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Arsenic Induces Blood‒Brain Barrier Disruption and Regulates T Lymphocyte Subpopulation Differentiation in the Cerebral Cortex and Hippocampus Associated with the Nrf2 Pathway In Vivo

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Abstract

Increasing evidence has confirmed that the nervous system shows innate and adaptive immunity, which also participates in nerve damage. This study aimed to explore the neuroimmune imbalance induced by arsenic and its possible mechanism. Mice were exposed to NaAsO2 (0, 5, 10, 25, and 50 mg/L) for 1 month by drinking water. Y-maze and Morris water maze tests revealed that arsenic impaired learning and memory. The optical density of Evans blue showed a marked dose-dependent increase in the brain, and the mRNA and protein levels of the BBB tight junctions (TJs), occludin at 25 and 50 mg/L arsenic, and claudin-5 at 50 mg/L arsenic, were markedly decreased in the cerebral cortex. Arsenic downregulated occludin and claudin-5 mRNA expression at 50 mg/L and protein expression at 25 and 50 mg/L in the hippocampus. Immunohistochemical staining showed that 50 mg/L arsenic increased corticocerebral and hippocampal CD3+ T, CD4+ T, and CD8+ T cells; CD4 and CD8 proteins were increased with 25 and 50 mg/L arsenic. Arsenic decreased the corticocerebral and hippocampal Th1, Th17, and regulatory Treg transcription factors T-bet, Rorγt, and Foxp3 and the cytokine IFN-γ, IL-17, and TGF-β mRNA levels and increased the Th2 transcription factor GATA3 and cytokine IL-4 mRNA levels. Moreover, arsenic enhanced the expression of nuclear factor E2-related factor (Nrf2) and its downstream enzymes heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST). In conclusion, these results demonstrate that arsenic exposure induces BBB dysfunction and T lymphocyte infiltration and affects CD4+ T lymphocyte differentiation, which may be associated with Nrf2 activation.

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No data were used to support this study.

Abbreviations

As:

Arsenic

BBB:

Blood‒brain barrier

CNS:

Central nervous system

Foxp3:

Forkhead box p3

GATA3:

GATA‒binding protein 3

GCLM:

Glutamate‒cysteine ligase regulatory subunit

GST:

Glutathione S‒transferase

HO‒1:

Heme oxygenase-1

IFN‒γ:

Interfern gamma

IL-17:

Interleukin 17

NQO1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

Nuclear factor‒erythroid 2-related factor 2

Rorγt:

Retinoic acid‒related orphan receptor

T‒bet:

T-box transcription factor

TGF‒β:

Transforming growth factor‒β

Th1:

T helper 1

TJs:

Tight junction proteins

Treg cell:

Regulatory T cells

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Funding

This study was supported by grants from the National Natural Science Foundation of China (NSFC) (no. 81803180 and 81803200), the Basic Research Project of Liaoning Provincial Department of Education Youth Project (no. LJKQZ2021173), the Shenyang Middleyounger Scientific and Technological Innovation Support Plan (no. RC190479 and RC200238), the Liaoning Province Key Research and Development Program Guidance (no. 2019JH8/10300047), the Shenyang Science and Technology Plan Project Social Governance Science and Technology Special Project (no. 21-108-9-11), and the Science and Technology Innovation Fund of Shenyang Medical College (no. Y20210513).

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  1. Nan Yan and Hui Jing contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Applied Technology, Shenyang Medical College, Liaoning, Shenyang, China

    Nan Yan

  2. Department of Toxicology, School of Public Health, Shenyang Medical College, Liaoning, Shenyang, China

    Hui Jing, Zhou Li, Kangjie Xu, Qian Wang, Jingwen Zheng & Xiaoxu Duan

  3. Department of Scientific Research, Shenyang Medical College, Liaoning, Shenyang, China

    Jie Wang

  4. Affiliated Health School, Shenyang Medical College, Liaoning, Shenyang, China

    Lei Shi

  5. Department of General Surgery, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Liaoning, Shenyang, China

    Xiankui Cao

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Contributions

N.Y. and H.J. designed the study; J.W. and Z.L. performed the study; K.J.X., Q.W., J.W.Z., and L.S. analyzed the data; X.K.C. and X.X.D. wrote and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiankui Cao or Xiaoxu Duan.

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Yan, N., Jing, H., Wang, J. et al. Arsenic Induces Blood‒Brain Barrier Disruption and Regulates T Lymphocyte Subpopulation Differentiation in the Cerebral Cortex and Hippocampus Associated with the Nrf2 Pathway In Vivo. Biol Trace Elem Res 201, 3981–3993 (2023). https://doi.org/10.1007/s12011-022-03500-3

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