Skip to main content
Springer Nature Link
Log in

Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice

  • Inorganic compounds
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the biological methylation of inorganic arsenic, could be a key carcinogenic species. Thus, pregnant CD1 mice were provided drinking water containing MMA3+ at 0 (control), 12.5, or 25 parts per million (ppm) from gestational days 8 to 18. Tumors were assessed in groups of male or female (initial n = 25) offspring up to 2 years of age. In utero treatment had no effect on survival or body weights. Female offspring exhibited increases in total epithelial uterine tumors (control 0%; 12.5 ppm 26%; 25 ppm 30%), oviduct hyperplasia (control 4%; 12.5 ppm 35%; 25 ppm 43%), adrenal cortical adenoma at 25 ppm (control 0%; 12.5 ppm 9%; 25 ppm 26%), and total epithelial ovarian tumors (control 0%; 12.5 ppm 39%; 25 ppm 26%). Male offspring showed dose-related increases in hepatocellular carcinoma (control 0%; 12.5 ppm 12%; 25 ppm 22%), adrenal adenoma (control 0%; 12.5 ppm 28%; 25 ppm 17%), and lung adenocarcinoma (control 17%; 12.5 ppm 44%). Male offspring had unusual testicular lesions, including two rete testis carcinomas, two adenomas, and three interstitial cell tumors. Overall, maternal consumption of MMA3+ during pregnancy in CD1 mice produced some similar proliferative lesions as gestationally applied inorganic arsenic in the offspring during adulthood.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anderson LM, Diwan BA, Fear NT et al (2000) Critical windows of exposure for children’s health: cancer in human epidemiological studies and neoplasms in experimental animal models. Environ Health Perspect 108(Suppl 3):573–594

    PubMed  Google Scholar 

  • Chen Y, O’Brien T, Del Razo LM et al (2008) Tissue levels of arsenicals and skin tumor response following administration of monomethylarsonous acid and arsenite to K6/ODC mice. J Environ Pathol Toxicol Oncol 27:43–52

    PubMed  CAS  Google Scholar 

  • Cohen SM, Ohnishi T, Arnold LL et al (2007) Arsenic-induced bladder cancer in an animal model. Toxicol Appl Pharmacol 222:258–263

    Article  PubMed  CAS  Google Scholar 

  • Devesa V, Adair BM, Liu J et al (2006) Arsenicals in maternal and fetal mouse tissues after gestational exposure to arsenite. Toxicology 224:147–155

    Article  PubMed  CAS  Google Scholar 

  • Eblin KE, Bredfeldt TG, Gandolfi AJ (2008) Immortalized human urothelial cells as a model of arsenic-induced bladder cancer. Toxicology 248:67–76

    Article  PubMed  CAS  Google Scholar 

  • Hirano S, Kobayashi Y, Cui X et al (2004) The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds. Toxicol Appl Pharmacol 198:458–467

    Article  PubMed  CAS  Google Scholar 

  • Hood RD, Vedel-Macrander GC, Zaworotko MJ et al (1987) Distribution, metabolism, and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration. Teratology 35:19–25

    Article  PubMed  CAS  Google Scholar 

  • Institute of Laboratory Animal Resources (1996) Guide for the care and use of laboratory animals, 7th edn. National Academy Press, Washington

    Google Scholar 

  • International Agency for Research on Cancer (IARC) (2004) monographs on the evaluation of carcinogenic risks to humans. Some drinking-water disinfectants and contaminants, including arsenic, arsenic in drinking-water, vol 84. IARC Press, Lyon, pp 3–267

  • International Agency for Research on Cancer (IARC) (2011) Monographs on the evaluation of carcinogenic risks to humans. A review of human carcinogens: arsenic, metals, fibres, and dusts, vol 100C. IARC Press, Lyon, pp 41–93

  • Jin Y, Xi S, Li X et al (2006) Arsenic speciation transported through the placenta from mother mice to their newborn pups. Environ Res 101:349–355

    Article  PubMed  CAS  Google Scholar 

  • Kitchin KT (2001) Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol 172:249–261

    Article  PubMed  CAS  Google Scholar 

  • Liaw J, Marshall G, Yuan Y (2008) Increased childhood liver cancer mortality and arsenic in drinking water in Chile. Cancer Epidemiol Biomarkers Prev 17:1982–1987

    Article  PubMed  CAS  Google Scholar 

  • National Toxicology Program (NTP) (2011) Report on carcinogens, 12th edition: arsenic and inorganic arsenic compounds. US Department of Health and Human Services, Research Triangle Park, NC, USA, pp 50–53

  • Newbold RR, Bullock BC, McLachlan JA (1985) Lesions of the rete testis in mice exposed prenatally to diethylstilbestrol. Cancer Res 45:5145–5150

    PubMed  CAS  Google Scholar 

  • Newbold RR, Bullock BC, McLachlan JA (1987) Testicular tumors in mice exposed in utero to diethylstilbestrol. J Urol 138:1446–1450

    PubMed  CAS  Google Scholar 

  • Newbold RR, Hanson RB, Jefferson WN et al (2000) Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 21:1355–1363

    Article  PubMed  CAS  Google Scholar 

  • Shen J, Liu J, Xie Y et al (2007) Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure. Toxicol Sci 95:313–320

    Article  PubMed  CAS  Google Scholar 

  • Smith AH, Marshall G, Yuan Y et al (2006) Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood. Environ Health Perspect 114:1293–1296

    Article  PubMed  CAS  Google Scholar 

  • Tennant AH, Kligerman AD (2011) Superoxide dismutase protects cells from DNA damage induced by trivalent methylated arsenicals. Environ Mol Mutagen 52:238–243

    Article  PubMed  CAS  Google Scholar 

  • Thomas DJ (2007) Molecular processes in cellular arsenic metabolism. Toxicol Appl Pharmacol 222:365–373

    Article  PubMed  CAS  Google Scholar 

  • Thomas DJ, Li J, Waters SB et al (2007) Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp Biol Med 232:3–13

    CAS  Google Scholar 

  • Tokar EJ, Benbrahim-Tallaa L, Ward JM et al (2010a) Cancer in experimental animals exposed to arsenic and arsenic compounds. Crit Rev Toxicol 40:912–927

    Article  PubMed  CAS  Google Scholar 

  • Tokar EJ, Diwan BA, Waalkes MP (2010b) Arsenic exposure in utero and nonepidermal proliferative response in adulthood in Tg.AC mice. Int J Toxicol 29:291–296

    Article  PubMed  CAS  Google Scholar 

  • Tokar EJ, Qu W, Waalkes MP (2011) Arsenic, stem cells, and the developmental basis of adult cancer. Toxicol Sci 120(Suppl 1):S192–S203

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Ward JM, Liu J et al (2003) Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary and adrenal tumors in mice. Toxicol Appl Pharmacol 186:7–17

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Ward JM, Diwan BA (2004a) Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis 25:133–141

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Chen H et al (2004b) Estrogen signaling in livers of male mice with hepatocellular carcinoma induced by exposure to arsenic in utero. J Natl Cancer Inst 96:466–474

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Ward JM et al (2006a) Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen. Toxicol Appl Pharmacol 215:295–305

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Ward JM et al (2006b) Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment. Cancer Res 66:1337–1345

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Diwan BA (2007) Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol 222:271–280

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP, Liu J, Germolec DR et al (2008) Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res 68:8278–8285

    Article  PubMed  CAS  Google Scholar 

  • Wnek SM, Kuhlman CL, Camarillo JM et al (2011) Interdependent genotoxic mechanisms of monomethylarsonous acid: role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells. Toxicol Appl Pharmacol. doi:10.1016/j.taap.2011.08.029

    PubMed  Google Scholar 

  • Xi S, Jin Y, Lv X et al (2010) Distribution and speciation of arsenic by transplacental and early life exposure to inorganic arsenic in offspring rats. Biol Trace Elem Res 134:84–97

    Article  PubMed  CAS  Google Scholar 

  • Yorifuji T, Tsuda T, Grandjean P (2010) Unusual cancer excess after neonatal arsenic exposure from contaminated milk powder. J Natl Cancer Inst 102:360–361

    Article  PubMed  Google Scholar 

  • Yorifuji T, Tsuda T, Doi H et al (2011) Cancer excess after arsenic exposure from contaminated milk powder. Environ Health Prev Med 16:164–170

    Article  PubMed  CAS  Google Scholar 

  • Yuan Y, Marshall G, Ferreccio C et al (2010) Kidney cancer mortality: fifty-year latency patterns related to arsenic exposure. Epidemiology 21:103–108

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Drs. Jon Freedman, Dan Morgan, Nigel Walker, and John Bucher for critical evaluation of this manuscript, Dr. Jerry Ward for assistance in pathological assessments, and Dan Logsdon and the Pathology and Histotechnology Laboratory of SAIC Frederick for expert technical assistance. This research was supported in part by the National Toxicology Program, NIEHS, and by the Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIH). However, the statements contained herein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH, or the US Government. This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This project was also supported in part by federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Author information

Authors and Affiliations

  1. Inorganic Toxicology Group, National Toxicology Program Laboratory Branch, Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, 111 Alexander Drive, P.O. Box 12233, MD E1-07, Research Triangle Park, NC, 27709, USA

    Erik J. Tokar & Michael P. Waalkes

  2. Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, 111 Alexander Drive, P.O. Box 12233, MD E1-07, Research Triangle Park, NC, 27709, USA

    Erik J. Tokar & Michael P. Waalkes

  3. Basic Research Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD, USA

    Bhalchandra A. Diwan

  4. Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA

    David J. Thomas

Authors
  1. Erik J. Tokar
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Bhalchandra A. Diwan
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. David J. Thomas
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Michael P. Waalkes
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Michael P. Waalkes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tokar, E.J., Diwan, B.A., Thomas, D.J. et al. Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice. Arch Toxicol 86, 975–982 (2012). https://doi.org/10.1007/s00204-012-0820-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-012-0820-8

Keywords