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Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway

  • Inorganic compounds
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Abstract

Arsenic pollution is a major public health problem worldwide. Inorganic arsenic (iAs) is usually more harmful than organic ones. iAs pollution increases the risk of human diseases such as peripheral vascular disease and cancer. However, the toxicological effects of iAs in the brain are mostly unclear. Here, we investigated the toxic effects and possible mechanisms of iAs in the cerebrum of mice after exposure to iAs (0.5 and 5 ppm (mg/l) As2O3, via the drinking water), which was the possible human exposed dose via the ingestion in iAs-contaminated areas, for 6 consecutive weeks. iAs dose-dependently caused an increase of LPO production in the plasma and cerebral cortex. iAs also decreased the reduced glutathione levels and the expressions of NQO1 and GPx mRNA in the cerebral cortex. These impairments in the cerebral cortex caused by iAs exposure were significantly correlated with the accumulation of As. Moreover, iAs induced the production of apoptotic cells and activation of caspase-3, up-regulation of Bax and Bak, and down-regulation of Mcl-1 in the cerebral cortex. Exposure to iAs also triggered the expression of ER stress-related genes, including GRP78, GRP94, and CHOP. Meanwhile, an increase of p38 activation and dephosphorylation of ERK1/2 were shown in the cerebral cortex as a result of iAs-exposed mice. These iAs-induced damages and apoptosis-related signals could be significantly reversed by NAC. Taken together, these results suggest that iAs-induced oxidative stress causes cellular apoptosis in the cerebrum, signaling of p38 and ERK1/2, and ER stress may be involved in iAs-induced cerebral toxicity.

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Abbreviations

LPO:

Lipid peroxidation

GSH:

Glutathione

NQO1:

NAD(P)H: quinone oxidoreductase-1

GPx:

Glutathione peroxidase

Bax:

Bcl-associated X protein

Bak:

Bcl-2 homologous antagonist killer

Mcl-1:

Myeloid cell leukemia sequence 1

ER:

Endoplasmic reticulum

GRP:

Glucose-regulated protein

CHOP:

C/EBP homologous protein

ERK:

Extracellular signal-regulated kinase

NAC:

N-acetylcysteine

ROS:

Reactive oxygen species

MDA:

Malondiadehyde

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Acknowledgments

This study was supported by research grants from the China Medical University Hospital, Taichung, Taiwan (DMR-100-074), the Central Region Hospital Alliance, Department of Health (P10017), and also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004).

Conflict of interest

All authors declare that they have no conflicts of interest in this study.

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Authors and Affiliations

  1. Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, No. 110, Sec. 1, Jian-Guo N. Rd., Taichung, 40201, Taiwan

    Cheng Chien Yen

  2. Department of Occupational Medicine, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jian-Guo N. Rd., Taichung, 40201, Taiwan

    Cheng Chien Yen

  3. School of Chinese Medicine, College of Chinese Medicine, China Medical University, No. 91 Hsueh-Shih Rd., Taichung, 40402, Taiwan

    Tsung Jung Ho, Tzyy Rong Jinn, Yi Chang Su & Chun Fa Huang

  4. Department of Public Health, China Medical University, No. 91 Hsueh-Shih Rd., Taichung, 40402, Taiwan

    Chin Ching Wu

  5. Department of Chinese Medicine, Chiayi Hospital, No. 312 Bei-gang Rd., Chiayi, 60096, Taiwan

    Chun Fang Chang

  6. Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, No. 135 Nanxiao St., 50072, Changhua City, Changhua County, Taiwan

    Chin Chuan Su

  7. Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, No. 91 Hsueh-Shih Rd., Taichung, 40402, Taiwan

    Ya Wen Chen

  8. Graduate Institute of Drug Safety, College of Pharmacy, China Medical University, No. 91 Hsueh-Shih Rd., Taichung, 40402, Taiwan

    Tien Hui Lu

  9. Department of Otolaryngology, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nan-Ya S. Rd., Banciao Dist., New Taipei City, 22060, Taiwan

    Po Wen Cheng

  10. Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd., Taipei, 10051, Taiwan

    Shing Hwa Liu

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  1. Cheng Chien Yen
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  2. Tsung Jung Ho
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  3. Chin Ching Wu
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  5. Chin Chuan Su
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  11. Shing Hwa Liu
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  12. Chun Fa Huang
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Corresponding authors

Correspondence to Shing Hwa Liu or Chun Fa Huang.

Additional information

C. C. Yen, T. J. Ho and C. C. Wu are contributed equally to this work.

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Yen, C.C., Ho, T.J., Wu, C.C. et al. Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Arch Toxicol 85, 565–575 (2011). https://doi.org/10.1007/s00204-011-0709-y

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