Abstract
Chronic exposure to inorganic arsenic (As) [As(III) + As(V)], which affects millions of people, increases the incidence of some kinds of cancer and other non-carcinogenic pathologies. Although the oral pathway is the main form of exposure, in vivo studies have not been conducted to verify the intestinal toxicity of this metalloid. The aim of this study is to perform an in vivo evaluation of the intestinal toxicity of inorganic As, using female BALB/c mice exposed through drinking water to various concentrations of As(III) (20, 50, and 80 mg/L) for 2 months. An increase was observed in oxygen and/or nitrogen reactive species, and in gene and protein expression of pro-inflammatory cytokines (IL-1β, IL-2, IL-6) at concentrations equal to or greater than 50 mg/L. These changes were accompanied by a profound remodeling of the intestinal microbial profile in terms of diversity and global composition, which could be at the basis or exacerbate As(III) toxic effects. The histological study showed that there was moderate inflammation of the mucosa and submucosa, accompanied by hyperplasia of crypts at the highest administered dose. In addition, all the treatments with As(III) resulted in a decreased expression of Muc2, which encodes one of the main components of the intestinal layer of mucus. The effects described are compatible with the increased intestinal permeability observed at concentrations equal to or greater than 50 mg/L, indicative of loss of barrier function.
Highlights
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In vivo intestinal toxicity of As(III) was evaluated using female BALB/c mice.
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As(III) increases oxidative stress and the pro-inflammatory response in large intestine.
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As(III) produces down-regulation of Muc2, the main mucin of the intestinal mucus.
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As(III) alters the barrier function and produces changes in the intestinal microbiota.
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This is the first study that shows the intestinal toxicity of As(III) in subchronic exposure.
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Acknowledgements
This work was supported by the Spanish Ministry of Science, Innovation and Universities (AGL2015-68920-R), for which the authors are deeply indebted. Gabriela M. Chiocchetti received a fellowship from the Brazilian Government (CAPES BEX1086/14-6). We thank M.C. Collado, C. Alcántara, M. Selma, M. Dzidic and A. Boix for their advice in metagenome analyses. We also thank Inmaculada Noguera, from the Animal Production Service from the University of Valencia, for her assistance in the animal experiments.
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Chiocchetti, G.M., Domene, A., Kühl, A.A. et al. In vivo evaluation of the effect of arsenite on the intestinal epithelium and associated microbiota in mice. Arch Toxicol 93, 2127–2139 (2019). https://doi.org/10.1007/s00204-019-02510-w
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DOI: https://doi.org/10.1007/s00204-019-02510-w