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Dimethylarsinic acid (DMA) enhanced lung carcinogenesis via histone H3K9 modification in a transplacental mouse model

Abstract

Pregnant CD-1 mice received 200 ppm dimethylarsinic acid (DMA) in the drinking water from gestation day 8–18, and tumor formation was assessed in offspring at the age of 84 weeks. DMA elevated the incidence of lung adenocarcinoma (10.0%) and total tumors (33.3%) in male offspring compared to male control offspring (1.9 and 15.1%, respectively). DMA also elevated the incidence of hepatocellular carcinoma (10.0%) in male offspring compared to male control offspring (0.0%). DMA and its metabolites were detected in the lungs of transplacental DMA-treated neonatal mice. Transplacental DMA exposure increased cell proliferation in the epithelium in the lungs of both neonatal and 6-week-old male mice. Microarray and real-time PCR analyses detected high expression of keratin 8 (Krt8) in the lungs of both neonatal and 6-week-old DMA-treated mice. Western blot analysis indicated that DMA elevated methylation of histone H3K9, but not H3K27, in the lungs of male mice. Importantly, chromatin immunoprecipitation sequencing (ChIP-seq) analysis using an H3K9me3 antibody found differences in heterochromatin formation between mice exposed to DMA and the controls. Notably, ChIP-seq analysis also found regions of lower heterochromatin formation in DMA-treated mice, and one of these regions contained the Krt8 gene, agreeing with the results obtained by microarray analysis. High expression of Krt8 was also detected in adenoma and adenocarcinoma of the lung in male offspring. Overall, these data indicate that transplacental DMA treatment enhanced lung and liver carcinogenesis in male mice. In the lung, DMA caused aberrant methylation of histone H3K9, increased Krt8 expression, and enhanced cell proliferation.

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Acknowledgements

This work was supported by Grants from the Food Safety Commission, Cabinet Office, Government of Japan (Nos. 1407 and 1604), Health Labour Sciences Research Grants from Ministry of Health, Labor and Welfare, Japan, Grant-in-Aid for Scientific Research form Japan Society for the Promotion of Science (JSPS KAKENHI No. 17K09162), a Grant from AMED (No. JP19ck016264s), and a Grant from The Japan Food Chemical Research Foundation. The authors gratefully acknowledge the technical assistance of Rie Onodera, Keiko Sakata, Yuko Hisabayashi, and Yukiko Iura (Department of Molecular Patholoby, Osaka City University Graduate School of Medicine School, Osaka, Japan), and Shiota Masayuki (Research Support Platform, Osaka City University Graduate School of Medicine, Osaka, Japan).

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Correspondence to Hideki Wanibuchi.

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Fujioka, M., Suzuki, S., Gi, M. et al. Dimethylarsinic acid (DMA) enhanced lung carcinogenesis via histone H3K9 modification in a transplacental mouse model. Arch Toxicol (2020). https://doi.org/10.1007/s00204-020-02665-x

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Keywords

  • Dimethylarsinic acid (DMA)
  • Transplacental exposure
  • Lung carcinogenesis
  •  Histone methylation
  • Keratin 8
  • Mice