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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Anderson LM (2004) Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination. Toxicol Appl Pharmacol 199(2):162–174. https://doi.org/10.1016/j.taap.2004.02.008
Aposhian HV, Arroyo A, Cebrian ME et al (1997) DMPS-arsenic challenge test I: increased urinary excretion of monomethylarsonic acid in humans given dimercaptopropane sulfonate. J Pharmacol Exp Ther 282(1):192–200
Arnold LL, Eldan M, Nyska A, van Gemert M, Cohen SM (2006) Dimethylarsinic acid: results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice. Toxicology 223(1–2):82–100
Bu N, Wang HY, Hao WH et al (2011) Generation of thioarsenicals is dependent on the enterohepatic circulation in rats. Metallomics 3(10):1064–1073. https://doi.org/10.1039/c1mt00036e
Burgio E, Piscitelli P, Colao A (2018) Environmental carcinogenesis and transgenerational transmission of carcinogenic risk: from genetics to epigenetics. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph15081791
Byron WR, Bierbower GW, Brouwer JB, Hansen WH (1967) Pathologic changes in rats and dogs from 2-year feeding of sodium arsenite or sodium arsenate. Toxicol Appl Pharmacol 10(1):132–147
Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD (2006) Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol 36(2):99–133
Cui X, Kobayashi Y, Hayakawa T, Hirano S (2004) Arsenic speciation in bile and urine following oral and intravenous exposure to inorganic and organic arsenics in rats. Toxicol Sci 82(2):478–487
Fortier AM, Asselin E, Cadrin M (2013) Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation. J Biol Chem 288(16):11555–11571. https://doi.org/10.1074/jbc.M112.428920
Fritsch L, Robin P, Mathieu JR et al (2010) A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell 37(1):46–56. https://doi.org/10.1016/j.molcel.2009.12.017
Fry RC, Navasumrit P, Valiathan C et al (2007) Activation of inflammation/NF-kappaB signaling in infants born to arsenic-exposed mothers. PLoS Genet 3(11):e207. https://doi.org/10.1371/journal.pgen.0030207
Hayashi H, Kanisawa M, Yamanaka K et al (1998) Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice. Cancer Lett 125(1–2):83–88
IARC (2012) Arsenic, metals, fibres, and dusts. WHO Press, Lyon
Kanaji N, Bandoh S, Ishii T et al (2011) Cytokeratins negatively regulate the invasive potential of lung cancer cell lines. Oncol Rep 26(4):763–768. https://doi.org/10.3892/or.2011.1357
Kenyon EM, Hughes MF, Adair BM et al (2008) Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in C57BL6 mice following subchronic exposure to arsenate in drinking water. Toxicol Appl Pharmacol 232(3):448–455. https://doi.org/10.1016/j.taap.2008.07.018
Kleinjans J, Botsivali M, Kogevinas M, Merlo DF, NewGeneris C (2015) Fetal exposure to dietary carcinogens and risk of childhood cancer: what the NewGeneris project tells us. BMJ 351:h4501. https://doi.org/10.1136/bmj.h4501
Lau AT, Chiu JF (2007) The possible role of cytokeratin 8 in cadmium-induced adaptation and carcinogenesis. Cancer Res 67(5):2107–2113. https://doi.org/10.1158/0008-5472.CAN-06-3771
Li H, Durbin R (2009) Fast and accurate short read alignment with burrows–wheeler transform. Bioinformatics 25(14):1754–1760. https://doi.org/10.1093/bioinformatics/btp324
Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128(4):707–719. https://doi.org/10.1016/j.cell.2007.01.015
Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129(6):705–733. https://doi.org/10.1007/s00418-008-0435-6
Nishikawa T, Wanibuchi H, Ogawa M et al (2002) Promoting effects of monomethylarsonic acid, dimethylarsinic acid and trimethylarsine oxide on induction of rat liver preneoplastic glutathione S-transferase placental form positive foci: a possible reactive oxygen species mechanism. Int J Cancer 100(2):136–139. https://doi.org/10.1002/ijc.10471
Nohara K, Tateishi Y, Suzuki T et al (2012) Late-onset increases in oxidative stress and other tumorigenic activities and tumors with a Ha-ras mutation in the liver of adult male C3H mice gestationally exposed to arsenic. Toxicol Sci 129(2):293–304. https://doi.org/10.1093/toxsci/kfs203
Salim EI, Wanibuchi H, Morimura K et al (2003) Carcinogenicity of dimethylarsinic acid in p53 heterozygous knockout and wild-type C57BL/6J mice. Carcinogenesis 24(2):335–342. https://doi.org/10.1093/carcin/24.2.335
Severson PL, Tokar EJ, Vrba L, Waalkes MP, Futscher BW (2012) Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation. Epigenetics 7(11):1238–1248. https://doi.org/10.4161/epi.22163
Suzuki T, Nohara K (2013) Long-term arsenic exposure induces histone H3 Lys9 dimethylation without altering DNA methylation in the promoter region of p16(INK4a) and down-regulates its expression in the liver of mice. J Appl Toxicol 33(9):951–958. https://doi.org/10.1002/jat.2765
Waalkes MP, Ward JM, Liu J, Diwan BA (2003) Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. Toxicol Appl Pharmacol 186(1):7–17
Waalkes MP, Liu J, Ward JM, Diwan BA (2006a) Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen. Toxicol Appl Pharmacol 215(3):295–305. https://doi.org/10.1016/j.taap.2006.03.010
Waalkes MP, Liu J, Ward JM, Powell DA, Diwan BA (2006b) Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer Res 66(3):1337–1345. https://doi.org/10.1158/0008-5472.CAN-05-3530
Waalkes MP, Liu J, Diwan BA (2007) Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol 222(3):271–280
Wei M, Wanibuchi H, Morimura K et al (2002) Carcinogenicity of dimethylarsinic acid in male F344 rats and genetic alterations in induced urinary bladder tumors. Carcinogenesis 23(8):1387–1397
Xie L, Dang Y, Guo J et al (2019) High KRT8 expression independently predicts poor prognosis for lung adenocarcinoma patients. Genes (Basel). https://doi.org/10.3390/genes10010036
Yamanaka K, Mizol M, Kato K, Hasegawa A, Nakano M, Okada S (2001) Oral administration of dimethylarsinic acid, a main metabolite of inorganic arsenic, in mice promotes skin tumorigenesis initiated by dimethylbenz(a)anthracene with or without ultraviolet B as a promoter. Biol Pharm Bull 24(5):510–514
Zang C, Schones DE, Zeng C, Cui K, Zhao K, Peng W (2009) A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25(15):1952–1958. https://doi.org/10.1093/bioinformatics/btp340
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
- Dimethylarsinic acid (DMA)
- Transplacental exposure
- Lung carcinogenesis
- Histone methylation
- Keratin 8