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Arsenic exposure induced anxiety-like behaviors in male mice via influencing the GABAergic Signaling in the prefrontal cortex

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Abstract

Arsenic contamination in drinking water causes a global public health problem. Emerging evidence suggests that arsenic may act as an environmental risk factor for anxiety disorders. However, the exact mechanism underlying the adverse effects has not been fully elucidated. This study aimed to evaluate the anxiety-like behaviors of mice exposed to arsenic trioxide (As2O3), to observe the neuropathological changes, and to explore the link between the GABAergic system and behavioral manifestations. For this purpose, male C57BL/6 mice were exposed to various doses of As2O3 (0, 0.15, 1.5, and 15 mg/L) through drinking water for 12 weeks. Anxiety-like behaviors were assessed using the open field test (OFT), light/dark choice test, and elevated zero maze (EZM). Neuronal injuries in the cerebral cortex and hippocampus were assessed by light microscopy with H&E and Nissl staining. Ultrastructural alteration in the cerebral cortex was assessed by transmission electron microscope (TEM). The expression levels of GABAergic system-related molecules (i.e., glutamate decarboxylase, GABA transporter, and GABAB receptor subunits) in the prefrontal cortex (PFC) were determined by qRT-PCR and western blotting. Arsenic exposure showed a striking anxiogenic effect on mice, especially in the group exposed to 15 mg/L As2O3. Light microscopy showed neuron necrosis and reduced cell counts. TEM revealed marked ultrastructural changes, including the vacuolated mitochondria, disrupted Nissl bodies, an indentation in the nucleus membrane, and delamination of myelin sheath in the cortex. In addition, As2O3 influenced the GABAergic system in the PFC by decreasing the expression of the glutamate decarboxylase 1 (GAD1) and the GABAB2 receptor subunit, but not the GABAB1 receptor subunit. To sum up, sub-chronic exposure to As2O3 is associated with increased anxiety-like behaviors, which may be mediated by altered GABAergic signaling in the PFC. These findings shed light on the mechanisms responsible for the neurotoxic effects of arsenic and therefore more cautions should be taken.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors highly acknowledge Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine at Shanxi Agricultural University for providing the instruments of behavioral tests.

Funding

This study was funded by the Natural Science Foundation of Shanxi Province (No. 201901D111232) and National Natural Science Foundation of China (31302155).

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Authors and Affiliations

  1. College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China

    Xin Hu, Xiaohong Yuan, Mingyu Yang, Mingsheng Han, Mohammad Mehdi Ommati & Yanqin Ma

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  1. Xin Hu
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  2. Xiaohong Yuan
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  3. Mingyu Yang
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  4. Mingsheng Han
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Contributions

Xin Hu: experiment design and performance, as well as statistical analysis and writing manuscript draft. Xiaohong Yuan: assisting in morphometric analysis. Mingyu Yang: assisting in behavior tests and analysis. Mingsheng Han: assisting in animal housing and operation. Mohammad Mehdi Ommati: assisting in statistical analysis and manuscript editing. Yanqin Ma: supervision, manuscript reviewing and editing, funding acquisition.

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Correspondence to Yanqin Ma.

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The animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All experiments were approved by the Animal Care Committee of Shanxi Agricultural University (Approval Number: SXAU-EAW-2019R0704).

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Hu, X., Yuan, X., Yang, M. et al. Arsenic exposure induced anxiety-like behaviors in male mice via influencing the GABAergic Signaling in the prefrontal cortex. Environ Sci Pollut Res 30, 86352–86364 (2023). https://doi.org/10.1007/s11356-023-28426-8

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