alterations; oxidative stress.

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Figures

Figure 1
Figure 1
Schematic representation of the experimental procedure. IP, intraperitoneal injection.
Figure 2
Figure 2
Changes of body weight throughout the experiment (A) and As concentrations in brain (B). Results are expressed as mean ± SEM (n = 8). **P < 0.01 when compared with control group.
Figure 3
Figure 3
Date from Morris water maze test. This figure shows (A) cumulative distance, (B) EL during the training trial, (C) first touched platform time, (D) annulus crossing, (E) percent time in quadrant and (F) heatmap of swimming track in each group from the probe trial. S1–S4 represents four different quadrants, respectively. S4 is target quadrant. The black arrow indicates the position of removed previous platform. Results are expressed as mean ± SEM (n = 8). *P < 0.05, **P < 0.01 when compared with control group.
Figure 4
Figure 4
Comparison of mean level of ROS generation (A) and SOD activity (B) in hippocampus between NaAsO2-exposed and control group. Values are expressed as mean ± SEM (n = 5). **P < 0.01 when compared with control group.
Figure 5
Figure 5
The morphological changes of coronal sections of CA1 in hippocampus were observed with light microscope after Nissl staining (magnification of ×400). (A) Control group and (B) NaAsO2 exposed group. Increased number of degenerating neurons with smaller cell bodies or pyknotic nuclei (black arrow) and ectopic pyramidal cells (red arrow) can be found in hippocampus of NaAsO2 exposedmice.
Figure 6
Figure 6
Western blot analysis showing the expression of oxidative stress markers in hippocampus of control and NaAsO2 exposed mice. Representative images of immunoblottings (A), and relative protein levels of PPARγ, Nrf2, HO-1 and GPx3 (B). For internal control, β-actin was used. Results were expressed as mean ± SEM (n = 3). *P < 0.05, **P < 0.01 when compared with control group.
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