Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses
- 772 Downloads
In mice, inorganic arsenic in the drinking water in the parts per million range via the dam during in utero life or with whole-life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied “whole-life” inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5,000 ppb arsenic (as sodium arsenite) in the drinking water for 3 weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birthweight or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50-ppb group (51 %) and 500-ppb group (54 %), but not at 5,000-ppb group (28 %) compared to control (22 %). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50-ppb group (27 %) compared to controls (8 %). An increase (p < 0.05) in lung adenoma (25 %) in the 50-ppb group compared to control (11 %) occurred in female offspring. Thus, in CD1 mice whole-life arsenic exposure induced lung tumors at human-relevant doses (i.e., 50 and 500 ppb).
KeywordsArsenic Carcinogenesis Mice Whole-life exposure Lung cancer
The authors wish to thank Dr. Bhalchandra Diwan, NCI-Frederick for aid with experimental design, Drs. Thayer, Sills and Bucher, DNTP, for critical evaluation of this manuscript, Dan Logsdon and Mark Schrader NCI-Frederick for expert technical assistance in animal husbandry, for provision of critical information on diet and water, and provision of diet samples, and Matthew Bell, DNTP, for assistance with graphics. This research was supported in part by the DNTP, NIEHS and in part by the National Cancer Institute, Center for Cancer Research.
- Bodwell JE, Kingsley LA, Hamilton JW (2004) Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression: complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem Res Toxicol 17:1064–1076PubMedCrossRefGoogle Scholar
- Institute of Laboratory Animal Resources (1996) Guide for the care and use of laboratory animals, 7th edn. National Academy Press, WashingtonGoogle Scholar
- International Agency for Research on Cancer (IARC) (2004) Arsenic in drinking water. In: Some drinking water disinfectants and contaminants, including arsenic; International agency for research on cancer monographs on the evaluation of carcinogenic risk to humans, vol 84. IARC Press, Lyon, pp 269–477 Google Scholar
- International Agency for Research on Cancer (IARC) (2012) 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 Google Scholar
- Waalkes MP, Ward JM, Diwan BA (2004) 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 25:133–141PubMedCrossRefGoogle Scholar