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Role of microglial activation and neuroinflammation in neurotoxicity of acrylamide in vivo and in vitro

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Abstract

Acrylamide, a soft electrophile, is widely used in the industry and laboratories, and also contaminates certain foods. Neurotoxicity and neurodegenerative effects of acrylamide have been reported in humans and experimental animals, although the underlying mechanism remains obscure. Activation of microglia and neuroinflammation has been demonstrated in various neurodegenerative diseases as well as other pathologies of the brain. The present study aimed to investigate the role of microglial activation and neuroinflammation in acrylamide neurotoxicity. Male 10-week-old Wistar rats were exposed to acrylamide by gavage at 0, 0.2, 2, or 20 mg/kg BW, once per day for 5 weeks. The results showed that 5-week exposure to acrylamide induced inflammatory responses in the cerebral cortex, evident by upregulated mRNA and protein expression of pro-inflammatory cytokines IL-1β, IL-6, and IL-18. Acrylamide also induced activation of microglia, indicated by increased expression of microglial markers, CD11b and CD40, and increased CD11b/c-positive microglial area and microglial process length. In vitro studies using BV-2 microglial cells confirmed microglial inflammatory response, as evident by time- (0–36 h; 50 μM) and dose- (0–500 μM; 24 h) dependent increase in mRNA expression of IL-1β and IL-18, as well as the inflammatory marker iNOS. Furthermore, acrylamide-induced upregulation of pro-inflammatory cytokines was mediated through the NLRP3 inflammasome pathway, as evident by increased expression of NLRP3, caspase 1, and ASC in the rat cerebral cortex, and by the inhibitory effects of NLRP3 inflammasome inhibitor on the acrylamide-induced upregulation of NLRP3, caspase 1, IL-1β, and IL-18 in BV-2 microglia.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (#17H06396) and for Scientific Research (B) (#16H02965), Japan Society for the Promotion of Science. The authors would like to thank Ms. Satoko Arai for the excellent secretarial supports.

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, Graduate School of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan

    Cai Zong, Rieka Hasegawa, Lingyi Zhang, Daichi Nagashima, Toshihiro Sakurai & Gaku Ichihara

  2. Department of Neurology, Shiga University of Medical Science, Shiga, 520-2192, Japan

    Makoto Urushitani

  3. Department of Hygiene, Public Health, and Preventive Medicine, Showa University School of Medicine, Tokyo, 142-8555, Japan

    Daichi Nagashima

  4. Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Tochigi, 329-0498, Japan

    Sahoko Ichihara

  5. Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Seiichiroh Ohsako

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  1. Cai Zong
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Zong, C., Hasegawa, R., Urushitani, M. et al. Role of microglial activation and neuroinflammation in neurotoxicity of acrylamide in vivo and in vitro. Arch Toxicol 93, 2007–2019 (2019). https://doi.org/10.1007/s00204-019-02471-0

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